Different Phenotypes of the Two Chinese Probands with the Same c.889G>A (p.C162Y) Mutation in COCH Gene Verify Different Mechanisms Underlying Autosomal Dominant Nonsyndromic Deafness 9

Abstract

ObjectivesBy analyzing the different phenotypes of two Chinese DFNA9 families with the same mutation located in the intervening region between the LCCL and vWFA domains of cochlin and testing the functional changes in the mutant cochlin, we investigated the different pathogeneses for mutations in LCCL and vWFA domains.MethodsTargeted next-generation sequencing for deafness-related genes was used to identify the mutation in the proband in family #208. The probands of family #208 and family #32 with the same p.C162Y mutation were followed for more than 3 years to evaluate the progression of hearing loss and vestibular dysfunction using pure-tone audiometry, caloric testing, electrocochleogram, vestibular-evoked myogenic potential, and video head-impulse test. The disruption of normal cleavage to produce secreted LCCL domain fragments and the tendency to form aggregations of mutant cochlins were tested by in vitro cell experiments.ResultsThe two families showed different clinical symptoms. Family #32 was identified as having early-onset, progressive sensorineural hearing loss, similar to the symptoms in DFNA9 patients with cochlin mutations in the vWFA domain. The proband of family #208 endured late-onset recurrent paroxysmal vertigo attacks and progressively deteriorating hearing, similar to symptoms in those with cochlin mutations in the LCCL domain. We therefore suggest that the disrupted cleavage of the LCCL domain fragment is likely to cause vestibular dysfunction, and aggregation of mutant cochlin caused by mutations in the vWFA domain is responsible for early-onset hearing loss. The p.C162Y mutation causes either disruption of LCCL domain fragment cleavage or aggregation of mutant cochlin, resulting in the different phenotypes in the two families.ConclusionThis study demonstrates that DFNA9 families with the same genotype may have significantly different phenotypes. The mutation site in cochlin is related to the pathological mechanism underlying the different phenotypes.

Whole exome sequencing identified a second pathogenic variant in HOMER2 for autosomal dominant non‐syndromic deafness

“…Targeted genomic sequencing including 134 nuclear genes, three miRNA and three mitochondrial genes known to be responsible for NSHL or syndromic hearing loss (Table S1, supporting information), was performed in proband (III‐10), as previously described …”

“…Targeted genomic sequencing including 134 nuclear genes, three miRNA and three mitochondrial genes known to be responsible for NSHL or syndromic hearing loss (Table S1, supporting information), was performed in proband (III-10), as previously described. 23,24 Whole exome capture was performed with the NimbleGen SeqCap EZ Exome 64 Mb V3 (Roche-NimbleGen, Madison, Wisconsin) according to the manufacturer's protocol. The qualified genomic DNA sample was randomly fragmented into 200 to 300 bp.…”

Genotype-Phenotype Correlations of Pathogenic COCH Variants in DFNA9: A HuGE Systematic Review and Audiometric Meta-Analysis

“…After full-text screening, 48 studies met the eligibility criteria and together reported on 27 different COCH variants ( Figure 1 and Figure S1 ). Thirty-seven of these studies were retrospective family studies, describing the (audiovestibular) phenotype of COCH variants [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ]. Eleven of the included studies were not primarily genotype-phenotype studies but validation studies of genetic analyses or histopathological studies [ 9 , 56 , 57 , 58 , 59 , 60 , 61 , 62...…”

“…The number of subjects with other pathogenic variants in COCH , and thus the amount of available phenotypic data, is much smaller. The audiometric evaluations of these subjects are therefore prone to selection bias, especially because inter-and intrafamilial variation is known to occur in DFNA9 [ 23 , 26 , 29 , 35 , 39 , 52 ]. In studies with large numbers of included subjects, as is the case for the p.(Pro51Ser) variant, the influence of selection bias decreases.…”

Evaluation of a new variant in the aggrecan gene potentially associated with chondrodysplastic dwarfism in Miniature horses

“…Since ACAN-D2 was found in heterozygosity in one Mangalarga Marchador horse, despite the small number of sampled animals, we suggest that the potential association between ACAN:c.6465A > T (RefSeq XM_005602799.2-EquCab3.0) and dwarfism in Miniature horses would continue to be relevant; moreover, ACAN:c.6465A > T has provided population, genetic, and informatics prediction evidence that it could be a potential causative variant of dwarfism in this breed 22 . Indeed, a mutation may not always cause the same effects, or it may lead to different phenotypes of the same disorder in different individuals 23,24 . Several genetic modifiers can produce unexpected phenotypes of the primary disease-causing variant 25 , and the genetic background of Miniature horses and Shetland ponies, which were selected for diminutive size over the www.nature.com/scientificreports/ years, differs from horses of large breeds [26][27][28][29] and may generate a predisposition to the condition characterized as dwarfism due to ACAN variants.…”