Predicting pathogenicity for novel hearing loss mutations based on genetic and protein structure approaches.
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ABSTRACT:
SUBMITTER: Buonfiglio PI
PROVIDER: S-EPMC8741999 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Autosomal dominant nonsyndromic hearing loss (ADNSHL) is a common and often progressive sensory deficit. ADNSHL displays a high degree of genetic heterogeneity and varying rates of progression. Accurate, comprehensive, and cost-effective genetic testing facilitates genetic counseling and provides valuable prognostic information to affected individuals. In this article, we describe the algorithm underlying AudioGene, a software system employing machine-learning techniques that utilizes phenotypic information derived from audiograms to predict the genetic cause of hearing loss in persons segregating ADNSHL. Our data show that AudioGene has an accuracy of 68% in predicting the causative gene within its top three predictions, as compared with 44% for a majority classifier. We also show that AudioGene remains effective for audiograms with high levels of clinical measurement noise. We identify audiometric outliers for each genetic locus and hypothesize that outliers may reflect modifying genetic effects. As personalized genomic medicine becomes more common, AudioGene will be increasingly useful as a phenotypic filter to assess pathogenicity of variants identified by massively parallel sequencing.
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Project description: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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Project description:To assist in distinguishing disease-causing mutations from nonpathogenic polymorphisms, we developed an objective algorithm to calculate an "estimate of pathogenic probability" (EPP) based on the prevalence of a specific variation, its segregation within families, and its predicted effects on protein structure. Eleven missense variations in the RPE65 gene were evaluated in patients with Leber congenital amaurosis (LCA) using the EPP algorithm. The accuracy of the EPP algorithm was evaluated using a cell-culture assay of RPE65-isomerase activity The variations were engineered into plasmids containing a human RPE65 cDNA and the retinoid isomerase activity of each variant was determined in cultured cells. The EPP algorithm predicted eight substitution mutations to be disease-causing variants. The isomerase catalytic activities of these RPE65 variants were all less than 6% of wild-type. In contrast, the EPP algorithm predicted the other three substitutions to be non-disease-causing, with isomerase activities of 68%, 127%, and 110% of wild-type, respectively. We observed complete concordance between the predicted pathogenicities of missense variations in the RPE65 gene and retinoid isomerase activities measured in a functional assay. These results suggest that the EPP algorithm may be useful to evaluate the pathogenicity of missense variations in other disease genes where functional assays are not available.
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Project description:BackgroundThe American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) guidelines recommend using variant enrichment among cases as "strong" evidence for pathogenicity per the PS4 criterion. However, quantitative support for PS4 thresholds from real-world Mendelian case-control cohorts is lacking.MethodsTo address this gap, we evaluated and established PS4 thresholds using data from the Chinese Deafness Genetics Consortium. A total of 9,050 variants from 13,845 patients with hearing loss (HL) and 6,570 ancestry-matched controls were analyzed. Positive likelihood ratio and local positive likelihood ratio values were calculated to determine the thresholds corresponding to each strength of evidence across three variant subsets.ResultsIn subset 1, consisting of variants present in both cases and controls with an allele frequency (AF) in cases ≥ 0.0005, an odds ratio (OR) ≥ 6 achieved strong evidence, while OR ≥ 3 represented moderate evidence. For subset 2, which encompassed variants present in both cases and controls with a case AF < 0.0005, and subset 3, comprising variants found only in cases and absent from controls, we defined the PS4_Supporting threshold (OR > 2.27 or allele count ≥ 3) and the PS4_Moderate threshold (allele count ≥ 6), respectively. Reanalysis applying the adjusted PS4 criteria changed the classification of 15 variants and enabled diagnosis of an additional four patients.ConclusionsOur study quantified evidence strength thresholds for variant enrichment in genetic HL cases, highlighting the importance of defining disease/gene-specific thresholds to improve the precision and accuracy of clinical genetic testing.
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Project description:Activating transcription factor 6 (Atf6) is a key regulator of the unfolded protein response (UPR) and is important for endoplasmic reticulum (ER) function and protein homeostasis in metazoan cells. Patients carrying loss-of-function ATF6 disease alleles develop the cone dysfunction disorder, achromatopsia. The impact of loss of ATF6 function on other cell types, organs, and diseases in people remains unclear. Here, we reported that progressive sensorineural hearing loss was a notable complaint in some patients carrying ATF6 disease alleles and that Atf6-/- mice also showed progressive auditory deficits affecting both genders. In mice with hearing deficits, we found disorganized stereocilia on hair cells and focal loss of outer hair cells. Transcriptomic analysis of Atf6-/- cochleae revealed marked induction of UPR, especially through the PERK arm. These findings identify ATF6 as an essential regulator of cochlear health and function. Furthermore, they supported that ATF6 inactivation in people causes progressive sensorineural hearing loss as part of a blindness-deafness genetic syndrome targeting hair cells and cone photoreceptors. Lastly, our genetic findings support ER stress as an important pathomechanism underlying cochlear damage and hearing loss with clinical implications for patient lifestyle modifications that minimize environmental/physiologic sources of ER stress to the ear.
2024-11-19 | GSE242321 | GEO
Project description:Mutations in the CLDN14 gene are known to cause autosomal recessive (AR) non-sydromic hearing loss (NSHL) at the DFNB29 locus on chromosome 21q22.13. As part of an ongoing study to localize and identify NSHL genes, the ARNSHL segregating in four Pakistani consanguineous families were mapped to the 21q22.13 region with either established or suggestive linkage. Given the known involvement of CLDN14 gene in NSHL, DNA samples from hearing-impaired members from the four families were sequenced to potentially identify causal variants within this gene. Three novel CLDN14 mutations, c.167G>A (p.Trp56*), c.242G>A (p.Arg81His), and c.694G>A (p.Gly232Arg), segregate with hearing loss (HL) in three of the families. The previously reported CLDN14 mutation c.254T>A (p.Val85Asp) was observed in the fourth family. None of the mutations were detected in 400 Pakistani control chromosomes and all were deemed damaging based on bioinformatics analyses. The non-sense mutation c.167G>A (p.Trp56*) is the first stop codon mutation in CLDN14 gene to be identified to cause NSHL. The c.242G>A (p.Arg81His) and c.694G>A (p.Gly232Arg) mutations were identified within the first extracellular loop and the carboxyl-tail of claudin-14, respectively, which highlights the importance of the extracellular domains and phosphorylation of cytoplasmic tail residues to claudin function within the inner ear. The HL due to novel CLDN14 mutations is prelingual, severe-to-profound with greater loss in the high frequencies.
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Project description:BackgroundAlthough the mitochondrial DNA (mtDNA) mutations m.1555A > G and m.3243A > G are the primary causes of maternally inherited sensorineural hearing loss (SNHL), several other mtDNA mutations are also reported to be associated with SNHL.MethodsScreening of m.1555A > G and m.3243A > G mutations was performed for 145 probands. Nine probands fulfilled the following criteria: 1) bilateral and symmetric SNHL, 2) ≥ 4 family members with SNHL with a maternal trait of inheritance in ≥ 2 generations, 3) onset of SNHL before the age of 40 years, 4) high-frequency SNHL, and 5) no record of environmental factors related to SNHL. Sequencing of additional mtDNA regions was performed for five subjects meeting the clinical criteria, but the screening results were negative.ResultsAmong the nine cases meeting the five clinical criteria detailed above, three had the m.1555A > G mutation in MTRNR1, one had a m.3243A > G mutation in MTTL1, and one case had a m.7511T > C mutation in MTTS1. In the family with the m.7511T > C mutation, penetrance of SNHL among maternally related subjects was 9/17 (53%). The age at onset varied from birth (congenital) to adulthood. Hearing levels varied from normal to moderately impaired, unlike previously reported subjects with this mutation, where some maternal family members presented with profound SNHL. Family members with the m.7511T > C mutation and SNHL did not exhibit any specific clinical characteristics distinct from those of other individuals with SNHL and different mtDNA mutations. Among the 136 probands who did not meet the criteria detailed above, one case had the m.1555A > G mutation, and three cases had the m.3243A > G mutation.ConclusionsSince five of nine probands with the clinical criteria used in this study had mtDNA mutations, these criteria may be helpful for identification of candidate patients likely to have mtDNA mutations.
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Project description:BackgroundHearing loss is the most common sensory disorder worldwide, affecting about 1 out of every 1000 newborns. The disease has major genetic components, and can be inherited as a single gene disorder either in autosomal dominant or recessive fashions. Due to the high rate of consanguineous unions, Iran has one of the highest prevalence of autosomal recessive nonsyndromic deafness (ARNSD) in the world.MethodsWe carried out a genetic screening of ten Iranian kindreds with more than one offspring affected by ARNSD caused by consanguineous unions. Sanger sequencing and whole exome sequencing together with in silico 3D structure modeling and protein stability prediction were used to identify the underlying disease causing genes.ConclusionWe identified the causes of deafness in all 10 kindred. In six kindreds homozygous mutations were identified in GJB2 gene by Sanger sequencing. By using whole exome sequencing (WES), a homozygous missense mutation was identified in ESRRB gene as the first ever reported disease gene in Iran. Also two novel homozygous frameshift and missense mutations were identified in MYO15A gene and one previously reported mutation in TMC1 gene in three independent kindred. Our study shows the efficacy of WES for unraveling new pathogenic mutations in ARNSD patients and expands the spectrum of genes contributing to ARNSD in the Iranian population. The findings of our study can facilitate future genetic screening of patients with ARNSD , early screening and optimal design of novel therapeutics.
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Project description:Autosomal recessive non-syndromic hearing loss (ARNSHL) is a highly heterogeneous genetic condition. PDZD7 has emerged as a new genetic etiology of ARNSHL. Biallelic mutations in the PDZD7 gene have been reported in two German families, four Iranian families, and a Pakistani family with ARNSHL. The effect of PDZD7 on ARNSHL in other population has yet to be elucidated. Two Chinese ARNSHL families, each of which had two affected siblings, were included in this study. The families underwent target region capture and high-throughput sequencing to analyze the exonic, splice-site, and intronic sequences of 128 genes. Furthermore, 1751 normal Chinese individuals served as controls, and 122 Chinese families segregating with apparent ARNSHL, who had been previously excluded for variants in the common deafness genes GJB2 and SLC26A4, were subjected to screening for candidate mutations. We identified a novel homozygous missense mutation (p.Arg66Leu) and novel compound heterozygous frameshift mutations (p.Arg56fsTer24 and p.His403fsTer36) in Chinese families with ARNSHL. This is the first report to identify PDZD7 as an ARNSHL-associated gene in the Chinese population. Our finding could expand the pathogenic spectrum and strengthens the clinical diagnostic role of the PDZD7 gene in ARNSHL patients.
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