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Hearing loss (HL) is the most prevalent sensorineural disorders, affecting about one in 1000 newborns. Over half of the cases are attributed to genetic factors; however, due to the extensive clinical and genetic heterogeneity, many cases remain without a conclusive genetic diagnosis. The advent of next-generation sequencing methodologies in recent years has greatly helped unravel the genetic etiology of HL by identifying numerous genes and causative variants. Despite this, much remains to be uncovered about the genetic basis of sensorineural hearing loss (SNHL). Here, we report an Iranian consanguineous family with postlingual, moderate-to-severe autosomal recessive SNHL. After first excluding plausible variants in known deafness-causing genes using whole exome sequencing, we reanalyzed the data, using a gene/variant prioritization pipeline established for novel gene discovery for HL. This approach identified a novel homozygous frameshift variant c.1934_1937del; (p.Thr645Lysfs*52) in ANKRD24, which segregated with the HL phenotype in the family. Recently, ANKRD24 has been shown to be a pivotal constituent of the stereocilia rootlet in cochlea hair cells and interacts with TRIOBP, a protein already implicated in human deafness. Our data implicate for the first time, ANKRD24 in human nonsyndromic HL (NSHL) and expands the genetic spectrum of HL.
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A 6-yr-old female orangutan presented with a history of dark urine that turned brown upon standing since birth. Repeated routine urinalysis and urine culture were unremarkable. Urine organic acid analysis showed elevation in homogentisic acid consistent with alkaptonuria. Sequence analysis identified a homozygous missense variant, c.1081G>A (p.Gly361Arg), of the homogentisate 1,2-dioxygenase (HGD) gene. Familial studies, molecular modeling, and comparison to human variant databases support this variant as the underlying cause of alkaptonuria in this orangutan. This is the first report of molecular confirmation of alkaptonuria in a nonhuman primate.
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Alcaptonúria , Pongo abelii , Animais , Humanos , Feminino , Alcaptonúria/diagnóstico , Alcaptonúria/genética , Pongo abelii/genética , Ácido Homogentísico , Mutação de Sentido Incorreto , HomozigotoRESUMO
BACKGROUND: It is well established that biallelic mutations in transmembrane protease, serine 3 (TMPRSS3) cause hearing loss. Currently, there is controversy regarding the audiological outcomes after cochlear implantation (CI) for TMPRSS3-associated hearing loss. This controversy creates confusion among healthcare providers regarding the best treatment options for individuals with TMPRSS3-related hearing loss. METHODS: A literature review was performed to identify all published cases of patients with TMPRSS3-associated hearing loss who received a CI. CI outcomes of this cohort were compared with published adult CI cohorts using postoperative consonant-nucleus-consonant (CNC) word performance. TMPRSS3 expression in mouse cochlea and human auditory nerves (HAN) was determined by using hybridisation chain reaction and single-cell RNA-sequencing analysis. RESULTS: In aggregate, 27 patients (30 total CI ears) with TMPRSS3-associated hearing loss treated with CI, and 85% of patients reported favourable outcomes. Postoperative CNC word scores in patients with TMPRSS3-associated hearing loss were not significantly different than those seen in adult CI cohorts (8 studies). Robust Tmprss3 expression occurs throughout the mouse organ of Corti, the spindle and root cells of the lateral wall and faint staining within <5% of the HAN, representing type II spiral ganglion neurons. Adult HAN express negligible levels of TMPRSS3. CONCLUSION: The clinical features after CI and physiological expression of TMPRSS3 suggest against a major role of TMPRSS3 in auditory neurons.
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Implante Coclear , Surdez , Perda Auditiva , Adulto , Humanos , Camundongos , Animais , Gânglio Espiral da Cóclea/metabolismo , Serina Endopeptidases/genética , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Surdez/genética , Perda Auditiva/genética , Neurônios/metabolismoRESUMO
Hearing loss and peripheral neuropathy are two clinical entities that are genetically and phenotypically heterogeneous and sometimes co-occurring. Using exome sequencing and targeted segregation analysis, we investigated the genetic etiology of peripheral neuropathy and hearing loss in a large Ashkenazi Jewish family. Moreover, we assessed the production of the candidate protein via western blotting of lysates from fibroblasts from an affected individual and an unaffected control. Pathogenic variants in known disease genes associated with hearing loss and peripheral neuropathy were excluded. A homozygous frameshift variant in the BICD1 gene, c.1683dup (p.(Arg562Thrfs*18)), was identified in the proband and segregated with hearing loss and peripheral neuropathy in the family. The BIDC1 RNA analysis from patient fibroblasts showed a modest reduction in gene transcripts compared to the controls. In contrast, protein could not be detected in fibroblasts from a homozygous c.1683dup individual, whereas BICD1 was detected in an unaffected individual. Our findings indicate that bi-allelic loss-of-function variants in BICD1 are associated with hearing loss and peripheral neuropathy. Definitive evidence that bi-allelic loss-of-function variants in BICD1 cause peripheral neuropathy and hearing loss will require the identification of other families and individuals with similar variants with the same phenotype.
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Surdez , Perda Auditiva , Doenças do Sistema Nervoso Periférico , Humanos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas do Citoesqueleto/genética , Surdez/genética , Perda Auditiva/genética , Linhagem , Doenças do Sistema Nervoso Periférico/genética , FenótipoRESUMO
Hearing loss (HL) is an etiologically heterogeneous disorder that affects around 5% of the world's population. There has been an exponential increase in the identification of genes and variants responsible for hereditary HL over recent years. Iran, a country located in the Middle East, has a high prevalence of consanguineous marriages, so heterogeneous diseases such as HL are more common. Comprehensive studies using different strategies from linkage analysis to next-generation sequencing, especially exome-sequencing, have achieved significant success in identifying possible pathogens in deaf Iranian families. About 12% of non-syndromic autosomal recessive HL genes investigated to date, were first identified in families from Iran. Variations of 56 genes have been observed in families with NSHL in Iran. Variants in GJB2, SLC26A4, MYO15A, MYO7A, CDH23, and TMC1 account for 16.5%, 16.25%, 13.5%, 9.35%, 6.9% and 4.92%, cases of NSHL, respectively. In summary, there are also different diagnostic rates between studies conducted in Iran. In the comprehensive investigations conducted by the Genetic Research Center of the University of Social Welfare and Rehabilitation Sciences over the past 20 years, the overall diagnosis rate is about 80% while there are other studies with lower diagnostic rates which could reflect differences in project designs, sampling, and accuracy and validity of the methods used. Furthermore, there are several syndromic HHLs in Iran including, Waardenburg syndrome, BOR syndrome, Brown-Vialetto-Van Laere syndrome, Wolfram syndrome, among which Pendred and Usher syndromes are well-studied. These results are of importance for further investigation and elucidation of the molecular basis of HHL in Iran.
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Surdez , Perda Auditiva Neurossensorial , Perda Auditiva , Surdez/genética , Perda Auditiva/genética , Perda Auditiva Neurossensorial/genética , Humanos , Irã (Geográfico)/epidemiologia , Mutação , LinhagemRESUMO
Numerous computational prediction tools have been introduced to estimate the functional impact of variants in the human genome based on evolutionary constraints and biochemical metrics. However, their implementation in diagnostic settings to classify variants faced challenges with accuracy and validity. Most existing tools are pan-genome and pan-diseases, which neglected gene- and disease-specific properties and limited the accessibility of curated data. As a proof-of-concept, we developed a disease-specific prediction tool named Deafness Variant deleteriousness Prediction tool (DVPred) that focused on the 157 genes reportedly causing genetic hearing loss (HL). DVPred applied the gradient boosting decision tree (GBDT) algorithm to the dataset consisting of expert-curated pathogenic and benign variants from a large in-house HL patient cohort and public databases. With the incorporation of variant-level and gene-level features, DVPred outperformed the existing universal tools. It boasts an area under the curve (AUC) of 0.98, and showed consistent performance (AUC = 0.985) in an independent assessment dataset. We further demonstrated that multiple gene-level metrics, including low complexity genomic regions and substitution intolerance scores, were the top features of the model. A comprehensive analysis of missense variants showed a gene-specific ratio of predicted deleterious and neutral variants, implying varied tolerance or intolerance to variation in different genes. DVPred explored the utility of disease-specific strategy in improving the deafness variant prediction tool. It can improve the prioritization of pathogenic variants among massive variants identified by high-throughput sequencing on HL genes. It also shed light on the development of variant prediction tools for other genetic disorders.
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Surdez , Perda Auditiva , Genômica , Perda Auditiva/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , VirulênciaRESUMO
Bi-allelic variants in COLEC11 and MASP1 have been associated with 3MC syndrome, a clinical entity made of up four rare autosomal recessive disorders: Carnevale, Mingarelli, Malpuech, and Michels syndromes, characterized by variable expression of facial dysmorphia, cleft lip/palate, postnatal growth deficiency, hearing loss, cognitive impairment, craniosynostosis, radioulnar synostosis, and genital and vesicorenal anomalies. More recently, bi-allelic variants in COLEC10 have been described to be associated with 3MC syndrome. Syndromic features seen in 3MC syndrome are thought to be due to disruption of the chemoattractant properties that influence neural crest cell migration. We identified nine individuals from five families of Ashkenazi Jewish descent with homozygosity of the c.311G > T (p.Gly104Val) variant in COLEC10 and phenotype consistent with 3MC syndrome. Carrier frequency was calculated among 52,278 individuals of Jewish descent. Testing revealed 400 carriers out of 39,750 individuals of Ashkenazi Jewish descent, giving a carrier frequency of 1 in 99 or 1.01%. Molecular protein modeling suggested that the p.Gly104Val substitution alters local conformation. The c.311G > T (p.Gly104Val) variant likely represents a founder variant, and homozygosity is associated with features of 3MC syndrome. 3MC syndrome should be in the differential diagnosis for individuals with short stature, radioulnar synostosis, cleft lip and cleft palate.
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Anormalidades Múltiplas , Fenda Labial , Fissura Palatina , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Fenda Labial/diagnóstico , Fenda Labial/genética , Fissura Palatina/diagnóstico , Fissura Palatina/genética , Colectinas/genética , Humanos , Judeus/genética , Mutação , Fenótipo , Rádio (Anatomia)/anormalidades , Sinostose , Ulna/anormalidadesRESUMO
Deafness, the most frequent sensory deficit in humans, is extremely heterogeneous with hundreds of genes involved. Clinical and genetic analyses of an extended consanguineous family with pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identify CLRN2, encoding a tetraspan protein, as a new deafness gene. Homozygosity mapping followed by exome sequencing identified a 14.96 Mb locus on chromosome 4p15.32p15.1 containing a likely pathogenic missense variant in CLRN2 (c.494C > A, NM_001079827.2) segregating with the disease. Using in vitro RNA splicing analysis, we show that the CLRN2 c.494C > A variant leads to two events: (1) the substitution of a highly conserved threonine (uncharged amino acid) to lysine (charged amino acid) at position 165, p.(Thr165Lys), and (2) aberrant splicing, with the retention of intron 2 resulting in a stop codon after 26 additional amino acids, p.(Gly146Lysfs*26). Expression studies and phenotyping of newly produced zebrafish and mouse models deficient for clarin 2 further confirm that clarin 2, expressed in the inner ear hair cells, is essential for normal organization and maintenance of the auditory hair bundles, and for hearing function. Together, our findings identify CLRN2 as a new deafness gene, which will impact future diagnosis and treatment for deaf patients.
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Substituição de Aminoácidos , Cromossomos Humanos Par 4/química , Células Ciliadas Auditivas Internas/metabolismo , Perda Auditiva Neurossensorial/genética , Proteínas de Membrana/genética , Mutação Puntual , Tetraspaninas/genética , Adulto , Alelos , Animais , Sequência de Bases , Mapeamento Cromossômico , Consanguinidade , Feminino , Expressão Gênica , Genes Recessivos , Células Ciliadas Auditivas Internas/patologia , Perda Auditiva Neurossensorial/metabolismo , Perda Auditiva Neurossensorial/patologia , Humanos , Masculino , Proteínas de Membrana/deficiência , Camundongos , Linhagem , Tetraspaninas/deficiência , Sequenciamento do Exoma , Peixe-ZebraRESUMO
The classification of genetic variants represents a major challenge in the post-genome era by virtue of their extraordinary number and the complexities associated with ascribing a clinical impact, especially for disorders exhibiting exceptional phenotypic, genetic, and allelic heterogeneity. To address this challenge for hearing loss, we have developed the Deafness Variation Database (DVD), a comprehensive, open-access resource that integrates all available genetic, genomic, and clinical data together with expert curation to generate a single classification for each variant in 152 genes implicated in syndromic and non-syndromic deafness. We evaluate 876,139 variants and classify them as pathogenic or likely pathogenic (more than 8,100 variants), benign or likely benign (more than 172,000 variants), or of uncertain significance (more than 695,000 variants); 1,270 variants are re-categorized based on expert curation and in 300 instances, the change is of medical significance and impacts clinical care. We show that more than 96% of coding variants are rare and novel and that pathogenicity is driven by minor allele frequency thresholds, variant effect, and protein domain. The mutational landscape we define shows complex gene-specific variability, making an understanding of these nuances foundational for improved accuracy in variant interpretation in order to enhance clinical decision making and improve our understanding of deafness biology.
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Surdez/genética , Mutação/genética , Bases de Dados Genéticas , Frequência do Gene/genética , Genômica/métodos , Perda Auditiva/genética , HumanosRESUMO
PURPOSE: The ClinGen Variant Curation Expert Panels (VCEPs) provide disease-specific rules for accurate variant interpretation. Using the hearing loss-specific American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, the Hearing Loss VCEP (HL VCEP) illustrates the utility of expert specifications in variant interpretation. METHODS: A total of 157 variants across nine HL genes, previously submitted to ClinVar, were curated by the HL VCEP. The curation process involved collecting published and unpublished data for each variant by biocurators, followed by bimonthly meetings of an expert curation subgroup that reviewed all evidence and applied the HL-specific ACMG/AMP guidelines to reach a final classification. RESULTS: Before expert curation, 75% (117/157) of variants had single or multiple variants of uncertain significance (VUS) submissions (17/157) or had conflicting interpretations in ClinVar (100/157). After applying the HL-specific ACMG/AMP guidelines, 24% (4/17) of VUS and 69% (69/100) of discordant variants were resolved into benign (B), likely benign (LB), likely pathogenic (LP), or pathogenic (P). Overall, 70% (109/157) variants had unambiguous classifications (B, LB, LP, P). We quantify the contribution of the HL-specified ACMG/AMP codes to variant classification. CONCLUSION: Expert specification and application of the HL-specific ACMG/AMP guidelines effectively resolved discordant interpretations in ClinVar. This study highlights the utility of ClinGen VCEPs in supporting more consistent clinical variant interpretation.
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Genoma Humano , Perda Auditiva , Humanos , Testes Genéticos , Variação Genética/genética , Perda Auditiva/diagnóstico , Perda Auditiva/genéticaRESUMO
Hearing loss (HL) is one of the most common sensory defects affecting more than 466 million individuals worldwide. It is clinically and genetically heterogeneous with over 120 genes causing non-syndromic HL identified to date. Here, we performed exome sequencing (ES) on a cohort of Iranian families with no disease-causing variants in known deafness-associated genes after screening with a targeted gene panel. We identified likely causal variants in 20 out of 71 families screened. Fifteen families segregated variants in known deafness-associated genes. Eight families segregated variants in novel candidate genes for HL: DBH, TOP3A, COX18, USP31, TCF19, SCP2, TENM1, and CARMIL1. In the three of these families, intrafamilial locus heterogeneity was observed with variants in both known and novel candidate genes. In aggregate, we were able to identify the underlying genetic cause of HL in nearly 30% of our study cohort using ES. This study corroborates the observation that high-throughput DNA sequencing in populations with high rates of consanguineous marriages represents a more appropriate strategy to elucidate the genetic etiology of heterogeneous conditions such as HL.
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Exoma/genética , Predisposição Genética para Doença/genética , Perda Auditiva/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Sequenciamento do Exoma/métodos , Adulto JovemRESUMO
The Cell Division-Cycle-14 gene encodes a dual-specificity phosphatase necessary in yeast for exit from mitosis. Numerous disparate roles of vertebrate Cell Division-Cycle-14 (CDC14A) have been proposed largely based on studies of cultured cancer cells in vitro. The in vivo functions of vertebrate CDC14A are largely unknown. We generated and analyzed mutations of zebrafish and mouse CDC14A, developed a computational structural model of human CDC14A protein and report four novel truncating and three missense alleles of CDC14A in human families segregating progressive, moderate-to-profound deafness. In five of these families segregating pathogenic variants of CDC14A, deaf males are infertile, while deaf females are fertile. Several recessive mutations of mouse Cdc14a, including a CRISPR/Cas9-edited phosphatase-dead p.C278S substitution, result in substantial perinatal lethality, but survivors recapitulate the human phenotype of deafness and male infertility. CDC14A protein localizes to inner ear hair cell kinocilia, basal bodies and sound-transducing stereocilia. Auditory hair cells of postnatal Cdc14a mutants develop normally, but subsequently degenerate causing deafness. Kinocilia of germ-line mutants of mouse and zebrafish have normal lengths, which does not recapitulate the published cdc14aa knockdown morphant phenotype of short kinocilia. In mutant male mice, degeneration of seminiferous tubules and spermiation defects result in low sperm count, and abnormal sperm motility and morphology. These findings for the first time define a new monogenic syndrome of deafness and male infertility revealing an absolute requirement in vivo of vertebrate CDC14A phosphatase activity for hearing and male fertility.
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Perda Auditiva/genética , Infertilidade Masculina/genética , Monoéster Fosfórico Hidrolases/genética , Proteínas Tirosina Fosfatases/genética , Animais , Sistemas CRISPR-Cas , Feminino , Estudos de Associação Genética , Perda Auditiva/fisiopatologia , Humanos , Masculino , Camundongos Mutantes , Linhagem , Monoéster Fosfórico Hidrolases/química , Proteínas Tirosina Fosfatases/metabolismo , Testículo/fisiopatologia , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
COCH is the most abundantly expressed gene in the cochlea. Unsurprisingly, mutations in COCH underly hearing loss in mice and humans. Two forms of hearing loss are linked to mutations in COCH, the well-established autosomal dominant nonsyndromic hearing loss, with or without vestibular dysfunction (DFNA9) via a gain-of-function/dominant-negative mechanism, and more recently autosomal recessive nonsyndromic hearing loss (DFNB110) via nonsense variants. Using a combination of targeted gene panels, exome sequencing, and functional studies, we identified four novel pathogenic variants (two nonsense variants, one missense, and one inframe deletion) in COCH as the cause of autosomal recessive hearing loss in a multi-ethnic cohort. To investigate whether the non-truncating variants exert their effect via a loss-of-function mechanism, we used minigene splicing assays. Our data showed both the missense and inframe deletion variants altered RNA splicing by creating an exon splicing silencer and abolishing an exon splicing enhancer, respectively. Both variants create frameshifts and are predicted to result in a null allele. This study confirms the involvement of loss-of-function mutations in COCH in autosomal recessive nonsyndromic hearing loss, expands the mutational landscape of DFNB110 to include coding variants that alter RNA splicing, and highlights the need to investigate the effect of coding variants on RNA splicing.
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Surdez/genética , Proteínas da Matriz Extracelular/genética , Genes Recessivos/genética , Mutação com Perda de Função/genética , Adolescente , Adulto , Criança , Pré-Escolar , Cóclea/metabolismo , Cóclea/patologia , Códon sem Sentido/genética , Surdez/patologia , Éxons/genética , Feminino , Mutação da Fase de Leitura/genética , Humanos , Masculino , LinhagemRESUMO
We present detailed comparative analyses to assess population-level differences in patterns of genetic deafness between European/American and Japanese cohorts with non-syndromic hearing loss. One thousand eighty-three audiometric test results (921 European/American and 162 Japanese) from members of 168 families (48 European/American and 120 Japanese) with non-syndromic hearing loss secondary to pathogenic variants in one of three genes (KCNQ4, TECTA, WFS1) were studied. Audioprofile characteristics, specific mutation types, and protein domains were considered in the comparative analyses. Our findings support differences in audioprofiles driven by both mutation type (non-truncating vs. truncating) and ethnic background. The former finding confirms data that ascribe a phenotypic consequence to different mutation types in KCNQ4; the latter finding suggests that there are ethnic-specific effects (genetic and/or environmental) that impact gene-specific audioprofiles for TECTA and WFS1. Identifying the drivers of ethnic differences will refine our understanding of phenotype-genotype relationships and the biology of hearing and deafness.
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Proteínas da Matriz Extracelular/genética , Genótipo , Perda Auditiva Neurossensorial/genética , Canais de Potássio KCNQ/genética , Proteínas de Membrana/genética , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Audiometria , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Proteínas Ligadas por GPI/genética , Expressão Gênica , Estudos de Associação Genética , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/etnologia , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Lactente , Recém-Nascido , Japão , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Estados Unidos , População BrancaRESUMO
Mutations in the CDC14A (Cell Division-Cycle 14A) gene, which encodes a conserved dual-specificity protein tyrosine phosphatase, have been identified as a cause of autosomal recessive non-syndromic hearing loss (DFNB32) and hearing impairment infertility male syndrome (HIIMS). We used next-generation sequencing to screen six deaf probands from six families segregating sensorineural moderate-to-profound hearing loss. Data analysis and variant prioritization were completed using a custom bioinformatics pipeline. We identified three homozygous loss of function variants (p.Arg345Ter, p.Arg376Ter, and p.Ala451Thrfs*43) in the CDC14A gene, segregating with deafness in each family. Of the six families, four segregated the p.Arg376Ter mutation, one family segregated the p.Arg345Ter mutation and one family segregated a novel frameshift (p.Ala451Thrfs*43) mutation. In-depth phenotyping of affected individuals ruled out secondary syndromic findings. This study implicates the p.Arg376Ter mutation might be as a founder mutation in the Iranian population. It also provides the first semen analysis for deaf males carrying mutations in exon 11 of CDC14A and reveals a genotype-phenotype correlation that delineates between DFNB32 and HIIMS. The clinical results from affected males suggest the NM_033313.2 transcript alone is sufficient for proper male fertility, but not for proper auditory function. We conclude that DFNB32 is a distinct phenotypic entity in males.
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Perda Auditiva Neurossensorial/genética , Perda Auditiva/genética , Infertilidade Masculina/genética , Proteínas Tirosina Fosfatases/genética , Adolescente , Adulto , Diagnóstico Diferencial , Éxons/genética , Feminino , Mutação da Fase de Leitura/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Perda Auditiva/complicações , Perda Auditiva/diagnóstico , Perda Auditiva/patologia , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Infertilidade Masculina/complicações , Infertilidade Masculina/diagnóstico , Infertilidade Masculina/patologia , Irã (Geográfico) , Masculino , Linhagem , Adulto JovemRESUMO
Deafness due to mutations in the DFNA5 gene is caused by the aberrant splicing of exon 8, which results in a constitutively active truncated protein. In a large family of European descent (MORL-ADF1) segregating autosomal dominant nonsyndromic hearing loss, we used the OtoSCOPE platform to identify the genetic cause of deafness. After variant filtering and prioritization, the only remaining variant that segregated with the hearing loss in the family was the previously described c.991-15_991-13delTTC mutation in DFNA5. This 3-base pair deletion in the polypyrimidine of intron 7 is a founder mutation in the East Asian population. Using ethnicity-informative markers and haplotype reconstruction within the DFNA5 gene, we confirmed family MORL-ADF1 is of European ancestry, and that the c.991-15_991-13delTTC mutation arose on a unique haplotype, as compared to that of East Asian families segregating this mutation. In-depth audiometric analysis showed no statistical difference between the audiometric profile of family MORL-ADF1 and the East Asian families. Our data suggest the polypyrimidine tract in intron 7 may be a hotspot for mutations.
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Efeito Fundador , Perda Auditiva Neurossensorial/genética , Mutação , Receptores de Estrogênio/genética , Audiometria , Éxons , Feminino , Deleção de Genes , Haplótipos , Humanos , Íntrons , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único , Pirimidinas/metabolismo , Splicing de RNARESUMO
PURPOSE: The aim of this study was to determine the genetic cause of autosomal dominant nonsyndromic hearing loss segregating in a multigenerational family. METHODS: Clinical examination, genome-wide linkage analysis, and exome sequencing were carried out on the family. RESULTS: Affected individuals presented with early-onset progressive mild hearing impairment with a fairly flat, gently downsloping or U-shaped audiogram configuration. Detailed clinical examination excluded any additional symptoms. Linkage analysis detected an interval on chromosome 1p21 with a logarithm of the odds (LOD) score of 8.29: designated locus DFNA37. Exome sequencing identified a novel canonical acceptor splice-site variant c.652-2A>C in the COL11A1 gene within the DFNA37 locus. Genotyping of all 48 family members confirmed segregation of this variant with the deafness phenotype in the extended family. The c.652-2A>C variant is novel, highly conserved, and confirmed in vitro to alter RNA splicing. CONCLUSION: We have identified COL11A1 as the gene responsible for deafness at the DFNA37 locus. Previously, COL11A1 was solely associated with Marshall and Stickler syndromes. This study expands its phenotypic spectrum to include nonsyndromic deafness. The implications of this discovery are valuable in the clinical diagnosis, prognosis, and treatment of patients with COL11A1 pathogenic variants.
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Colágeno Tipo XI/genética , Surdez/genética , Ligação Genética , Isoformas de Proteínas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Surdez/fisiopatologia , Exoma/genética , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Fenótipo , Sequenciamento do Exoma , Adulto JovemRESUMO
PURPOSE: Proper interpretation of genomic variants is critical to successful medical decision making based on genetic testing results. A fundamental prerequisite to accurate variant interpretation is the clear understanding of the clinical validity of gene-disease relationships. The Clinical Genome Resource (ClinGen) has developed a semiquantitative framework to assign clinical validity to gene-disease relationships. METHODS: The ClinGen Hearing Loss Gene Curation Expert Panel (HL GCEP) uses this framework to perform evidence-based curations of genes present on testing panels from 17 clinical laboratories in the Genetic Testing Registry. The HL GCEP curated and reviewed 142 genes and 164 gene-disease pairs, including 105 nonsyndromic and 59 syndromic forms of hearing loss. RESULTS: The final outcome included 82 Definitive (50%), 12 Strong (7%), 25 Moderate (15%), 32 Limited (20%), 10 Disputed (6%), and 3 Refuted (2%) classifications. The summary of each curation is date stamped with the HL GCEP approval, is live, and will be kept up-to-date on the ClinGen website ( https://search.clinicalgenome.org/kb/gene-validity ). CONCLUSION: This gene curation approach serves to optimize the clinical sensitivity of genetic testing while reducing the rate of uncertain or ambiguous test results caused by the interrogation of genes with insufficient evidence of a disease link.
Assuntos
Surdez/genética , Testes Genéticos/métodos , Perda Auditiva/genética , Curadoria de Dados/métodos , Bases de Dados Genéticas , Testes Genéticos/normas , Variação Genética , Genoma Humano , Genômica/métodos , Humanos , Mutação , Reprodutibilidade dos TestesRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.