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Journal articles on the topic 'Phenotypic Spectrum'

Author: Grafiati

Published: 4 June 2025

Last updated: 23 June 2025

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1

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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Leoni, Chiara, Marta Tedesco, Francesca Clementina Radio, et al. "Broadening the phenotypic spectrum of Beta3GalT6 ‐associated phenotypes." American Journal of Medical Genetics Part A 185, no. 10 (2021): 3153–60. http://dx.doi.org/10.1002/ajmg.a.62399.

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3

Havrilla, James Margolin, Mengge Zhao, Cong Liu, et al. "Clinical Phenotypic Spectrum of 4095 Individuals with Down Syndrome from Text Mining of Electronic Health Records." Genes 12, no. 8 (2021): 1159. http://dx.doi.org/10.3390/genes12081159.

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Human genetic disorders, such as Down syndrome, have a wide variety of clinical phenotypic presentations, and characterizing each nuanced phenotype and subtype can be difficult. In this study, we examined the electronic health records of 4095 individuals with Down syndrome at the Children’s Hospital of Philadelphia to create a method to characterize the phenotypic spectrum digitally. We extracted Human Phenotype Ontology (HPO) terms from quality-filtered patient notes using a natural language processing (NLP) approach MetaMap. We catalogued the most common HPO terms related to Down syndrome patients and compared the terms with those from a baseline population. We characterized the top 100 HPO terms by their frequencies at different ages of clinical visits and highlighted selected terms that have time-dependent distributions. We also discovered phenotypic terms that have not been significantly associated with Down syndrome, such as “Proptosis”, “Downslanted palpebral fissures”, and “Microtia”. In summary, our study demonstrated that the clinical phenotypic spectrum of individual with Mendelian diseases can be characterized through NLP-based digital phenotyping on population-scale electronic health records (EHRs).

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Johannesen, Katrine, Carla Marini, Siona Pfeffer, et al. "Phenotypic spectrum of GABRA1." Neurology 87, no. 11 (2016): 1140–51. http://dx.doi.org/10.1212/wnl.0000000000003087.

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Nishimura, Gen, Nobuhiko Haga, Hiroshi Kitoh, et al. "The phenotypic spectrum ofCOL2A1mutations." Human Mutation 26, no. 1 (2005): 36–43. http://dx.doi.org/10.1002/humu.20179.

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Zhang, Yue-Hua, Rosemary Burgess, Jodie P. Malone, et al. "Genetic epilepsy with febrile seizures plus." Neurology 89, no. 12 (2017): 1210–19. http://dx.doi.org/10.1212/wnl.0000000000004384.

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Objective:Following our original description of generalized epilepsy with febrile seizures plus (GEFS+) in 1997, we analyze the phenotypic spectrum in 409 affected individuals in 60 families (31 new families) and expand the GEFS+ spectrum.Methods:We performed detailed electroclinical phenotyping on all available affected family members. Genetic analysis of known GEFS+ genes was carried out where possible. We compared our phenotypic and genetic data to those published in the literature over the last 19 years.Results:We identified new phenotypes within the GEFS+ spectrum: focal seizures without preceding febrile seizures (16/409 [4%]), classic genetic generalized epilepsies (22/409 [5%]), and afebrile generalized tonic-clonic seizures (9/409 [2%]). Febrile seizures remains the most frequent phenotype in GEFS+ (178/409 [44%]), followed by febrile seizures plus (111/409 [27%]). One third (50/163 [31%]) of GEFS+ families tested have a pathogenic variant in a known GEFS+ gene.Conclusion:As 37/409 (9%) affected individuals have focal epilepsies, we suggest that GEFS+ be renamed genetic epilepsy with febrile seizures plus rather than generalized epilepsy with febrile seizures plus. The phenotypic overlap between GEFS+ and the classic generalized epilepsies is considerably greater than first thought. The clinical and molecular data suggest that the 2 major groups of generalized epilepsies share genetic determinants.

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Yoshioka, Mieko. "Phenotypic spectrum of Fukutinopathy: Most severe phenotype of Fukutinopathy." Brain and Development 31, no. 6 (2009): 419–22. http://dx.doi.org/10.1016/j.braindev.2008.07.012.

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8

Kröger, Cornelia, Alexander Afeyan, Jasmin Mraz, et al. "Acquisition of a hybrid E/M state is essential for tumorigenicity of basal breast cancer cells." Proceedings of the National Academy of Sciences 116, no. 15 (2019): 7353–62. http://dx.doi.org/10.1073/pnas.1812876116.

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Carcinoma cells residing in an intermediate phenotypic state along the epithelial–mesenchymal (E–M) spectrum are associated with malignant phenotypes, such as invasiveness, tumor-initiating ability, and metastatic dissemination. Using the recently described CD104+/CD44hi antigen marker combination, we isolated highly tumorigenic breast cancer cells residing stably—both in vitro and in vivo—in an intermediate phenotypic state and coexpressing both epithelial (E) and mesenchymal (M) markers. We demonstrate that tumorigenicity depends on individual cells residing in this E/M hybrid state and cannot be phenocopied by mixing two cell populations that reside stably at the two ends of the spectrum, i.e., in the E and in the M state. Hence, residence in a specific intermediate state along the E–M spectrum rather than phenotypic plasticity appears critical to the expression of tumor-initiating capacity. Acquisition of this E/M hybrid state is facilitated by the differential expression of EMT-inducing transcription factors (EMT-TFs) and is accompanied by the expression of adult stem cell programs, notably, active canonical Wnt signaling. Furthermore, transition from the highly tumorigenic E/M state to a fully mesenchymal phenotype, achieved by constitutive ectopic expression of Zeb1, is sufficient to drive cells out of the E/M hybrid state into a highly mesenchymal state, which is accompanied by a substantial loss of tumorigenicity and a switch from canonical to noncanonical Wnt signaling. Identifying the gatekeepers of the various phenotypic states arrayed along the E–M spectrum is likely to prove useful in developing therapeutic approaches that operate by shifting cancer cells between distinct states along this spectrum.

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9

Finsterer, Josef, and Sinda Zarrouk-Mahjoub. "Phenotypic Spectrum of SBF2 Mutations." Open Access Journal of Internal Medicine 2, no. 1 (2019): 34–35. http://dx.doi.org/10.22259/2638-5279.0201004.

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10

Kruijt, Charlotte C., Gerard C. de Wit, Arthur A. Bergen, Ralph J. Florijn, Nicoline E. Schalij-Delfos, and Maria M. van Genderen. "The Phenotypic Spectrum of Albinism." Ophthalmology 125, no. 12 (2018): 1953–60. http://dx.doi.org/10.1016/j.ophtha.2018.08.003.

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11

Finsterer, Josef, Carla A. Scorza, and Fulvio A. Scorza. "Phenotypic spectrum of FARS2-deficiency." Molecular Genetics and Metabolism Reports 14 (March 2018): 41–42. http://dx.doi.org/10.1016/j.ymgmr.2017.11.003.

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12

Lemke, Johannes R., Kirsten Geider, Katherine L. Helbig, et al. "Delineating the GRIN1 phenotypic spectrum." Neurology 86, no. 23 (2016): 2171–78. http://dx.doi.org/10.1212/wnl.0000000000002740.

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13

Robitaille, Johane M., Binyou Zheng, Karen Wallace, Mark Samuels, Jill Beis, and Duane Guernsey. "Phenotypic Spectrum of FZD4 Mutations." Journal of American Association for Pediatric Ophthalmology and Strabismus 10, no. 1 (2006): 92. http://dx.doi.org/10.1016/j.jaapos.2006.01.194.

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14

Finsterer, Josef, and Sinda Zarrouk-Mahjoub. "Phenotypic spectrum of DARS2 mutations." Journal of the Neurological Sciences 376 (May 2017): 117–18. http://dx.doi.org/10.1016/j.jns.2017.03.006.

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15

Johannesen, Katrine M., Elena Gardella, Tarja Linnankivi, et al. "Defining the phenotypic spectrum ofSLC6A1mutations." Epilepsia 59, no. 2 (2018): 389–402. http://dx.doi.org/10.1111/epi.13986.

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Finsterer, Josef, and Fulvio A. Scorza. "Phenotypic spectrum of POLG1 mutations." Neurological Sciences 39, no. 3 (2017): 571–73. http://dx.doi.org/10.1007/s10072-017-3116-1.

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17

Schaaf, Christian P., Philip M. Boone, Srirangan Sampath, et al. "Phenotypic spectrum and genotype–phenotype correlations of NRXN1 exon deletions." European Journal of Human Genetics 20, no. 12 (2012): 1240–47. http://dx.doi.org/10.1038/ejhg.2012.95.

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18

Paredes, Diego I., Jenina E. Capasso, Celeste S. Wyman, and Alex V. Levin. "Genetics of the anterior segment dysgenesis." Taiwan Journal of Ophthalmology 13, no. 4 (2023): 500–504. http://dx.doi.org/10.4103/tjo.tjo-d-23-00062.

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The anterior segment dysgeneses are a broad group of heterogeneous disorders characterized by developmental abnormalities of the anterior segment of the eye, including primary congenital aphakia, Peters sequence, aniridia, and Axenfeld–Rieger spectrum. These conditions can have overlapping phenotypes and both genotypic and phenotypic heterogeneity. This article provides a strategy for both phenotyping and then genotyping using a targeted stepwise approach.

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19

Amaral, Gilda Rose S., Graciela M. Dias, Michiyo Wellington-Oguri, et al. "Genotype to phenotype: identification of diagnostic vibrio phenotypes using whole genome sequences." International Journal of Systematic and Evolutionary Microbiology 64, Pt_2 (2014): 357–65. http://dx.doi.org/10.1099/ijs.0.057927-0.

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Vibrios are ubiquitous in the aquatic environment and can be found in association with animal or plant hosts. The range of ecological relationships includes pathogenic and mutualistic associations. To gain a better understanding of the ecology of these microbes, it is important to determine their phenotypic features. However, the traditional phenotypic characterization of vibrios has been expensive, time-consuming and restricted in scope to a limited number of features. In addition, most of the commercial systems applied for phenotypic characterization cannot characterize the broad spectrum of environmental strains. A reliable and possible alternative is to obtain phenotypic information directly from whole genome sequences. The aim of the present study was to evaluate the usefulness of whole genome sequences as a source of phenotypic information. We performed a comparison of the vibrio phenotypes obtained from the literature with the phenotypes obtained from whole genome sequences. We observed a significant correlation between the previously published phenotypic data and the phenotypic data retrieved from whole genome sequences of vibrios. Analysis of 26 vibrio genomes revealed that all genes coding for the specific proteins involved in the metabolic pathways responsible for positive phenotypes of the 14 diagnostic features (Voges–Proskauer reaction, indole production, arginine dihydrolase, ornithine decarboxylase, utilization of myo-inositol, sucrose and l-leucine, and fermentation of d-mannitol, d-sorbitol, l-arabinose, trehalose, cellobiose, d-mannose and d-galactose) were found in the majority of the vibrios genomes. Vibrio species that were negative for a given phenotype revealed the absence of all or several genes involved in the respective biochemical pathways, indicating the utility of this approach to characterize the phenotypes of vibrios. The absence of the global regulation and regulatory proteins in the Vibrio parahaemolyticus genome indicated a non-vibrio phenotype. Whole genome sequences represent an important source for the phenotypic identification of vibrios.

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20

Marian, Ali J. "Phenotypic spectrum of mutations in cardiolaminopathies." Cardiogenetics 1, no. 1 (2011): 6. http://dx.doi.org/10.4081/cardiogenetics.2011.e6.

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21

Suri, Mohnish. "The phenotypic spectrum of ARX mutations." Developmental Medicine & Child Neurology 47, no. 2 (2007): 133–37. http://dx.doi.org/10.1111/j.1469-8749.2005.tb01102.x.

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22

Rerknimitr, Pawinee, Wiwat Korkij, Jade Wititsuwannakul, Wipa Panmontha, Kanya Suphapeetiporn, and Vorasuk Shotelersuk. "Expanding Phenotypic Spectrum of Familial Comedones." Dermatology 228, no. 3 (2014): 215–19. http://dx.doi.org/10.1159/000358170.

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23

Vahidnezhad, H., L. Youssefian, T. Baghdadi, et al. "Phenotypic heterogeneity inPIK3CA-related overgrowth spectrum." British Journal of Dermatology 175, no. 4 (2016): 810–14. http://dx.doi.org/10.1111/bjd.14618.

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24

Larsen, J., G. L. Carvill, E. Gardella, et al. "The phenotypic spectrum of SCN8A encephalopathy." Neurology 84, no. 5 (2015): 480–89. http://dx.doi.org/10.1212/wnl.0000000000001211.

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Suri, Mohnish. "The phenotypic spectrum of ARX mutations." Developmental Medicine & Child Neurology 47, no. 2 (2005): 133–37. http://dx.doi.org/10.1017/s001216220500023x.

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26

Kohli, Utkarsh, Chitra Ravishankar, and Douglas Nordli. "Cardiac phenotypic spectrum of KCNT1 mutations." Cardiology in the Young 30, no. 12 (2020): 1935–39. http://dx.doi.org/10.1017/s1047951120002735.

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AbstractWe report a 10-month-old girl with KCNT1 (c1420C > T; p. Arg474Cys, R474C) mutation-associated epileptic encephalopathy, systemic-to-pulmonary artery “collateralopathy”, and intermittent QTc prolongation. Spontaneous regression of systemic-to-pulmonary artery collateral-mediated left heart dilation was noted in this patient, a finding which was ominous as it heralded the onset of severe pulmonary hypertension. The structural and electrical phenotypic features of KCNT1 mutation-associated heart disease, including the novel findings noted in our patient, are discussed in detail.

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27

Turkia, H. Ben, N. Tebib, H. Azzouz, et al. "Phenotypic spectrum of fucosidosis in Tunisia." Journal of Inherited Metabolic Disease 31, S2 (2008): 313–16. http://dx.doi.org/10.1007/s10545-008-0891-0.

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28

Salter, Claire G., Justin H. Davies, Rebecca J. Moon, Joanna Fairhurst, David Bunyan, and Nicola Foulds. "Further defining the phenotypic spectrum ofB4GALT7mutations." American Journal of Medical Genetics Part A 170, no. 6 (2016): 1556–63. http://dx.doi.org/10.1002/ajmg.a.37604.

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29

Yoneda, Yuriko, Kazuhiro Haginoya, Mitsuhiro Kato, et al. "Phenotypic Spectrum ofCOL4A1Mutations: Porencephaly to Schizencephaly." Annals of Neurology 73, no. 1 (2012): 48–57. http://dx.doi.org/10.1002/ana.23736.

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30

Samanta, Debopam, and Yuri A. Zarate. "Widening phenotypic spectrum of GABBR2 mutation." Acta Neurologica Belgica 119, no. 3 (2019): 493–96. http://dx.doi.org/10.1007/s13760-019-01088-5.

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31

Domenice, Sorahia, Aline Zamboni Machado, Frederico Moraes Ferreira, et al. "Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals." Birth Defects Research Part C: Embryo Today: Reviews 108, no. 4 (2016): 309–20. http://dx.doi.org/10.1002/bdrc.21145.

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Steroidogenic factor 1 (NR5A1, SF‐1, Ad4BP) is a transcriptional regulator of genes involved in adrenal and gonadal development and function. Mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. In 46,XY individuals, NR5A1‐related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from 46,XX ovotesticular and testicular DSD to primary ovarian insufficiency (POI). The most common 46,XY phenotype is atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Müllerian derivatives. Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty. In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels. Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling. Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients. A clear genotype‐phenotype correlation is not seen in patients bearing NR5A1 mutations, suggesting that genetic modifiers, such as pathogenic variants in other testis/ovarian‐determining genes, may contribute to the phenotypic expression. Here, we review the published literature on NR5A1‐related disease, and discuss our findings at a single tertiary center in Brazil, including ten novel NR5A1 mutations identified in 46,XY DSD patients. The ever‐expanding phenotypic range associated with NR5A1 variants in XY and XX individuals confirms its pivotal role in reproductive biology, and should alert clinicians to the possibility of NR5A1 defects in a variety of phenotypes presenting with gonadal dysfunction. Birth Defects Research (Part C) 108:309–320, 2016. © 2016 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc.

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Fernández-Caballero, Lidia, Inmaculada Martín-Merida, Fiona Blanco-Kelly, et al. "PRPH2-Related Retinal Dystrophies: Mutational Spectrum in 103 Families from a Spanish Cohort." International Journal of Molecular Sciences 25, no. 5 (2024): 2913. http://dx.doi.org/10.3390/ijms25052913.

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PRPH2, one of the most frequently inherited retinal dystrophy (IRD)-causing genes, implies a high phenotypic variability. This study aims to analyze the PRPH2 mutational spectrum in one of the largest cohorts worldwide, and to describe novel pathogenic variants and genotype–phenotype correlations. A study of 220 patients from 103 families recruited from a database of 5000 families. A molecular diagnosis was performed using classical molecular approaches and next-generation sequencing. Common haplotypes were ascertained by analyzing single-nucleotide polymorphisms. We identified 56 variants, including 11 novel variants. Most of them were missense variants (64%) and were located in the D2-loop protein domain (77%). The most frequently occurring variants were p.Gly167Ser, p.Gly208Asp and p.Pro221_Cys222del. Haplotype analysis revealed a shared region in families carrying p.Leu41Pro or p.Pro221_Cys222del. Patients with retinitis pigmentosa presented an earlier disease onset. We describe the largest cohort of IRD families associated with PRPH2 from a single center. Most variants were located in the D2-loop domain, highlighting its importance in interacting with other proteins. Our work suggests a likely founder effect for the variants p.Leu41Pro and p.Pro221_Cys222del in our Spanish cohort. Phenotypes with a primary rod alteration presented more severe affectation. Finally, the high phenotypic variability in PRPH2 hinders the possibility of drawing genotype–phenotype correlations.

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Moutton, Sébastien, Patricia Fergelot, Sophie Naudion, et al. "Otopalatodigital spectrum disorders: refinement of the phenotypic and mutational spectrum." Journal of Human Genetics 61, no. 8 (2016): 693–99. http://dx.doi.org/10.1038/jhg.2016.37.

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Varankar, Sagar S., Madhuri More, Ancy Abraham, et al. "Functional balance between Tcf21–Slug defines cellular plasticity and migratory modalities in high grade serous ovarian cancer cell lines." Carcinogenesis 41, no. 4 (2019): 515–26. http://dx.doi.org/10.1093/carcin/bgz119.

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Abstract Cellular plasticity and transitional phenotypes add to complexities of cancer metastasis that can be initiated by single cell epithelial to mesenchymal transition (EMT) or cooperative cell migration (CCM). Our study identifies novel regulatory cross-talks between Tcf21 and Slug in mediating phenotypic and migration plasticity in high-grade serous ovarian adenocarcinoma (HGSC). Differential expression and subcellular localization associate Tcf21, Slug with epithelial, mesenchymal phenotypes, respectively; however, gene manipulation approaches identify their association with additional intermediate phenotypic states, implying the existence of a multistep epithelial-mesenchymal transition program. Live imaging further associated distinct migratory modalities with the Tcf21/Slug status of cell systems and discerned proliferative/passive CCM, active CCM and EMT modes of migration. Tcf21–Slug balance identified across a phenotypic spectrum in HGSC cell lines, associated with microenvironment-induced transitions and the emergence of an epithelial phenotype following drug exposure. Phenotypic transitions and associated functionalities following drug exposure were affirmed to ensue from occupancy of Slug promoter E-box sequences by Tcf21. Our study effectively provides a framework for understanding the relevance of ovarian cancer plasticity as a function of two transcription factors.

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Traschütz, Andreas, Andrea Cortese, Selina Reich, et al. "Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease." Neurology 96, no. 9 (2021): e1369-e1382. http://dx.doi.org/10.1212/wnl.0000000000011528.

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ObjectiveTo delineate the full phenotypic spectrum, discriminative features, piloting longitudinal progression data, and sample size calculations of replication factor complex subunit 1 (RFC1) repeat expansions, recently identified as causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS).MethodsMultimodal RFC1 repeat screening (PCR, Southern blot, whole-exome/genome sequencing–based approaches) combined with cross-sectional and longitudinal deep phenotyping in (1) cross-European cohort A (70 families) with ≥2 features of CANVAS or ataxia with chronic cough (ACC) and (2) Turkish cohort B (105 families) with unselected late-onset ataxia.ResultsPrevalence of RFC1 disease was 67% in cohort A, 14% in unselected cohort B, 68% in clinical CANVAS, and 100% in ACC. RFC1 disease was also identified in Western and Eastern Asian individuals and even by whole-exome sequencing. Visual compensation, sensory symptoms, and cough were strong positive discriminative predictors (>90%) against RFC1-negative patients. The phenotype across 70 RFC1-positive patients was mostly multisystemic (69%), including dysautonomia (62%) and bradykinesia (28%) (overlap with cerebellar-type multiple system atrophy [MSA-C]), postural instability (49%), slow vertical saccades (17%), and chorea or dystonia (11%). Ataxia progression was ≈1.3 Scale for the Assessment and Rating of Ataxia points per year (32 cross-sectional, 17 longitudinal assessments, follow-up ≤9 years [mean 3.1 years]) but also included early falls, variable nonlinear phases of MSA-C–like progression (SARA points 2.5–5.5 per year), and premature death. Treatment trials require 330 (1-year trial) and 132 (2-year trial) patients in total to detect 50% reduced progression.ConclusionsRFC1 disease is frequent and occurs across continents, with CANVAS and ACC as highly diagnostic phenotypes yet as variable, overlapping clusters along a continuous multisystemic disease spectrum, including MSA-C-overlap. Our natural history data help to inform future RFC1 treatment trials.Classification of EvidenceThis study provides Class II evidence that RFC1 repeat expansions are associated with CANVAS and ACC.

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36

Mu, Weiyi, Teresa Heller, and Kristin W. Barañano. "Two siblings with a novel variant of EXOSC3 extended phenotypic spectrum of pontocerebellar hypoplasia 1B to an exceptionally mild form." BMJ Case Reports 14, no. 1 (2021): e236732. http://dx.doi.org/10.1136/bcr-2020-236732.

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Pontocerebellar hypoplasia type 1B (PCH1B) describes an autosomal recessive neurological condition that involves hypoplasia or atrophy of the cerebellum and pons, resulting in neurocognitive impairments. Although there is phenotypic variability, this is often an infantile lethal condition, and most cases have been described to be congenital and neurodegenerative. PCH1B is caused by mutations in the gene EXOSC3, which encodes exosome component 3, a subunit of the human RNA exosome complex. A range of pathogenic variants with some correlation to phenotype have been reported. The most commonly reported pathogenic variant in EXOSC3 is c.395A>C, p.(Asp132Ala); homozygosity for this variant has been proposed to lead to milder phenotypes than compound heterozygosity. In this case, we report two siblings with extraordinarily mild presentations of PCH1B who are compound heterozygous for variants in EXOSC3 c.155delC and c.80T>G. These patients drastically expand the phenotypic variability of PCH1B and raise questions about genotype–phenotype associations.

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Serpieri, Valentina, Tommaso Biagini, Concetta Mazzotta, et al. "Phenotypic Definition and Genotype-Phenotype Correlates in PMPCA-Related Disease." Applied Sciences 11, no. 2 (2021): 748. http://dx.doi.org/10.3390/app11020748.

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Background: Peptidase mitochondrial processing alpha (PMPCA) biallelic mutations cause a spectrum of disorders ranging from severe progressive multisystemic mitochondrial encephalopathy to a milder non-progressive cerebellar ataxia with or without intellectual disability. Recently, we and others described an intermediate phenotype in two unrelated patients. Methods: We report a second Italian patient carrying novel PMPCA variants (p.Trp278Leu; p.Arg362Gly). Molecular modeling, dynamics simulation, RT-qPCR, and Western blotting were performed to predict the pathogenic impact of variants in the two Italian patients and attempt genotype-phenotype correlates. Results: In line with the two patients with intermediate phenotypes, our case presented global psychomotor delay with regression, intellectual disability, spastic-ataxic gait, and hyperkinetic movements, with cerebellar atrophy and bilateral striatal hyperintensities. However, blood lactate, muscle biopsy, and MRI spectroscopy were normal. PMPCA protein levels were significantly higher than controls despite normal cDNA levels. Dynamics simulation of several PMPCA missense variants showed a variable impact on the flexibility of the glycine rich loop and, for some cases, on the overall protein stability, without clear genotype-phenotype correlates. Conclusion: We confirm the expansion of PMPCA phenotypic spectrum including an intermediate phenotype of progressive encephalopathy without systemic involvement. The association of cerebellar atrophy with “Leigh-like” striatal hyperintensities may represent a “red flag” for this condition.

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Komulainen-Ebrahim, Jonna, John M. Schreiber, Salla M. Kangas, et al. "Novel variants and phenotypes widen the phenotypic spectrum of GABRG2-related disorders." Seizure 69 (July 2019): 99–104. http://dx.doi.org/10.1016/j.seizure.2019.03.010.

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39

Mazzotta, Cosimo, Claudio Traversi, Stefano Baiocchi, Stefano Barabino, and Alessandro Mularoni. "Phenotypic Spectrum of Granular Corneal Dystrophy Type II in Two Italian Families Presenting an Unusual Granular Corneal Dystrophy Type I Clinical Appearance." Case Reports in Ophthalmological Medicine 2015 (2015): 1–6. http://dx.doi.org/10.1155/2015/703418.

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Clinical, instrumental, and genetic findings are reported in Italian families with Type II Granular Corneal Dystrophies (GCD2) presenting an initial unusual presentation of a Granular Corneal Dystrophy Type I (GCD1) phenotypic spectrum in female descendants. Slit-lamp examinations showed the typical phenotypic features of GCD2 in both mothers and a phenotypic appearance of GCD1 in both daughters. Despite the different phenotypic onset, the genetic diagnostic testing revealed the presence of a mutation in the TGFB-I gene, typical of GCD2 in both cases, excluding GCD1. Patients who were clinically suspected of corneal dystrophy need a genetic confirmatory testing for certain diagnosis. Genetic test may help to find the specific mutation distinguishing between different phenotypic spectra with relative diagnostic and prognostic implications. The study demonstrates that the phenotypic spectrum of genetically confirmed granular corneal dystrophies in patients may change over time. Since the R124H mutation has also been described in clinically asymptomatic individuals prior to LASIK, who then develop dramatic deposition, suggesting that this particular mutation and phenotype may be sensitive to, precipitated, or modified by central cornea trauma, a careful familial anamnesis excluding cornel dystrophies and specific preoperative genetic test are recommended prior to LASIK.

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Spedicati, Beatrice, Massimiliano Cocca, Roberto Palmisano, et al. "Natural human knockouts and Mendelian disorders: deep phenotyping in Italian isolates." European Journal of Human Genetics 29, no. 8 (2021): 1272–81. http://dx.doi.org/10.1038/s41431-021-00850-9.

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AbstractWhole genome sequencing (WGS) allows the identification of human knockouts (HKOs), individuals in whom loss of function (LoF) variants disrupt both alleles of a given gene. HKOs are a valuable model for understanding the consequences of genes function loss. Naturally occurring biallelic LoF variants tend to be significantly enriched in “genetic isolates,” making these populations specifically suited for HKO studies. In this work, a meticulous WGS data analysis combined with an in-depth phenotypic assessment of 947 individuals from three Italian genetic isolates led to the identification of ten biallelic LoF variants in ten OMIM genes associated with known autosomal recessive diseases. Notably, only a minority of the identified HKOs (C7, F12, and GPR68 genes) displayed the expected phenotype. For most of the genes, instead, (ACADSB, FANCL, GRK1, LGI4, MPO, PGAM2, and RP1L1), the carriers showed none or few of the signs and symptoms typically associated with the related diseases. Of particular interest is a case presenting with a FANCL biallelic LoF variant and a positive diepoxybutane test but lacking a full Fanconi anemia phenotypic spectrum. Identifying KO subjects displaying expected phenotypes suggests that the lack of correct genetic diagnoses may lead to inappropriate and delayed treatment. In contrast, the presence of HKOs with phenotypes deviating from the expected patterns underlines how LoF variants may be responsible for broader phenotypic spectra. Overall, these results highlight the importance of in-depth phenotypical characterization to understand the role of LoF variants and the advantage of studying these variants in genetic isolates.

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Lewitus, Eric, Leandro Aristide, and Hélène Morlon. "Characterizing and Comparing Phylogenetic Trait Data from Their Normalized Laplacian Spectrum." Systematic Biology 69, no. 2 (2019): 234–48. http://dx.doi.org/10.1093/sysbio/syz061.

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Abstract The dissection of the mode and tempo of phenotypic evolution is integral to our understanding of global biodiversity. Our ability to infer patterns of phenotypes across phylogenetic clades is essential to how we infer the macroevolutionary processes governing those patterns. Many methods are already available for fitting models of phenotypic evolution to data. However, there is currently no comprehensive nonparametric framework for characterizing and comparing patterns of phenotypic evolution. Here, we build on a recently introduced approach for using the phylogenetic spectral density profile (SDP) to compare and characterize patterns of phylogenetic diversification, in order to provide a framework for nonparametric analysis of phylogenetic trait data. We show how to construct the SDP of trait data on a phylogenetic tree from the normalized graph Laplacian. We demonstrate on simulated data the utility of the SDP to successfully cluster phylogenetic trait data into meaningful groups and to characterize the phenotypic patterning within those groups. We furthermore demonstrate how the SDP is a powerful tool for visualizing phenotypic space across traits and for assessing whether distinct trait evolution models are distinguishable on a given empirical phylogeny. We illustrate the approach in two empirical data sets: a comprehensive data set of traits involved in song, plumage, and resource-use in tanagers, and a high-dimensional data set of endocranial landmarks in New World monkeys. Considering the proliferation of morphometric and molecular data collected across the tree of life, we expect this approach will benefit big data analyses requiring a comprehensive and intuitive framework.

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Perrier, Stefanie, Laurence Gauquelin, Catherine Fallet-Bianco, et al. "Expanding the phenotypic and molecular spectrum of RNA polymerase III–related leukodystrophy." Neurology Genetics 6, no. 3 (2020): e425. http://dx.doi.org/10.1212/nxg.0000000000000425.

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ObjectiveTo expand the phenotypic spectrum of severity of POLR3-related leukodystrophy and identify genotype-phenotype correlations through study of patients with extremely severe phenotypes.MethodsWe performed an international cross-sectional study on patients with genetically proven POLR3-related leukodystrophy and atypical phenotypes to identify 6 children, 3 males and 3 females, with an extremely severe phenotype compared with that typically reported. Clinical, radiologic, and molecular features were evaluated for all patients, and functional and neuropathologic studies were performed on 1 patient.ResultsEach patient presented between 1 and 3 months of age with failure to thrive, severe dysphagia, and developmental delay. Four of the 6 children died before age 3 years. MRI of all patients revealed a novel pattern with atypical characteristics, including progressive basal ganglia and thalami abnormalities. Neuropathologic studies revealed patchy areas of decreased myelin in the cerebral hemispheres, cerebellum, brainstem, and spinal cord, with astrocytic gliosis in the white matter and microglial activation. Cellular vacuolization was observed in the thalamus and basal ganglia, and neuronal loss was evident in the putamen and caudate. Genotypic similarities were also present between all 6 patients, with one allele containing a POLR3A variant causing a premature stop codon and the other containing a specific intronic splicing variant (c.1771-7C>G), which produces 2 aberrant transcripts along with some wild-type transcript.ConclusionsWe describe genotype-phenotype correlations at the extreme end of severity of the POLR3-related leukodystrophy spectrum and shed light on the complex disease pathophysiology.

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Priestley, Jessica, Lisa Pace, Nicole Engelhardt, et al. "MALATE DEHYDROGENASE DEFICIENCY: EXPANDING THE PHENOTYPIC SPECTRUM." Molecular Genetics and Metabolism 135, no. 4 (2022): 255. http://dx.doi.org/10.1016/j.ymgme.2022.01.010.

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Groh, Veronika, Helmut Gadner, Thaddeus Radaszkiewicz, et al. "Then Phenotypic Spectrum of Histiocytosis X Cells." Journal of Investigative Dermatology 90, no. 4 (1988): 441–47. http://dx.doi.org/10.1111/1523-1747.ep12460878.

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Delcourt, Marion, Florence Riant, Josette Mancini, et al. "Severe phenotypic spectrum of biallelic mutations inPRRT2gene." Journal of Neurology, Neurosurgery & Psychiatry 86, no. 7 (2015): 782–85. http://dx.doi.org/10.1136/jnnp-2014-309025.

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Chourasia, Nitish, Henry Ossó-Rivera, Ankita Ghosh, Gretchen Von Allmen, and Mary Kay Koenig. "Expanding the Phenotypic Spectrum of CACNA1H Mutations." Pediatric Neurology 93 (April 2019): 50–55. http://dx.doi.org/10.1016/j.pediatrneurol.2018.11.017.

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Adang, Laura A., Amy Pizzino, Alka Malhotra, et al. "Phenotypic and Imaging Spectrum Associated With WDR45." Pediatric Neurology 109 (August 2020): 56–62. http://dx.doi.org/10.1016/j.pediatrneurol.2020.03.005.

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Respondek, G., and G. U. Höglinger. "The phenotypic spectrum of progressive supranuclear palsy." Parkinsonism & Related Disorders 22 (January 2016): S34—S36. http://dx.doi.org/10.1016/j.parkreldis.2015.09.041.

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Caumes, Roseline, Thomas Smol, Caroline Thuillier, et al. "Phenotypic spectrum of SHANK2-related neurodevelopmental disorder." European Journal of Medical Genetics 63, no. 12 (2020): 104072. http://dx.doi.org/10.1016/j.ejmg.2020.104072.

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Reynolds, Claire, Mary D. King, and Kathleen M. Gorman. "The phenotypic spectrum of SCN2A-related epilepsy." European Journal of Paediatric Neurology 24 (January 2020): 117–22. http://dx.doi.org/10.1016/j.ejpn.2019.12.016.

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