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Ng, Kevin, Erron W. Titus, Krystien V. Lieve, et al. "An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2 -Catecholaminergic Polymorphic Ventricular Tachycardia." Circulation 142, no. 10 (2020): 932–47. http://dx.doi.org/10.1161/circulationaha.120.045723.
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Background: Genetic variants in calsequestrin-2 ( CASQ2 ) cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of CASQ2 -CPVT was sought through an international multicenter collaboration. Methods: Genotype-phenotype segregation in CASQ2 -CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant CASQ2 missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure. Results: A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic CASQ2 variant, were identified. Among CASQ2 homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6–11). Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to CASQ2 heterozygotes, CASQ2 homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3–8.0; P =0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6–269.1; P <0.001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant CASQ2 missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers. Conclusions: This international multicenter study of CASQ2 -CPVT redefines its heritability and confirms that pathogenic heterozygous CASQ2 variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.
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Töpf, Ana, Yavuz Oktay, Sunitha Balaraju, et al. "Severe neurodevelopmental disease caused by a homozygous TLK2 variant." European Journal of Human Genetics 28, no. 3 (2019): 383–87. http://dx.doi.org/10.1038/s41431-019-0519-x.
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Abstract A distinct neurodevelopmental phenotype characterised mainly by mild motor and language delay and facial dysmorphism, caused by heterozygous de novo or dominant variants in the TLK2 gene has recently been described. All cases reported carried either truncating variants located throughout the gene, or missense changes principally located at the C-terminal end of the protein mostly resulting in haploinsufficiency of TLK2. Through whole exome sequencing, we identified a homozygous missense variant in TLK2 in a patient showing more severe symptoms than those previously described, including cerebellar vermis hypoplasia and West syndrome. Both parents are heterozygous for the variant and clinically unaffected highlighting that recessive variants in TLK2 can also be disease causing and may act through a different pathomechanism.
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Accogli, Andrea, Judith St-Onge, Nassima Addour-Boudrahem, et al. "Heterozygous Missense Pathogenic Variants Within the Second Spectrin Repeat of SPTBN2 Lead to Infantile-Onset Cerebellar Ataxia." Journal of Child Neurology 35, no. 2 (2019): 106–10. http://dx.doi.org/10.1177/0883073819878917.
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The term spinocerebellar ataxia encompasses a heterogeneous group of neurodegenerative disorders due to pathogenic variants in more than 100 genes, underlying 2 major groups of ataxia: autosomal dominant cerebellar ataxias (ADCA, also known as spinocerebellar ataxias [SCAs]) due to heterozygous variants or polyglutamine triplet expansions leading to adult-onset ataxia, and autosomal recessive spinocerebellar ataxias (ARCAs, also known as SCARs) due to biallelic variants, usually resulting in more severe and earlier-onset cerebellar ataxia. Certain ataxia genes, including SPTBN2 which encodes β-III spectrin, are responsible for both SCA and SCAR, depending on whether the pathogenic variant occurs in a monoallelic or biallelic state, respectively. Accordingly, 2 major phenotypes have been linked to SPTBN2: pathogenic heterozygous in-frame deletions and missense variants result in an adult-onset, slowly progressive ADCA (SCA5) through a dominant negative effect, whereas biallelic loss-of-function variants cause SCAR14, an allelic disorder characterized by infantile-onset cerebellar ataxia and cognitive impairment. Of note, 2 heterozygous missense variants (c.1438C>T, p.R480 W; c.1309C>G, p.R437G), both lying in the second spectrin repeat of SPTBN2, have been linked to infantile-onset cerebellar ataxia, similar to SCAR14. Here, we report a novel de novo heterozygous pathogenic missense variant (c.1310G>A) in SPTBN2 in a child with infantile-onset cerebellar ataxia and mild cognitive impairment. This variant affects the same R437 residue of the second spectrin repeat but results in a different amino acid change (p.R437Q). We review previously reported cases and discuss possible pathomechanisms responsible for the early-onset cerebellar phenotype due to disease-causing variants in the second spectrin repeat.
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Cadieux-Dion, Maxime, Simone Meneghini, Chiara Villa, et al. "Variants in CHRNB2 and CHRNA4 Identified in Patients with Insular Epilepsy." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 47, no. 6 (2020): 800–809. http://dx.doi.org/10.1017/cjn.2020.126.
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Abstract:Purpose:Our purpose was to determine the role of CHRNA4 and CHRNB2 in insular epilepsy.Method:We identified two patients with drug-resistant predominantly sleep-related hypermotor seizures, one harboring a heterozygous missense variant (c.77C>T; p. Thr26Met) in the CHRNB2 gene and the other a heterozygous missense variant (c.1079G>A; p. Arg360Gln) in the CHRNA4 gene. The patients underwent electrophysiological and neuroimaging studies, and we performed functional characterization of the p. Thr26Met (c.77C>T) in the CHRNB2 gene.Results:We localized the epileptic foci to the left insula in the first case (now seizure-free following epilepsy surgery) and to both insulae in the second case. Based on tools predicting the possible impact of amino acid substitutions on the structure and function of proteins (sorting intolerant from tolerant and PolyPhen-2), variants identified in this report could be deleterious. Functional expression in human cell lines of α4β2 (wild-type), α4β2-Thr26Met (homozygote), and α4β2/β2-Thr26Met (heterozygote) nicotinic acetylcholine receptors revealed that the mutant subunit led to significantly higher whole-cell nicotinic currents. This feature was observed in both homo- and heterozygous conditions and was not accompanied by major alterations of the current reversal potential or the shape of the concentration-response relation.Conclusions:This study suggests that variants in CHRNB2 and CHRNA4, initially linked to autosomal dominant nocturnal frontal lobe epilepsy, are also found in patients with predominantly sleep-related insular epilepsy. Although the reported variants should be considered of unknown clinical significance for the moment, identification of additional similar cases and further functional studies could eventually strengthen this association.
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Iarossi, Giancarlo, Valerio Marino, Paolo Enrico Maltese, et al. "Expanding the Clinical and Genetic Spectrum of RAB28-Related Cone-Rod Dystrophy: Pathogenicity of Novel Variants in Italian Families." International Journal of Molecular Sciences 22, no. 1 (2020): 381. http://dx.doi.org/10.3390/ijms22010381.
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The small Ras-related GTPase Rab-28 is highly expressed in photoreceptor cells, where it possibly participates in membrane trafficking. To date, six alterations in the RAB28 gene have been associated with autosomal recessive cone-rod dystrophies. Confirmed variants include splicing variants, missense and nonsense mutations. Here, we present a thorough phenotypical and genotypical characterization of five individuals belonging to four Italian families, constituting the largest cohort of RAB28 patients reported in literature to date. All probands displayed similar clinical phenotype consisting of photophobia, decreased visual acuity, central outer retinal thinning, and impaired color vision. By sequencing the four probands, we identified: a novel homozygous splicing variant; two novel nonsense variants in homozygosis; a novel missense variant in compound heterozygous state with a previously reported nonsense variant. Exhaustive molecular dynamics simulations of the missense variant p.(Thr26Asn) in both its active and inactive states revealed an allosteric structural mechanism that impairs the binding of Mg2+, thus decreasing the affinity for GTP. The impaired GTP-GDP exchange ultimately locks Rab-28 in a GDP-bound inactive state. The loss-of-function mutation p.(Thr26Asn) was present in a compound heterozygosis with the nonsense variant p.(Arg137*), which does not cause mRNA-mediated decay, but is rather likely degraded due to its incomplete folding. The frameshift p.(Thr26Valfs4*) and nonsense p.(Leu13*) and p.(Trp107*) variants, if translated, would lack several key structural components necessary for the correct functioning of the encoded protein.
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Letko, Anna, Fabienne Leuthard, Vidhya Jagannathan, et al. "Whole Genome Sequencing Indicates Heterogeneity of Hyperostotic Disorders in Dogs." Genes 11, no. 2 (2020): 163. http://dx.doi.org/10.3390/genes11020163.
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Craniomandibular osteopathy (CMO) and calvarial hyperostotic syndrome (CHS) are proliferative, non-neoplastic disorders affecting the skull bones in young dogs. Different forms of these hyperostotic disorders have been described in many dog breeds. However, an incompletely dominant causative variant for CMO affecting splicing of SLC37A2 has been reported so far only in three Terrier breeds. The purpose of this study was to identify further possible causative genetic variants associated with CHS in an American Staffordshire Terrier, as well as CMO in seven affected dogs of different breeds. We investigated their whole-genome sequences (WGS) and filtered variants using 584 unrelated genomes, which revealed no variants shared across all affected dogs. However, filtering for private variants of each case separately yielded plausible dominantly inherited candidate variants in three of the eight cases. In an Australian Terrier, a heterozygous missense variant in the COL1A1 gene (c.1786G>A; p.(Val596Ile)) was discovered. A pathogenic missense variant in COL1A1 was previously reported in humans with infantile cortical hyperostosis, or Caffey disease, resembling canine CMO. Furthermore, in a Basset Hound, a heterozygous most likely pathogenic splice site variant was found in SLC37A2 (c.1446+1G>A), predicted to lead to exon skipping as shown before in SLC37A2-associated canine CMO of Terriers. Lastly, in a Weimaraner, a heterozygous frameshift variant in SLC35D1 (c.1021_1024delTCAG; p.(Ser341ArgfsTer22)) might cause CMO due to the critical role of SLC35D1 in chondrogenesis and skeletal development. Our study indicates allelic and locus heterogeneity for canine CMO and illustrates the current possibilities and limitations of WGS-based precision medicine in dogs.
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Trottier, Amy M., Lawrence J. Druhan, Ira L. Kraft, et al. "Heterozygous germ line CSF3R variants as risk alleles for development of hematologic malignancies." Blood Advances 4, no. 20 (2020): 5269–84. http://dx.doi.org/10.1182/bloodadvances.2020002013.
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Abstract Colony-stimulating factor 3 receptor (CSF3R) encodes the receptor for granulocyte colony-stimulating factor (G-CSF), a cytokine vital for granulocyte proliferation and differentiation. Acquired activating heterozygous variants in CSF3R are the main cause of chronic neutrophilic leukemia, a hyperproliferative disorder. In contrast, biallelic germ line hypomorphic variants in CSF3R are a rare cause of severe congenital neutropenia, a hypoproliferative condition. The impact of heterozygous germ line CSF3R variants, however, is unknown. We identified CSF3R as a new germ line hematologic malignancy predisposition gene through analysis of 832 next-generation sequencing tests conducted in 632 patients with hematologic malignancies. Among germ line CSF3R variants, 3 were abnormal in functional testing, indicating their deleterious nature. p.Trp547* was identified in 2 unrelated men with myelodysplastic syndromes diagnosed at 76 and 33 years of age, respectively. p.Trp547* is a loss-of-function nonsense variant in the extracellular domain that results in decreased CSF3R messenger RNA expression and abrogation of CSF3R surface expression and proliferative responses to G-CSF. p.Ala119Thr is a missense variant found in 2 patients with multiple myeloma and acute lymphoblastic leukemia, respectively. This variant is located between the extracellular immunoglobulin-like and cytokine receptor homology domains and results in decreased G-CSF sensitivity. p.Pro784Thr was identified in a 67-year-old man with multiple myeloma. p.Pro784Thr is a missense variant in the cytoplasmic domain that inhibits CSF3R internalization, producing a gain-of-function phenotype and G-CSF hypersensitivity. Our findings identify germ line heterozygous CSF3R variants as risk factors for development of myeloid and lymphoid malignancies.
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Marbach, Felix, Georgi Stoyanov, Florian Erger, et al. "Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain." Genetics in Medicine 23, no. 8 (2021): 1465–73. http://dx.doi.org/10.1038/s41436-021-01152-7.
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Abstract Purpose We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). Methods Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Results Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.
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Kloth, Katja, Bernarda Lozic, Julia Tagoe, et al. "ANK3 related neurodevelopmental disorders: expanding the spectrum of heterozygous loss-of-function variants." neurogenetics 22, no. 4 (2021): 263–69. http://dx.doi.org/10.1007/s10048-021-00655-4.
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AbstractANK3 encodes multiple isoforms of ankyrin-G, resulting in variegated tissue expression and function, especially regarding its role in neuronal development. Based on the zygosity, location, and type, ANK3 variants result in different neurodevelopmental phenotypes. Autism spectrum disorder has been associated with heterozygous missense variants in ANK3, whereas a more severe neurodevelopmental phenotype is caused by isoform-dependent, autosomal-dominant, or autosomal-recessive loss-of-function variants. Here, we present four individuals affected by a variable neurodevelopmental phenotype harboring a heterozygous frameshift or nonsense variant affecting all ANK3 transcripts. Thus, we provide further evidence of an isoform-based phenotypic continuum underlying ANK3-associated pathologies and expand its phenotypic spectrum.
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Kovesdi, Erzsebet, Reka Ripszam, Etelka Postyeni, et al. "Whole Exome Sequencing in a Series of Patients with a Clinical Diagnosis of Tuberous Sclerosis Not Confirmed by Targeted TSC1/TSC2 Sequencing." Genes 12, no. 9 (2021): 1401. http://dx.doi.org/10.3390/genes12091401.
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Background: Approximately fifteen percent of patients with tuberous sclerosis complex (TSC) phenotype do not have any genetic disease-causing mutations which could be responsible for the development of TSC. The lack of a proper diagnosis significantly affects the quality of life for these patients and their families. Methods: The aim of our study was to use Whole Exome Sequencing (WES) in order to identify the genes responsible for the phenotype of nine patients with clinical signs of TSC, but without confirmed tuberous sclerosis complex 1/ tuberous sclerosis complex 2 (TSC1/TSC2) mutations using routine molecular genetic diagnostic tools. Results: We found previously overlooked heterozygous nonsense mutations in TSC1, and a heterozygous intronic variant in TSC2. In one patient, two heterozygous missense variants were found in polycystic kidney and hepatic disease 1 (PKHD1), confirming polycystic kidney disease type 4. A heterozygous missense mutation in solute carrier family 12 member 5 (SLC12A5) was found in one patient, which is linked to cause susceptibility to idiopathic generalized epilepsy type 14. Heterozygous nonsense variant ring finger protein 213 (RNF213) was identified in one patient, which is associated with susceptibility to Moyamoya disease type 2. In the remaining three patients WES could not reveal any variants clinically relevant to the described phenotypes. Conclusion: Patients without appropriate diagnosis due to the lack of sensitivity of the currently used routine diagnostic methods can significantly profit from the wider application of next generation sequencing technologies in order to identify genes and variants responsible for their symptoms.
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Wonkam-Tingang, Edmond, Isabelle Schrauwen, Kevin K. Esoh, et al. "Bi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment." Genes 11, no. 11 (2020): 1249. http://dx.doi.org/10.3390/genes11111249.
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DNA samples from five members of a multiplex non-consanguineous Cameroonian family, segregating prelingual and progressive autosomal recessive non-syndromic sensorineural hearing impairment, underwent whole exome sequencing. We identified novel bi-allelic compound heterozygous pathogenic variants in CLIC5. The variants identified, i.e., the missense [NM_016929.5:c.224T>C; p.(L75P)] and the splicing (NM_016929.5:c.63+1G>A), were validated using Sanger sequencing in all seven available family members and co-segregated with hearing impairment (HI) in the three hearing impaired family members. The three affected individuals were compound heterozygous for both variants, and all unaffected individuals were heterozygous for one of the two variants. Both variants were absent from the genome aggregation database (gnomAD), the Single Nucleotide Polymorphism Database (dbSNP), and the UK10K and Greater Middle East (GME) databases, as well as from 122 apparently healthy controls from Cameroon. We also did not identify these pathogenic variants in 118 unrelated sporadic cases of non-syndromic hearing impairment (NSHI) from Cameroon. In silico analysis showed that the missense variant CLIC5-p.(L75P) substitutes a highly conserved amino acid residue (leucine), and is expected to alter the stability, the structure, and the function of the CLIC5 protein, while the splicing variant CLIC5-(c.63+1G>A) is predicted to disrupt a consensus donor splice site and alter the splicing of the pre-mRNA. This study is the second report, worldwide, to describe CLIC5 involvement in human hearing impairment, and thus confirms CLIC5 as a novel non-syndromic hearing impairment gene that should be included in targeted diagnostic gene panels.
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Ali, Amanat, Fatmah Saeed Ali Almesmari, Nahid Al Dhahouri, et al. "Clinical, Biochemical, and Genetic Heterogeneity in Glutaric Aciduria Type II Patients." Genes 12, no. 9 (2021): 1334. http://dx.doi.org/10.3390/genes12091334.
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The variants of electron transfer flavoprotein (ETFA, ETFB) and ETF dehydrogenase (ETFDH) are the leading cause of glutaric aciduria type II (GA-II). In this study, we identified 13 patients harboring six variants of two genes associated with GA-II. Out of the six variants, four were missense, and two were frameshift mutations. A missense variant (ETFDH:p.Gln269His) was observed in a homozygous state in nine patients. Among nine patients, three had experienced metabolic crises with recurrent vomiting, abdominal pain, and nausea. In one patient with persistent metabolic acidosis, hypoglycemia, and a high anion gap, the ETFDH:p.Gly472Arg, and ETFB:p.Pro94Thrfs*8 variants were identified in a homozygous, and heterozygous state, respectively. A missense variant ETFDH:p.Ser442Leu was detected in a homozygous state in one patient with metabolic acidosis, hypoglycemia, hyperammonemia and liver dysfunction. The ETFDH:p.Arg41Leu, and ETFB:p.Ile346Phefs*19 variants were observed in a homozygous state in one patient each. Both these variants have not been reported so far. In silico approaches were used to evaluate the pathogenicity and structural changes linked with these six variants. Overall, the results indicate the importance of a newborn screening program and genetic investigations for patients with GA-II. Moreover, careful interpretation and correlation of variants of uncertain significance with clinical and biochemical findings are needed to confirm the pathogenicity of such variants.
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Pilarowski, Genay O., Hilary J. Vernon, Carolyn D. Applegate, et al. "Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability." Journal of Medical Genetics 55, no. 8 (2017): 561–66. http://dx.doi.org/10.1136/jmedgenet-2017-104759.
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BackgroundThe list of Mendelian disorders of the epigenetic machinery has expanded rapidly during the last 5 years. A few missense variants in the chromatin remodeler CHD1 have been found in several large-scale sequencing efforts focused on uncovering the genetic aetiology of autism.ObjectivesTo explore whether variants in CHD1 are associated with a human phenotype.MethodsWe used GeneMatcher to identify other physicians caring for patients with variants in CHD1. We also explored the epigenetic consequences of one of these variants in cultured fibroblasts.ResultsHere we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features. Importantly, three of these variants occurred de novo. We also report on a subject with a de novo deletion covering a large fraction of the CHD1 gene without any obvious neurological phenotype. Finally, we demonstrate increased levels of the closed chromatin modification H3K27me3 in fibroblasts from a subject carrying a de novo variant in CHD1.ConclusionsOur results suggest that variants in CHD1 can lead to diverse phenotypic outcomes; however, the neurodevelopmental phenotype appears to be limited to patients with missense variants, which is compatible with a dominant negative mechanism of disease.
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Parenti, Ilaria, Daphné Lehalle, Caroline Nava, et al. "Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy." Human Genetics 140, no. 7 (2021): 1109–20. http://dx.doi.org/10.1007/s00439-021-02283-2.
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AbstractLocated in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic–clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.
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Ullah, Aman, Ranjha Khan, and Muhammad Naeem. "Whole exome sequencing identified a heterozygous KCNJ2 missense variant underlying autosomal dominant familial hypokalemic periodic paralysis in a Pakistani family." Journal of Pediatric Endocrinology and Metabolism 32, no. 12 (2019): 1385–89. http://dx.doi.org/10.1515/jpem-2019-0276.
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Abstract Background Familial hypokalemic periodi9c paralysis (hypoKPP) is a rare autosomal dominant disorder characterized by episodic paralytic attacks caused by fall in blood potassium. CACNA1S, SCN4A or KCNJ2 variants can cause hypoKPP. Case presentation We investigated a Pakistani family affected with autosomal dominant familial hypoKPP through whole exome sequencing (WES). A heterozygous KCNJ2 missense variant c.919A > G was found segregating with the disease phenotype in the family. Conclusions The KCNJ2 missense variant is the likely cause of the disorder in the affected family. The finding should help improve antenatal screening and genetic counselling of this family.
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Chen, Dong-Hui, Caitlin Latimer, Mayumi Yagi, et al. "Heterozygous STUB1 missense variants cause ataxia, cognitive decline, and STUB1 mislocalization." Neurology Genetics 6, no. 2 (2020): e397. http://dx.doi.org/10.1212/nxg.0000000000000397.
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ObjectiveTo identify the genetic cause of autosomal dominant ataxia complicated by behavioral abnormalities, cognitive decline, and autism in 2 families and to characterize brain neuropathologic signatures of dominant STUB1-related ataxia and investigate the effects of pathogenic variants on STUB1 localization.MethodsClinical and research-based exome sequencing was used to identify the causative variants for autosomal dominant ataxia in 2 families. Gross and microscopic neuropathologic evaluations were performed on the brains of 4 affected individuals in these families.ResultsMutations in STUB1 have been primarily associated with childhood-onset autosomal recessive ataxia, but here we report heterozygous missense variants in STUB1 (p.Ile53Thr and p.The37Leu) confirming the recent reports of autosomal dominant inheritance. Cerebellar atrophy on imaging and cognitive deficits often preceded ataxia. Unique neuropathologic examination of the 4 brains showed the marked loss of Purkinje cells (PCs) without microscopic evidence of significant pathology outside the cerebellum. The normal pattern of polarized somatodendritic STUB1 protein expression in PCs was lost, resulting in aberrant STUB1 localization in the distal PC dendritic arbors.ConclusionsThis study confirms a dominant inheritance pattern in STUB1-ataxia in addition to a recessive one and documents its association with cognitive and behavioral disability, including autism. In the most extensive analysis of cerebellar pathology in this disease, we demonstrate disruption of STUB1 protein in PCs as part of the underlying pathogenesis.
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Cannaerts, Elyssa, Marlies Kempers, Alessandra Maugeri, et al. "Novel pathogenic SMAD2 variants in five families with arterial aneurysm and dissection: further delineation of the phenotype." Journal of Medical Genetics 56, no. 4 (2018): 220–27. http://dx.doi.org/10.1136/jmedgenet-2018-105304.
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BackgroundMissense variants in SMAD2, encoding a key transcriptional regulator of transforming growth factor beta signalling, were recently reported to cause arterial aneurysmal disease.ObjectivesThe aims of the study were to identify the genetic disease cause in families with aortic/arterial aneurysmal disease and to further define SMAD2 genotype–phenotype correlations.Methods and resultsUsing gene panel sequencing, we identified a SMAD2 nonsense variant and four SMAD2 missense variants, all affecting highly conserved amino acids in the MH2 domain. The premature stop codon (c.612dup; p.(Asn205*)) was identified in a marfanoid patient with aortic root dilatation and in his affected father. A p.(Asn318Lys) missense variant was found in a Marfan syndrome (MFS)-like case who presented with aortic root aneurysm and in her affected daughter with marfanoid features and mild aortic dilatation. In a man clinically diagnosed with Loeys-Dietz syndrome (LDS) that presents with aortic root dilatation and marked tortuosity of the neck vessels, another missense variant, p.(Ser397Tyr), was identified. This variant was also found in his affected daughter with hypertelorism and arterial tortuosity, as well as his affected mother. The third missense variant, p.(Asn361Thr), was discovered in a man presenting with coronary artery dissection. Variant genotyping in three unaffected family members confirmed its absence. The last missense variant, p.(Ser467Leu), was identified in a man with significant cardiovascular and connective tissue involvement.ConclusionTaken together, our data suggest that heterozygous loss-of-function SMAD2 variants can cause a wide spectrum of autosomal dominant aortic and arterial aneurysmal disease, combined with connective tissue findings reminiscent of MFS and LDS.
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Dougherty, Michael P., Lynn P. Chorich, and Lawrence Clarke Layman. "Evaluation of Mayer-Rokitansky-Kuster-Hauser (MRKH) Patient Families by Whole Genome Sequencing." Journal of the Endocrine Society 5, Supplement_1 (2021): A501—A502. http://dx.doi.org/10.1210/jendso/bvab048.1025.
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Abstract Introduction: MRKH is a characterized by the congenital absence of the uterus and vagina in 46,XX individuals. A subset of these patients also has associated renal, skeletal, cardiac and/or auditory defects. Familial cases suggest a genetic component, but to date only pathogenic variants in WNT4 and HNF1B have been confirmed. We hypothesize that de novo heterozygous variants in candidate genes will be present in some patients with MRKH. Methods: DNAs from 30 quads (an MRKH proband and three relatives) were subjected to whole genome sequencing (WGS), and heterozygous variants in coding regions with &lt; 0.02 frequency were filtered by two different methods. In the first approach, variants were filtered by 1) top consequence variant (splice site, stop-gain, frameshift, and missense, respectively); 2) impact score; 3) mapping quality; 4) cytobands; 5) intolerance; 6) de novo variants; and 7) plausibility based on familial genotype. The second approach considered only heterozygous variants found in the proband and absent in all other family members, which were then filtered by top consequence (splice donor and acceptor sites, stop-gain, frameshift). Results: Five pedigrees were excluded for inadequate sequence in one or more individuals. 55,033 variants in coding regions with &lt; 2% frequency were identified in the 25 remaining quads for analysis. Using the first approach, 42 candidate gene variants in 32 genes were identified - 12 splice variants, 10 stop-gains, 15 frameshift variants and 5 missense variants. Of these, MUC22 contained 2 missense variants from different families. Additionally, DICER1 had multiple splice variants and is essential for mouse urogenital tract development. In the second approach, 39 candidate genes were identified—6 splice variants in 6 genes, 18 stop-gains in 17 genes, and 17 frameshift variants in 16 genes. Zinc finger genes (ZNF418, ZNF646, ZNF135, and ZNF772) comprised the most frequent class of the 39 genes. Two genes (MIR4436A and ZNF418) contained attractive variants in two different families. Conclusion: WGS has been shown to improve detection of gene variants in coding regions, more so than whole exome sequencing (WES). We previously performed WES on 111 MRKH probands without family members and analyzed variants in candidate genes suggested by mouse and preliminary human studies. Interestingly, in this study, only three genes overlapped with previously suspected candidate genes. Here, we identified new candidates based upon potential deleteriousness. These candidate genes will be studied further in our families to determine their role in Mullerian development.
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Li, Jinying, Hongen Xu, Jianfeng Sun, et al. "Missense Variant of Endoplasmic Reticulum Region of WFS1 Gene Causes Autosomal Dominant Hearing Loss without Syndromic Phenotype." BioMed Research International 2021 (March 4, 2021): 1–9. http://dx.doi.org/10.1155/2021/6624744.
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Objective. Genetic variants in the WFS1 gene can cause Wolfram syndrome (WS) or autosomal dominant nonsyndromic low-frequency hearing loss (HL). This study is aimed at investigating the molecular basis of HL in an affected Chinese family and the genotype-phenotype correlation of WFS1 variants. Methods. The clinical phenotype of the five-generation Chinese family was characterized using audiological examinations and pedigree analysis. Target exome sequencing of 129 known deafness genes and bioinformatics analysis were performed among six patients and four normal subjects to screen suspected pathogenic variants. We built a complete WFS1 protein model to assess the potential effects of the variant on protein structure. Results. A novel heterozygous pathogenic variant NM_006005.3 c.2020G>T (p.Gly674Trp) was identified in the WFS1 gene, located in the C-terminal domain of the wolframin protein. We further showed that HL-related WFS1 missense variants were mainly concentrated in the endoplasmic reticulum (ER) domain. In contrast, WS-related missense variants are randomly distributed throughout the protein. Conclusions. In this family, we identified a novel variant p.Gly674Trp of WFS1 as the primary pathogenic variant causing the low-frequency sensorineural HL, enriching the mutational spectrum of the WFS1 gene.
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Sommerville, Ewen W., Charlotte L. Alston, Angela Pyle, et al. "De novo CTBP1 variant is associated with decreased mitochondrial respiratory chain activities." Neurology Genetics 3, no. 5 (2017): e187. http://dx.doi.org/10.1212/nxg.0000000000000187.
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Objective:To determine the genetic etiology of a young woman presenting an early-onset, progressive neurodegenerative disorder with evidence of decreased mitochondrial complex I and IV activities in skeletal muscle suggestive of a mitochondrial disorder.Methods:A case report including diagnostic workup, whole-exome sequencing of the affected patient, filtering, and prioritization of candidate variants assuming a suspected autosomal recessive mitochondrial disorder and segregation studies.Results:After excluding candidate variants for an autosomal recessive mitochondrial disorder, re-evaluation of rare and novel heterozygous variants identified a recently reported, recurrent pathogenic heterozygous CTBP1 missense change (c.991C>T, p.Arg331Trp), which was confirmed to have arisen de novo.Conclusions:We report the fifth known patient harboring a recurrent pathogenic de novo c.991C>T p.(Arg331Trp) CTBP1 variant, who was initially suspected to have an autosomal recessive mitochondrial disorder. Inheritance of suspected early-onset mitochondrial disease could wrongly be assumed to be autosomal recessive. Hence, this warrants continued re-evaluation of rare and novel heterozygous variants in patients with apparently unsolved suspected mitochondrial disease investigated using next-generation sequencing.
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Shen, Wenyi, Cassandra M. Hirsch, Bartlomiej P. Przychodzen, et al. "Heterozygous CTC1 Variants in Acquired Bone Marrow Failure." Blood 132, Supplement 1 (2018): 3866. http://dx.doi.org/10.1182/blood-2018-99-115193.
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Abstract Germ line (GL) alterations of telomerase machinery genes may lead to inherited telomeropathies, but recent analysis of large control populations revealed that some of the previously assumed pathologic variants are present in comparable frequencies in healthy individuals. Pathogenic telomerase gene variants can be found, but are rare in idiopathic aplastic anemia (AA) and are associated with excessive telomere attrition. Previously, in a cohort of patients with MDS, pathogenic germ line variants of telomerase genes were very extremely rare. Recently a patient with bone marrow failure and liver cirrhosis presented with a biallelic CTC1 gene mutation. CTC1 is a member of the CTC complex, located on Chr 17p13.1, and critical for telomere replication. GL alterations of this gene were found to cause inherited disease, including Coats plus (CP), dyskeratosis congenital (DC) and cerebroretinal microangiopathy with calcifications and cysts (CRMCC) in a compound heterozygous manner. Our patient (age 28) had compound heterozygous CTC1 germline mutations (p.Lys242Leufs*41 and p.Cys985del) resulting in early childhood presentation of DC, subsequent severe AA at the age of 19, and a significant shortening of telomeres. Both parents as confirmed CTC1 variant carriers showed normal blood counts. Based on this index case and literature reports, manifest CTC1 diseases follow a recessive trait, however, but it is possible that heterozygous carriers may indeed have also an increased, albeit attenuated risk of BMF leading to a later manifestation or incomplete penetrance. To test this possible scenario we screened a cohort of acquired BMF (n=538) with AA/PNH (172), MDS/AML (n=366), with deep NGS of all coding regions of CTC1. In total, we identified 10 heterozygous CTC1 variants in 10 unrelated patients (8 AA/PNH and 2 MDS); 4/10 variants (1 stop gain R1202X and 3 frameshift deletions D405fs, P999fs, E454fs) were fulfilled the criteria of Tier-1 lesions and were found in AA/PNH patients (4/172, 2.3%), The remaining 6 missense variants were of uncertain significance or likely benign(Tier-2), 2 of which (H1092G and E1136K) were found in a compound heterozygous configuration in a AA/PNH patient. K438N, as a novel missense variant, was recurrently present in 2 MDS pts. Given the expected frequency of the CTC1 variants found in controls (104/33370, 0.3%), CTC1 variants appear to be enriched in AA/PNH subgroup (p<0.001). Of note is that none of the carriers of pathogenic CTC1 mutations showed any physical signs of inherited congenital BMF syndromes or any family history of leukemia, BMF and any other cancers. Interestingly, patients with sAA/PNH syndrome and biallelic CTC1 variant eventually evolved to MDS, while the other monoallelic CTC1 carriers showed stable disease and responsed to immunosuppression. Flow cytometric telomere length measurement (adjusted for age) showed a markedly shortened telomere in the index case, as well as 1 SAA case carrying biallelic CTC1 variants and 1 AA case with co-concurrent POT1 and CTC1 variants when compared with age matched controls. A significant difference was seen when comparing telomere length between CTC1 variants carriers and age-matched normal controls, while no difference was seen among CTC1 variants carriers, AA/PNH group without any variants. Because of the curious co-incidence of heterozygous CTC1 variants and AA/PNH, we further analyzed this subgroup for the presence of other telomerase gene mutations, 11/172 Tier-1 variants, while 6 Tier-1 GLVs detected in MDS. Most frequent SNVs were found in POT1 with 5/172 (3%) in AA/PNH and 3/366 (0.8%) in MDS/AML. Notably, in one AA/PNH patient POT1 stop gain variant (Q364X) was co-concurrent with CTC1 heterozygous frame shift deletion (P999fs). The enrichment of variants in TELO-related genes in AA/PNH subgroup was found in comparison to MDS/AML (p<.01) and ExAC database controls (p<.01). Further clinical phenotype analysis indicated that 3 AA/PNH cases harboring POT1, TINF2 and TERT Tier-1 variants had family history of cancer. Family history of cancer was also found in a MDS patient with a TINF2 variant. In sum, our results indicate that heterozygous CTC1 variants were associated with otherwise typical AA with clonal outgrowth of PNH clone and the presence of this variant does not seem to preclude response to immunosuppression. Disclosures Maciejewski: Ra Pharmaceuticals, Inc: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
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Gifford, Casey A., Sanjeev S. Ranade, Ryan Samarakoon, et al. "Oligogenic inheritance of a human heart disease involving a genetic modifier." Science 364, no. 6443 (2019): 865–70. http://dx.doi.org/10.1126/science.aat5056.
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Complex genetic mechanisms are thought to underlie many human diseases, yet experimental proof of this model has been elusive. Here, we show that a human cardiac anomaly can be caused by a combination of rare, inherited heterozygous mutations. Whole-exome sequencing of a nuclear family revealed that three offspring with childhood-onset cardiomyopathy had inherited three missense single-nucleotide variants in the MKL2, MYH7, and NKX2-5 genes. The MYH7 and MKL2 variants were inherited from the affected, asymptomatic father and the rare NKX2-5 variant (minor allele frequency, 0.0012) from the unaffected mother. We used CRISPR-Cas9 to generate mice encoding the orthologous variants and found that compound heterozygosity for all three variants recapitulated the human disease phenotype. Analysis of murine hearts and human induced pluripotent stem cell–derived cardiomyocytes provided histologic and molecular evidence for the NKX2-5 variant’s contribution as a genetic modifier.
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Yang, Xi, Xiaojin Zhang, Jiao Jiao, et al. "Rare variants in FANCA induce premature ovarian insufficiency." Human Genetics 138, no. 11-12 (2019): 1227–36. http://dx.doi.org/10.1007/s00439-019-02059-9.
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Abstract Premature ovarian insufficiency (POI) is a major cause of reduced female fertility and affects approximately 1% women under 40 years of age. Recent advances emphasize the genetic heterogeneity of POI. Fanconi anemia (FA) genes, traditionally known for their essential roles in DNA repair and cytogenetic instability, have been demonstrated to be involved in meiosis and germ cell development. Here, we conducted whole-exome sequencing (WES) in 50 Han Chinese female patients with POI. Rare missense variants were identified in FANCA (Fanconi anemia complementation group A): c.1772G > A (p.R591Q) and c.3887A > G (p.E1296G). Both variants are heterozygous in the patients and very rare in the human population. In vitro functional studies further demonstrated that these two missense variants of FANCA exhibited reduced protein expression levels compared with the wild type, suggesting the partial loss of function. Moreover, mono-ubiquitination levels of FANCD2 upon mitomycin C stimulation were significantly reduced in cells overexpressing FANCA variants. Furthermore, a loss-of-function mutation of Fanca was generated in C57BL/6 mice for in vivo functional assay. Consistently, heterozygous mutated female mice (Fanca+/−) showed reduced fertility and declined numbers of follicles with aging when compared with the wild-type female mice. Collectively, our results suggest that heterozygous pathogenic variants in FANCA are implicated in non-syndromic POI in Han Chinese women, provide new insights into the molecular mechanisms of POI and highlight the contribution of FANCA variants in female subfertility.
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Calpena, Eduardo, Araceli Cuellar, Krithi Bala, et al. "SMAD6 variants in craniosynostosis: genotype and phenotype evaluation." Genetics in Medicine 22, no. 9 (2020): 1498–506. http://dx.doi.org/10.1038/s41436-020-0817-2.
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Abstract Purpose Enrichment of heterozygous missense and truncating SMAD6 variants was previously reported in nonsyndromic sagittal and metopic synostosis, and interaction of SMAD6 variants with a common polymorphism nearBMP2 (rs1884302) was proposed to contribute to inconsistent penetrance. We determined the occurrence of SMAD6 variants in all types of craniosynostosis, evaluated the impact of different missense variants on SMAD6 function, and tested independently whether rs1884302 genotype significantly modifies the phenotype. Methods We performed resequencing of SMAD6 in 795 unsolved patients with any type of craniosynostosis and genotyped rs1884302 in SMAD6-positive individuals and relatives. We examined the inhibitory activity and stability of SMAD6 missense variants. Results We found 18 (2.3%) different rare damaging SMAD6 variants, with the highest prevalence in metopic synostosis (5.8%) and an 18.3-fold enrichment of loss-of-function variants comparedwith gnomAD data (P < 10−7). Combined with eight additional variants, ≥20/26 were transmitted from an unaffected parent but rs1884302 genotype did not predict phenotype. Conclusion Pathogenic SMAD6 variants substantially increase the risk of both nonsyndromic and syndromic presentations of craniosynostosis, especially metopic synostosis. Functional analysis is important to evaluate missense variants. Genotyping of rs1884302 is not clinically useful. Mechanisms to explain the remarkable diversity of phenotypes associated with SMAD6 variants remain obscure.
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Nakaguma, Marilena, Nathalia Garcia Bianchi Pereira Ferreira, Anna Flavia Figueredo Benedetti, et al. "Allelic Variants in Established Hypopituitarism Genes Expand Our Knowledge of the Phenotypic Spectrum." Genes 12, no. 8 (2021): 1128. http://dx.doi.org/10.3390/genes12081128.
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We report four allelic variants (three novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p.Phe 57Leufs*43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A hemizygous SOX3 allelic variant (p.Met304Ile) was found in a male patient with IGHD and hypoplastic anterior pituitary. YASARA, a tool to evaluate protein stability, suggests that p.Met304Ile destabilizes the SOX3 protein (ΔΔG = 2.49 kcal/mol). A rare, heterozygous missense variant in the TALE homeobox protein gene, TGIF1 (c.268C>T:p.Arg90Cys) was found in a patient with combined pituitary hormone deficiency (CPHD), diabetes insipidus, and syndromic features of holoprosencephaly (HPE). This variant was previously reported in a patient with severe holoprosencephaly and shown to affect TGIF1 function. A novel heterozygous TGIF1 variant (c.82T>C:p.Ser28Pro) was identified in a patient with CPHD, pituitary aplasia and ectopic posterior lobe. Both TGIF1 variants have an autosomal dominant pattern of inheritance with incomplete penetrance. In conclusion, we have found allelic variants in three genes in hypopituitarism patients. We discuss these variants and associated patient phenotypes in relation to previously reported variants in these genes, expanding our knowledge of the phenotypic spectrum in patient populations.
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Dawson, Paul A., Pearl Sim, David W. Mudge, and David Cowley. "HumanSLC26A1Gene Variants: A Pilot Study." Scientific World Journal 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/541710.
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Kidney stones are a global health problem, incurring massive health costs annually. Why stones recur in many patients remains unknown but likely involves environmental, physiological, and genetic factors. The solute linked carrier (SLC) 26A1 gene has previously been linked to kidney stones in mice.SLC26A1encodes the sulfate anion transporter 1 (SAT1) protein, and its loss in mice leads to hyperoxaluria and calcium oxalate renal stones. To investigate the possible involvement of SAT1 in human urolithiasis, we screened theSLC26A1gene in a cohort of 13 individuals with recurrent calcium oxalate urolithiasis, which is the commonest type. DNA sequence analyses showed missense mutations in seven patients: one individual was heterozygous R372H; 4 individuals were heterozygous Q556R; one patient was homozygous Q556R; and one patient with severe nephrocalcinosis (requiring nephrectomy) was homozygous Q556R and heterozygous M132T. The M132 amino acid in human SAT1 is conserved with 15 other species and is located within the third transmembrane domain of the predicted SAT1 protein structure, suggesting that this amino acid may be important for SAT1 function. These initial findings demonstrate genetic variants inSLC26A1of recurrent stone formers and warrant wider independent studies ofSLC26A1in humans with recurrent calcium oxalate stones.
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Zanoni, Paolo, Katharina Steindl, Deepanwita Sengupta, et al. "Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype." Genetics in Medicine 23, no. 8 (2021): 1474–83. http://dx.doi.org/10.1038/s41436-021-01158-1.
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Abstract Purpose Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf–Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood. Methods We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro. Results The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS. Patients carrying missense variants were significantly taller and had more frequent behavioral/psychological issues compared with those harboring truncating variants. Structural in silico modeling suggested interference with NSD2’s folding and function for all missense variants in known structures. In vitro testing showed reduced methylation activity and failure to reconstitute H3K36me2 in NSD2 knockout cells for most missense variants. Conclusion NSD2 loss-of-function variants lead to a distinct, rather mild phenotype partially overlapping with WHS. To avoid confusion for patients, NSD2 deficiency may be named Rauch–Steindl syndrome after the delineators of this phenotype.
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Makhdoom, Ehtisham Ul Haq, Syeda Seema Waseem, Maria Iqbal, et al. "Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ." Genes 12, no. 5 (2021): 731. http://dx.doi.org/10.3390/genes12050731.
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Congenital microcephaly is the clinical presentation of significantly reduced head circumference at birth. It manifests as both non-syndromic—microcephaly primary hereditary (MCPH)—and syndromic forms and shows considerable inter- and intrafamilial variability. It has been hypothesized that additional genetic variants may be responsible for this variability, but data are sparse. We have conducted deep phenotyping and genotyping of five Pakistani multiplex families with either MCPH (n = 3) or Seckel syndrome (n = 2). In addition to homozygous causal variants in ASPM or CENPJ, we discovered additional heterozygous modifier variants in WDR62, CEP63, RAD50 and PCNT—genes already known to be associated with neurological disorders. MCPH patients carrying an additional heterozygous modifier variant showed more severe phenotypic features. Likewise, the phenotype of Seckel syndrome caused by a novel CENPJ variant was aggravated to microcephalic osteodysplastic primordial dwarfism type II (MOPDII) in conjunction with an additional PCNT variant. We show that the CENPJ missense variant impairs splicing and decreases protein expression. We also observed centrosome amplification errors in patient cells, which were twofold higher in MOPDII as compared to Seckel cells. Taken together, these observations advocate for consideration of additional variants in related genes for their role in modifying the expressivity of the phenotype and need to be considered in genetic counseling and risk assessment.
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Musialik, Joanna, Anna Boguszewska-Chachulska, Dorota Pojda-Wilczek, et al. "A Rare Mutation in The APOB Gene Associated with Neurological Manifestations in Familial Hypobetalipoproteinemia." International Journal of Molecular Sciences 21, no. 4 (2020): 1439. http://dx.doi.org/10.3390/ijms21041439.
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Clinical phenotypes of familial hypobetalipoproteinemia (FHBL) are related to a number of defective apolipoprotein B (APOB) alleles. Fatty liver disease is a typical manifestation, but serious neurological symptoms can appear. In this study, genetic analysis of the APOB gene and ophthalmological diagnostics were performed for family members with FHBL. Five relatives with FHBL, including a proband who developed neurological disorders, were examined. A sequencing analysis of the whole coding region of the APOB gene, including flanking intronic regions, was performed using the next-generation sequencing (NGS) method. Electrophysiological ophthalmological examinations were also done. In the proband and his affected relatives, NGS identified the presence of the pathogenic, rare heterozygous splicing variant c.3696+1G>T. Two known heterozygous missense variants—c.2188G>A, p.(Val730Ile) and c.8353A>C, p.(Asn2785His)—in the APOB gene were also detected. In all patients, many ophthalmologic abnormalities in electrophysiological tests were also found. The identified splicing variant c.3696+1G>T can be associated with observed autosomal, dominant FHBL with coexisting neurological symptoms, and both identified missense variants could be excluded as the main cause of observed clinical signs, according to mutation databases and the literature. Electroretinography examination is a sensitive method for the detection of early neuropathy and should therefore be recommended for the care of patients with FHBL.
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Nicita, Francesco, Marta Nardella, Emanuele Bellacchio, et al. "Heterozygous missense variants of SPTBN2 are a frequent cause of congenital cerebellar ataxia." Clinical Genetics 96, no. 2 (2019): 169–75. http://dx.doi.org/10.1111/cge.13562.
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Wesdorp, Mieke, Pia A. M. de Koning Gans, Margit Schraders, et al. "Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction." Human Genetics 137, no. 5 (2018): 389–400. http://dx.doi.org/10.1007/s00439-018-1880-5.
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Khodaeian, Mehrnoosh, Ehsan Jafarinia, Fatemeh Bitarafan, et al. "Kabuki Syndrome: Identification of Two Novel Variants in KMT2D and KDM6A." Molecular Syndromology 12, no. 2 (2021): 118–26. http://dx.doi.org/10.1159/000513199.
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Kabuki syndrome (KS) is a rare genetic disorder characterized by the following 5 crucial symptoms: dysmorphic facial features, growth retardation, skeletal abnormalities, intellectual disability, and dermatoglyphic malformations. Studies show that most of the KS cases are caused by mutations or large deletions in the <i>KMT2D</i> gene, while the other cases show mutations in <i>KDM6A</i>. We studied 2 patients with suspected KS in 2 unrelated families by whole-exome sequencing to identify the possible genetic cause(s) and by Sanger sequencing to validate the identified variants and check the segregation in other members of the families. Finally, the potential effects of the variants on the structure and function of respective proteins were tested using in silico predictions. Both affected members of the families showed typical manifestations of KS including intellectual disability, developmental delay, and abnormal facial characteristics. A novel heterozygous frameshift variant in the <i>KMT2D</i> gene, c.4981del; p.(Glu1661Serfs*61), and a novel hemizygote missense variant in the <i>KDM6A</i> gene, c.3301G&#x3e;A; p.(Glu1101Lys), were detected in patients 1 and 2, respectively. The frameshift variant identified in the first family was de novo<i>,</i> while in the second family, the mother was also heterozygous for the missense variant. The frameshift variant in <i>KMT2D</i> is predicted to lead to a truncated protein which is functionally impaired. The Glu1101 residue of KDM6A (UTX) affected in the second patient is located in a conserved region on the surface of the Jumonji domain and predicted to be causative. Our findings provide evidence on the possible pathogenicity of these 2 variants; however, additional functional studies are necessary to confirm their impacts.
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Griffin, Tomás P., Caroline M. Joyce, Sumaya Alkanderi, et al. "Biallelic CYP24A1 variants presenting during pregnancy: clinical and biochemical phenotypes." Endocrine Connections 9, no. 6 (2020): 530–41. http://dx.doi.org/10.1530/ec-20-0150.
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Introduction Inactivating mutations in CYP24A1, encoding vitamin D-24-hydroxylase, can lead to an accumulation of active vitamin D metabolites and consequent hypercalcaemia. Patient (infantile and adult) presentation is varied and includes mild-severe hypercalcaemia, hypercalciuria, nephrocalcinosis and nephrolithiasis. This study aimed to characterize the clinical and biochemical phenotypes of a family with two CYP24A1 missense variants. Methods The proband and seven family members underwent detailed clinical and biochemical evaluation. Laboratory measurements included serum calcium, intact parathyroid hormone (iPTH), vitamin D metabolites and urine calcium and creatinine. Results The proband presented during the second trimester of a planned pregnancy with flu-like symptoms. Laboratory tests showed elevated adjusted calcium of 3.27 (upper reference limit (URL: 2.30) mmol/L), suppressed iPTH (<6 ng/L), elevated 25(OH)D (264 (URL: 55) nmol/L) and elevated 1,25(OH)D (293 (URL: <280) pmol/L). Ionized calcium was 1.55 (URL: 1.28) mmol/L. Sanger sequencing revealed two heterozygous missense variants in the CYP24A1: p.(Arg439Cys), R439C and p.(Trp275Arg), W275R. The proband’s brother and sister had the same genotype. The brother had intermittent hypercalcaemia and hypervitaminosis D. Only the sister had a history of nephrolithiasis. The proband’s daughter and two nephews were heterozygous for the R439C variant. The proband and her brother frequently had elevated 25(OH)D:24,25(OH)2D ratios (>50) during follow-up. Conclusions W275R is a new pathogenic CYP24A1 mutation in compound heterozygotic form with R439C in this family.
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Müller, C. R., S. Rost, M. Watzka, C. G. Bevans, and J. Oldenburg. "Comparative genetics of warfarin resistance." Hämostaseologie 34, no. 02 (2014): 143–59. http://dx.doi.org/10.5482/hamo-13-09-0047.
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SummaryWarfarin and other 4-hydroxycoumarinbased oral anticoagulants targeting vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) are administered to humans, mice and rats with different purposes in mind – to act as pesticides in high-dosage baits for killing rodents, but also to save lives when administered in low dosages as antithrombotic drugs in humans. However, high-dosage warfarin used to control rodent populations has resulted in numerous mutations causing warfarin resistance. Currently, six single missense mutations in mice, 12 distinct missense mutations in rats, as well as compound heterozygous or homozygous mutations with up to six distinct missense mutations per Vkorc1 allele have been described. Warfarin resistance missense mutations for human VKORC1 have also been found world-wide, but differ characteristically from those in rodents. In humans, 26 distinct mutations have been characterized, but occur only rarely either in heterozygous or, even rarer, in homozygous form.In this review, we summarize the known VKORC1 missense mutations causing warfarin and other 4-hydroxycoumarin drug resistance, identify genomics databases as new sources of data, explore possible underlying genetic mechanisms, and summarize similarities and differences between warfarin resistant VKORC1 variants in humans and rodents.
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Nguyen, Ngoc-Lan, Can Thi Bich Ngoc, Chi Dung Vu, Thi Thu Huong Nguyen, and Huy Hoang Nguyen. "Whole Exome Sequencing as a Diagnostic Tool for Unidentified Muscular Dystrophy in a Vietnamese Family." Diagnostics 10, no. 10 (2020): 741. http://dx.doi.org/10.3390/diagnostics10100741.
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Muscular dystrophies are a group of heterogeneous clinical and genetic disorders. Two siblings presented with characteristics like muscular dystrophy, abnormal white matter, and elevated serum creatine kinase level. The high throughput of whole exome sequencing (WES) makes it an efficient tool for obtaining a precise diagnosis without the need for immunohistochemistry. WES was performed in the two siblings and their parents, followed by prioritization of variants and validation by Sanger sequencing. Very rare variants with moderate to high predicted impact in genes associated with neuromuscular disorders were selected. We identified two pathogenic missense variants, c.778C>T (p.H260Y) and c.2987G>A (p.C996Y), in the LAMA2 gene (NM_000426.3), in the homozygous state in two siblings, and in the heterozygous state in their unaffected parents, which were confirmed by Sanger sequencing. Variant c.2987G>A has not been reported previously. These variants may lead to a change in the structure and function of laminin-α2, a member of the family of laminin-211, which is an extracellular matrix protein that functions to stabilize the basement membrane of muscle fibers during contractions. Overall, WES enabled an accurate diagnosis of both patients with LAMA2-related muscular dystrophy and expanded the spectrum of missense variants in LAMA2.
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Lin, Mao, Sen Zhao, Gang Liu, et al. "Identification of novel FBN1 variations implicated in congenital scoliosis." Journal of Human Genetics 65, no. 3 (2019): 221–30. http://dx.doi.org/10.1038/s10038-019-0698-x.
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AbstractCongenital scoliosis (CS) is a form of scoliosis caused by congenital vertebral malformations. Genetic predisposition has been demonstrated in CS. We previously reported that TBX6 loss-of-function causes CS in a compound heterozygous model; however, this model can explain only 10% of CS. Many monogenic and polygenic CS genes remain to be elucidated. In this study, we analyzed exome sequencing (ES) data of 615 Chinese CS from the Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) project. Cosegregation studies for 103 familial CS identified a novel heterozygous nonsense variant, c.2649G>A (p.Trp883Ter) in FBN1. The association between FBN1 and CS was then analyzed by extracting FBN1 variants from ES data of 574 sporadic CS and 828 controls; 30 novel variants were identified and prioritized for further analyses. A mutational burden test showed that the deleterious FBN1 variants were significantly enriched in CS subjects (OR = 3.9, P = 0.03 by Fisher’s exact test). One missense variant, c.2613A>C (p.Leu871Phe) was recurrent in two unrelated CS subjects, and in vitro functional experiments for the variant suggest that FBN1 may contribute to CS by upregulating the transforming growth factor beta (TGF-β) signaling. Our study expanded the phenotypic spectrum of FBN1, and provided nove insights into the genetic etiology of CS.
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Prasher, Priya, Katherine Redmond, Hillarey Stone, et al. "Persistent Hypoglycemia with Polycystic Kidneys: A Rare Combination – A Case Report." Biomedicine Hub 5, no. 3 (2020): 1–6. http://dx.doi.org/10.1159/000511389.
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We present the case of an infant referred to our NICU born at 39 weeks’ gestation with persistent hypoglycemia with elevated insulin levels (HI) requiring diazoxide to maintain normoglycemia. Additionally, polycystic kidney disease (PKD) was detected by ultrasound. Molecular genetic testing revealed pathogenic variants in the <i>PMM2</i>gene, i.e., a variant in the promoter region and a missense variant in the coding region. The precoding variant was recently described in 11 European families with similar phenotypes, either in a homozygous state or as compound heterozygous with a pathogenic coding variant. In neonates with HI associated with PKD, this rare recessive disorder should be considered.
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Nicolas, Gaël, Monica Sanchez-Contreras, Eliana Marisa Ramos, et al. "Brain calcifications and PCDH12 variants." Neurology Genetics 3, no. 4 (2017): e166. http://dx.doi.org/10.1212/nxg.0000000000000166.
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Objective:To assess the potential connection between PCDH12 and brain calcifications in a patient carrying a homozygous nonsense variant in PCDH12 and in adult patients with brain calcifications.Methods:We performed a CT scan in 1 child with a homozygous PCDH12 nonsense variant. We screened DNA samples from 53 patients with primary familial brain calcification (PFBC) and 26 patients with brain calcification of unknown cause (BCUC).Results:We identified brain calcifications in subcortical and perithalamic regions in the patient with a homozygous PCDH12 nonsense variant. The calcification pattern was different from what has been observed in PFBC and more similar to what is described in in utero infections. In patients with PFBC or BCUC, we found no protein-truncating variant and 3 rare (minor allele frequency <0.001) PCDH12 predicted damaging missense heterozygous variants in 3 unrelated patients, albeit with no segregation data available.Conclusions:Brain calcifications should be added to the phenotypic spectrum associated with PCDH12 biallelic loss of function, in the context of severe cerebral developmental abnormalities. A putative role for PCDH12 variants remains to be determined in PFBC.
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Dupuis, Arnaud, Doris Böckelmann, Patricia Laeuffer, Katharina Neubauer, Christian Gachet, and Barbara Zieger. "Two Novel Compound Heterozygous Pathogenic Variants in P2YR12 gene." Blood 132, Supplement 1 (2018): 1154. http://dx.doi.org/10.1182/blood-2018-99-112833.
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Abstract Introduction: P2Y12 receptor (P2Y12R) defect is a rare hemorrhagic disorder characterized by mild to moderate bleeding diathesis with easy bruising, mucosal bleedings, and excessive post-operative hemorrhage. It is due to mutations of the P2YR12 gene resulting in impairment of platelet responses to adenosine 5'-diphosphate (ADP) and subsequently to any other agonist as ADP is secreted from the dense granules during platelet activation. The P2Y12R plays a key role in platelet aggregation by amplifying the platelet activation process which is necessary to ensure appropriate primary hemostasis. The activation of the P2Y12R by ADP results in inhibition of adenylyl cyclase (AC) and in activation of phosphoinositide 3-kinase (PIK3), which amplifies and sustains the platelet aggregation response. To date only 12 pathogenic variants in the P2YR12 gene are listed in the Human Gene Mutation Database (HGMD®) (10 missense/nonsense mutations and 2 small deletions). Seven missense mutations are described in the literature in patients suffering from bleeding disorders of various severity. Autosomal recessive (homozygous and compound heterozygous pathogenic variants) as well as autosomal dominant (only one heterozygous pathogenic variant) inheritance has been reported. Patients and Methods: We investigated an 8 year old index patient who came to our outpatient clinic to investigate an increased bleeding tendency. He suffered from easy bruising and reported increased bleeding after tonsillectomy. His twin brother was also affected regarding bleeding disorder. Their father suffered sometimes from epistaxis, their mother and three older siblings were clinically unaffected. Platelet functions were assessed by light transmission aggregometry using citrated PRP. Membrane glycoprotein quantification, fibrinogen binding, von Willebrand factor (VWF) binding and the VASP assay were performed by flow cytometry. Molecular genetic analysis (Sanger sequencing) was performed for all exons including UTR regions and splice sites of the P2RY12-gene (NM_002788.4) for the twins and their parents. Results: The index patient and his brother showed normal values for platelet count, aPTT, INR, FXIII and VWF parameters. Both twins showed impaired platelet aggregation after stimulation with collagen, ADP and epinephrine. For both the index patient and his twin brother ADP (4-20 µM and 4-10 µM respectively) induced aggregation was markedly reduced and rapidly reversible. Flow cytometry revealed severely decreased fibrinogen binding for the index patient and his twin brother after stimulation with ADP (0.25-5.0 μmol/l) compared to control platelets. For CD42a/b (GP Ib/IX-complex), CD41 (GP IIb/IIIa-complex), ristocetin-induced VWF-binding, CD62- and CD63-expression, normal values were measured. The VASP assay revealed a strong defect with a PRI value of patient's platelets as low as 1.2% and 1% respectively (normal range > 69%). Molecular genetic analysis revealed two novel variants in the P2YR12 coding sequence (Tab.1). Conclusion: We have identified two novel variants in the P2YR12 gene with pathogenic predictions in a compound heterozygous state in twin brothers suffering from a chronic bleeding disorder. Flow cytometry analyses (fibrinogen binding) and VASP analyses are valuable tools to diagnose a platelet ADP-receptor defect. Table Table. Disclosures No relevant conflicts of interest to declare.
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Kotecha, Shrinal, and Venkatesh Kairamkonda. "Mitochondrial respiratory chain complex IV deficiency presenting as neonatal respiratory distress syndrome." BMJ Case Reports 12, no. 7 (2019): e229668. http://dx.doi.org/10.1136/bcr-2019-229668.
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A term girl infant delivered following foetal distress presented with early respiratory distress syndrome and lactic acidaemia. She subsequently underwent detailed investigation for primary lactic acidaemia and was identified as homozygous for the c.515A>G,p.(Tyr172Cys) missense variant in theLRPPRCgene. Variants in this gene are known to cause French-Canadian type Leigh syndrome. Both parents were confirmed to be heterozygous for this mutation. This is the first case report of mitochondrial respiratory chain complex IV deficiency presenting as foetal distress and neonatal respiratory distress syndrome.
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Canali, Giorgia, and Laurence Goutebroze. "CNTNAP2 Heterozygous Missense Variants: Risk Factors for Autism Spectrum Disorder and/or Other Pathologies?" Journal of Experimental Neuroscience 12 (January 2018): 117906951880966. http://dx.doi.org/10.1177/1179069518809666.
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Kumar, Anil, Rajni Sharma, Mohammed Faruq та ін. "Spectrum of Pathogenic Variants in SRD5A2 in Indian Children with 46,XY Disorders of Sex Development and Clinically Suspected Steroid 5α-Reductase 2 Deficiency". Sexual Development 13, № 5-6 (2019): 228–39. http://dx.doi.org/10.1159/000509812.
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The aim of this study was to assess the prevalence of pathogenic variants in the <i>SRD5A2</i> gene in children with 46,XY disorders of sex development (DSD) with normal to high serum testosterone levels and absence of Müllerian structures on imaging and to evaluate the genotype-phenotype correlation. Seventy-five patients with 46,XY DSD and probable clinical diagnosis of 5α-reductase 2 deficiency or androgen insensitivity syndrome were enrolled. Genetic analysis was done for pathogenic variants in <i>SRD5A2</i>, and the genotype-phenotype correlation was studied. As a result, 10 pathogenic or likely pathogenic biallelic variants in <i>SRD5A2, </i>either homozygous or compound heterozygous, were identified in 25 of 75 (33.3%) patients. The hCG stimulated testosterone: dihydrotestosterone (T:DHT) ratio was elevated in all patients with pathogenic variants in <i>SRD5A2</i> and in nearly 90% of those without pathogenic variants in <i>SRD5A2</i> in whom this was assessed. The missense pathogenic variant p.R246Q was a hotspot. One novel pathogenic variant p.Y178*, and a variant p.F194I, not previously reported in patients with 5α-reductase 2 deficiency, were identified. The missense variant p.F194I was predicted as deleterious and damaging by in silico analysis and as likely to reduce the enzyme activity by protein modeling. In conclusion, pathogenic variants in <i>SRD5A2 </i>can be detected in a wide spectrum of Indian patients with 46,XY DSD. Molecular genetic analysis should be considered as a first-line test as the T:DHT ratio lacks specificity and a hotspot variant is present in a vast majority.
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Albarry, Maan Abdullah, Muhammad Latif, Ahdab Qasem Alreheli, et al. "Frameshift variant in MITF gene in a large family with Waardenburg syndrome type II and a co-segregation of a C2orf74 variant." PLOS ONE 16, no. 2 (2021): e0246607. http://dx.doi.org/10.1371/journal.pone.0246607.
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Waardenburg syndrome (WS) is a hereditary disorder affecting the auditory system and pigmentation of hair, eyes, and skin. Different variants of the disease exist with the involvement of mutation in six genes. The aim of the study is to identify the genetic defects underlying Waardenburg syndrome in a large family with multiple affected individuals. Here, in this study, we recruited a large family with eleven affected individuals segregating WS type 2. We performed whole genome SNP genotyping, whole exome sequencing and segregation analysis using Sanger approach. Whole genome SNP genotyping, whole exome sequencing followed by Sanger validation of variants of interest identified a novel single nucleotide deletion mutation (c.965delA) in the MITF gene. Moreover, a rare heterozygous, missense damaging variant (c.101T>G; p.Val34Gly) in the C2orf74 has also been identified. The C2orf74 is an uncharacterized gene present in the linked region detected by DominantMapper. Variants in MITF and C2orf74 follows autosomal dominant segregation with the phenotype, however, the variant in C2orf74 is incompletely penetrant. We proposed a digenic inheritance of variants as an underlying cause of WS2 in this family.
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Mul, Karlien, Richard J. L. F. Lemmers, Marjolein Kriek, et al. "FSHD type 2 and Bosma arhinia microphthalmia syndrome." Neurology 91, no. 6 (2018): e562-e570. http://dx.doi.org/10.1212/wnl.0000000000005958.
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ObjectiveTo determine whether congenital arhinia/Bosma arhinia microphthalmia syndrome (BAMS) and facioscapulohumeral muscular dystrophy type 2 (FSHD2), 2 seemingly unrelated disorders both caused by heterozygous pathogenic missense variants in the SMCHD1 gene, might represent different ends of a broad single phenotypic spectrum associated with SMCHD1 dysfunction.MethodsWe examined and/or interviewed 14 patients with FSHD2 and 4 unaffected family members with N-terminal SMCHD1 pathogenic missense variants to identify BAMS subphenotypes.ResultsNone of the patients with FSHD2 or family members demonstrated any congenital defects or dysmorphic features commonly found in patients with BAMS. One patient became anosmic after nasal surgery and one patient was hyposmic; one man was infertile (unknown cause) but reported normal pubertal development.ConclusionThese data suggest that arhinia/BAMS and FSHD2 do not represent one phenotypic spectrum and that SMCHD1 pathogenic variants by themselves are insufficient to cause either of the 2 disorders. More likely, both arhinia/BAMS and FSHD2 are caused by complex oligogenic or multifactorial mechanisms that only partially overlap at the level of SMCHD1.
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Doll, Julia, Barbara Vona, Linda Schnapp, et al. "Genetic Spectrum of Syndromic and Non-Syndromic Hearing Loss in Pakistani Families." Genes 11, no. 11 (2020): 1329. http://dx.doi.org/10.3390/genes11111329.
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The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A, with an overall resolve rate of 61.9%. GJB2 and MYO7A were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4%). Overall, seven missense variants (53.8%), three nonsense variants (23.1%), two frameshift variants (15.4%), and one splice-site variant (7.7%) were observed. Syndromic HL was identified in five (23.8%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes.
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Jönsson, Åsa Lina M., Elisabeth Bendstrup, Susie Mogensen, et al. "Eight novel variants in the SLC34A2 gene in pulmonary alveolar microlithiasis." European Respiratory Journal 55, no. 2 (2019): 1900806. http://dx.doi.org/10.1183/13993003.00806-2019.
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BackgroundPulmonary alveolar microlithiasis (PAM) is caused by genetic variants in the SLC34A2 gene, which encodes the sodium-dependent phosphate transport protein 2B (NaPi-2b). PAM is characterised by deposition of calcium phosphate concretions (microliths) in the alveoli leading to pulmonary dysfunction. The variant spectrum of SLC34A2 has not been well investigated and it is not yet known whether a genotype–phenotype correlation exists.MethodsWe collected DNA from 14 patients with PAM and four relatives, and analysed the coding regions of SLC34A2 by direct DNA sequencing. To determine the phenotype characteristics, clinical data were collected and a severity score was created for each variant, based on type and localisation within the protein.ResultsWe identified eight novel allelic variants of SLC34A2 in 14 patients with PAM. Four of these were nonsense variants, three were missense and one was a splice site variant. One patient was heterozygous for two different variants and all other patients were homozygous. Four patients were asymptomatic and 10 patients were symptomatic. The severity of the disease was associated with the variant severity.ConclusionsOur findings support a significant role for SLC34A2 in PAM and expand the variant spectrum of the disease. Thus, SLC34A2 variants were detected in all patients and eight novel allelic variants were discovered. An association between disease severity and the severity of the variants was found; however, this needs to be investigated in larger patient populations.
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Stolyar, Helen, Teresa Berry, Amit Pal Singh, and Ichhcha Madan. "PIEZO1 mutation: a rare aetiology for fetal ascites." BMJ Case Reports 14, no. 4 (2021): e240682. http://dx.doi.org/10.1136/bcr-2020-240682.
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We present a case of isolated fetal ascites diagnosed at 20 weeks’ gestation. No aetiology was identified on extensive prenatal workup, including prenatal microarray. The patient terminated the pregnancy at 23 weeks’ gestation. Exome sequencing was performed on the products of conception, which ended up giving insight into a possible cause for the ascites. Two heterozygous missense variants of uncertain significance were identified in the PIEZO1 gene. The paternal variant has been linked to dehydrated hereditary stomatocytosis. The father of the baby suffers from haemolytic anaemia, splenomegaly and has had jaundice throughout his life. His brother and father have similar conditions. We suspect that at least one of the gene variants identified in our exome sequencing may be responsible for the illness that runs in this family, including the fetus with isolated ascites.
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Mosca, Lorena, Silvana Pileggi, Francesca Avemaria, et al. "De Novo MGC4607 Gene Heterozygous Missense Variants in a Child with Multiple Cerebral Cavernous Malformations." Journal of Molecular Neuroscience 47, no. 3 (2012): 475–80. http://dx.doi.org/10.1007/s12031-012-9741-5.
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Snijders Blok, Lot, Arianna Vino, Joery den Hoed, et al. "Heterozygous variants that disturb the transcriptional repressor activity of FOXP4 cause a developmental disorder with speech/language delays and multiple congenital abnormalities." Genetics in Medicine, October 28, 2020. http://dx.doi.org/10.1038/s41436-020-01016-6.
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Abstract Purpose Heterozygous pathogenic variants in various FOXP genes cause specific developmental disorders. The phenotype associated with heterozygous variants in FOXP4 has not been previously described. Methods We assembled a cohort of eight individuals with heterozygous and mostly de novo variants in FOXP4: seven individuals with six different missense variants and one individual with a frameshift variant. We collected clinical data to delineate the phenotypic spectrum, and used in silico analyses and functional cell-based assays to assess pathogenicity of the variants. Results We collected clinical data for six individuals: five individuals with a missense variant in the forkhead box DNA-binding domain of FOXP4, and one individual with a truncating variant. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia, cervical spine abnormalities, and ptosis. Luciferase assays showed loss-of-function effects for all these variants, and aberrant subcellular localization patterns were seen in a subset. The remaining two missense variants were located outside the functional domains of FOXP4, and showed transcriptional repressor capacities and localization patterns similar to the wild-type protein. Conclusion Collectively, our findings show that heterozygous loss-of-function variants in FOXP4 are associated with an autosomal dominant neurodevelopmental disorder with speech/language delays, growth defects, and variable congenital abnormalities.
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Ueda, Kimiko, Atsushi Araki, Atsushi Fujita, et al. "A Japanese adult and two girls with NEDMIAL caused by de novo missense variants in DHX30." Human Genome Variation 8, no. 1 (2021). http://dx.doi.org/10.1038/s41439-021-00155-9.
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AbstractLessel et al. reported a novel neurodevelopmental disorder with severe motor impairment and absent language (NEDMIAL) in 12 individuals and identified six different de novo heterozygous missense variants in DHX30. The other clinical features included muscular hypotonia, feeding difficulties, brain anomalies, autistic features, sleep disturbances, and joint hypermobility. We report a Japanese adult with a novel missense variant and two girls with de novo missense variants in DHX30.