Molecular screening of patients with nonsyndromic hearing loss from Nanjing city of China

Hearing loss is the most frequent sensory disorder involving a multitude of factors,and at least 50% of cases are due to genetic etiology.To further characterize the molecular etiology of hearing loss in the Chinese population,we recruited a total of 135 unrelated patients with nonsyndromic sensorineural hearing loss (NSHL) for mutational screening of GJB2,GJB3,GJB6,SLC26A4,SLC26A5 IVS2-2A>G and mitochondrial 12SrRNA,tRNA Ser(UCN) by PCR amplification and direct DNA sequencing.The carrier frequencies of deafness-causing mutations in these patients were 35.55% in GJB2,3.70% in GJB6,15.56% in SLC26A4 and 8.14% in mitochondrial 12SrRNA,respectively.The results indicate the necessity of genetic screening for mutations of these causative genes in Chinese population with nonsyndromic hearing loss.     

Recurrent variants in OTOF are significant contributors to prelingual nonsydromic hearing loss in Saudi patients

PurposeHearing loss is more prevalent in the Saudi Arabian population than in other populations; however, the full range of genetic etiologies in this population is unknown. We report the genetic findings from 33 Saudi hearing-loss probands of tribal ancestry, with predominantly prelingual severe to profound hearing loss.MethodsTesting was performed over the course of 2012–2016, and involved initial GJB2 sequence and GJB6-D13S1830 deletion screening, with negative cases being reflexed to a next-generation sequencing panel with 70, 71, or 87 hearing-loss genes.ResultsA “positive” result was reached in 63% of probands, with two recurrent OTOF variants (p.Glu57* and p.Arg1792His) accountable for a third of all “positive” cases. The next most common cause was pathogenic variants in MYO7A and SLC26A4, each responsible for three “positive” cases. Interestingly, only one “positive” diagnosis had a DFNB1-related cause, due to a homozygous GJB6-D13S1830 deletion, and no sequence variants in GJB2 were detected.ConclusionOur findings implicate OTOF as a potential major contributor to hearing loss in the Saudi population, while highlighting the low contribution of GJB2, thus offering important considerations for clinical testing strategies for Saudi patients. Further screening of Saudi patients is needed to characterize the genetic spectrum in this population.     

Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss

Consanguineous Pakistani pedigrees segregating deafness have contributed decisively to the discovery of 31 of the 68 genes associated with nonsyndromic autosomal recessive hearing loss (HL) worldwide. In this study, we utilized genome‐wide genotyping, Sanger and exome sequencing to identify 163 DNA variants in 41 previously reported HL genes segregating in 321 Pakistani families. Of these, 70 (42.9%) variants identified in 29 genes are novel. As expected from genetic studies of disorders segregating in consanguineous families, the majority of affected individuals (94.4%) are homozygous for HL‐associated variants, with the other variants being compound heterozygotes. The five most common HL genes in the Pakistani population are SLC26A4, MYO7A, GJB2, CIB2 and HGF, respectively. Our study provides a profile of the genetic etiology of HL in Pakistani families, which will allow for the development of more efficient genetic diagnostic tools, aid in accurate genetic counseling, and guide application of future gene‐based therapies. These findings are also valuable in interpreting pathogenicity of variants that are potentially associated with HL in individuals of all ancestries. The Pakistani population, and its infrastructure for studying human genetics, will continue to be valuable to gene discovery for HL and other inherited disorders.     

Comprehensive analysis via exome sequencing uncovers genetic etiology in autosomal recessive nonsyndromic deafness in a large multiethnic cohort

PurposeAutosomal recessive nonsyndromic deafness (ARNSD) is characterized by a high degree of genetic heterogeneity, with reported mutations in 58 different genes. This study was designed to detect deafness-causing variants in a multiethnic cohort with ARNSD by using whole-exome sequencing (WES).MethodsAfter excluding mutations in the most common gene, GJB2, we performed WES in 160 multiplex families with ARNSD from Turkey, Iran, Mexico, Ecuador, and Puerto Rico to screen for mutations in all known ARNSD genes.ResultsWe detected ARNSD-causing variants in 90 (56%) families, 54% of which had not been previously reported. Identified mutations were located in 31 known ARNSD genes. The most common genes with mutations were MYO15A (13%), MYO7A (11%), SLC26A4 (10%), TMPRSS3 (9%), TMC1 (8%), ILDR1 (6%), and CDH23 (4%). Nine mutations were detected in multiple families with shared haplotypes, suggesting founder effects.ConclusionWe report on a large multiethnic cohort with ARNSD in which comprehensive analysis of all known ARNSD genes identifies causative DNA variants in 56% of the families. In the remaining families, WES allows us to search for causative variants in novel genes, thus improving our ability to explain the underlying etiology in more families.     

Is it time to report carrier state for recessive disorders in every microarray analysis?—A pilot model based on hearing loss genes deletions

This study aimed to examine the implications of reporting heterozygous losses of recessive genes in Chromosomal Microarray Analysis (CMA), based on the incidence of microdeletions of three common hearing impairment genes in the local cohort and the prevalence of sequence variants in these genes in worldwide databases. Prevalence of heterozygous microdeletions in OTOA and STRC genes, as well as deletions in the DFNB1 locus encompassing GJB6 gene, was determined using electronic database of Rabin Medical Center. ClinVar archive and Deafness Variation Database were used to generate a list of clinically significant sequence variants in these three genes, as well as GJB2 gene, and estimation of the frequency of sequence variants was performed. Of the 19,189 CMA tests were performed in our laboratory, 107 STRC microdeletions were found (0.56%), followed in frequency by OTOA deletions (39, 0.2%), and DFNB1 locus deletions (10, 0.05%). The estimated risk for a hearing loss in the examined individual carrying the microdeletion was estimated as 0.11–0.67% for STRC, 0.016–0.13% for OTOA, and 1.9–7.5% in the DFNB1 locus (including double heterozygocity with GJB2 clinically significant sequence variants). The risks were higher in specific populations. In conclusion, we believe that that general decision whether to report or to disregard such incidental findings cannot be part of a uniform policy, but rather based on a detailed evaluation of origin-specific variants for each gene, with a careful consideration and discussion whether to include the microdeletion in the final report for each patient.Subject terms: Health policy, Epidemiology     

Targeted next-generation sequencing of deafness genes in hearing-impaired individuals uncovers informative mutations

PurposeTargeted next-generation sequencing provides a remarkable opportunity to identify variants in known disease genes, particularly in extremely heterogeneous disorders such as nonsyndromic hearing loss. The present study attempts to shed light on the complexity of hearing impairment.MethodsUsing one of two next-generation sequencing panels containing either 80 or 129 deafness genes, we screened 30 individuals with nonsyndromic hearing loss (from 23 unrelated families) and analyzed 9 normal-hearing controls.ResultsOverall, we found an average of 3.7 variants (in 80 genes) with deleterious prediction outcome, including a number of novel variants, in individuals with nonsyndromic hearing loss and 1.4 in controls. By next-generation sequencing alone, 12 of 23 (52%) probands were diagnosed with monogenic forms of nonsyndromic hearing loss; one individual displayed a DNA sequence mutation together with a microdeletion. Two (9%) probands have Usher syndrome. In the undiagnosed individuals (10/23; 43%) we detected a significant enrichment of potentially pathogenic variants as compared to controls.ConclusionNext-generation sequencing combined with microarrays provides the diagnosis for approximately half of the GJB2 mutation–negative individuals. Usher syndrome was found to be more frequent in the study cohort than anticipated. The conditions in a proportion of individuals with nonsyndromic hearing loss, particularly in the undiagnosed group, may have been caused or modified by an accumulation of unfavorable variants across multiple genes.Genet Med16 12, 945–953.     

New insights into cystinuria: 40 new mutations, genotype-phenotype correlation, and digenic inheritance causing partial phenotype

Objective: To clarify the genotype–phenotype correlation and elucidate the role of digenic inheritance in cystinuria. Methods: 164 probands from the International Cystinuria Consortium were screened for mutations in SLC3A1 (type A) and SLC7A9 (type B) and classified on the basis of urine excretion of cystine and dibasic amino acids by obligate heterozygotes into 37 type I (silent heterozygotes), 46 type non-I (hyperexcretor heterozygotes), 14 mixed, and 67 untyped probands. Results: Mutations were identified in 97% of the probands, representing 282 alleles (86.8%). Forty new mutations were identified: 24 in SLC3A1 and 16 in SLC7A9. Type A heterozygotes showed phenotype I, but mutation DupE5-E9 showed phenotype non-I in some heterozygotes. Type B heterozygotes showed phenotype non-I, with the exception of 10 type B mutations which showed phenotype I in some heterozygotes. Thus most type I probands carried type A mutations and all type non-I probands carried type B mutations. Types B and A mutations contributed to mixed type, BB being the most representative genotype. Two mixed cystinuria families transmitted mutations in both genes: double compound heterozygotes (type AB) had greater aminoaciduria than single heterozygotes in their family. Conclusions: Digenic inheritance is an exception (two of 164 families), with a limited contribution to the aminoaciduria values (partial phenotype) in cystinuria. Further mutational analysis could focus on one of the two genes (SLC3A1 preferentially for type I and SLC7A9 for type non-I probands), while for mixed probands analysis of both genes might be required, with priority given to SLC7A9.     

Origins and frequencies of SLC26A4 (PDS) mutations in east and south Asians: global implications for the epidemiology of deafness

Recessive mutations of SLC26A4 (PDS) are a common cause of Pendred syndrome and non-syndromic deafness in western populations. Although south and east Asia contain nearly one half of the global population, the origins and frequencies of SLC26A4 mutations in these regions are unknown. We PCR amplified and sequenced seven exons of SLC26A4 to detect selected mutations in 274 deaf probands from Korea, China, and Mongolia. A total of nine different mutations of SLC26A4 were detected among 15 (5.5%) of the 274 probands. Five mutations were novel and the other four had seldom, if ever, been identified outside east Asia. To identify mutations in south Asians, 212 Pakistani and 106 Indian families with three or more affected offspring of consanguineous matings were analysed for cosegregation of recessive deafness with short tandem repeat markers linked to SLC26A4. All 21 SLC26A4 exons were PCR amplified and sequenced in families segregating SLC26A4 linked deafness. Eleven mutant alleles of SLC26A4 were identified among 17 (5.4%) of the 318 families, and all 11 alleles were novel. SLC26A4 linked haplotypes on chromosomes with recurrent mutations were consistent with founder effects. Our observation of a diverse allelic series unique to each ethnic group indicates that mutational events at SLC26A4 are common and account for approximately 5% of recessive deafness in south Asians and other populations.     

Genetic analysis of presbycusis by arrayed primer extension

Using the Hereditary Hearing Loss arrayed primer extension (APEX) array, which contains 198 mutations across 8 hearing loss-associated genes (GJB2, GJB6, GJB3, GJA1, SLC26A4, SLC26A5, 12S-rRNA, and tRNA Ser), we compared the frequency of sequence variants in 94 individuals with early presbycusis to 50 unaffected controls and aimed to identify possible genetic contributors. This cross-sectional study was performed at Stanford University with presbycusis samples from the California Ear Institute. The patients were between ages 20 and 65 yr, with adult-onset sensorineural hearing loss of unknown etiology, and carried a clinical diagnosis of early presbycusis. Exclusion criteria comprised known causes of hearing loss such as significant noise exposure, trauma, ototoxic medication, neoplasm, and congenital infection or syndrome, as well as congenital or pediatric onset. Sequence changes were identified in 11.7% and 10% of presbycusis and control alleles, respectively. Among the presbycusis group, these solely occurred within the GJB2 and SLC26A4 genes. Homozygous and compound heterozygous pathogenic mutations were exclusively seen in affected individuals. We were unable to detect a statistically significant difference between our control and affected populations regarding the frequency of sequence variants detected with the APEX array. Individuals who carry two mild mutations in the GJB2 gene possibly have an increased risk of developing early presbycusis.     

Whole-exome sequencing reveals diverse modes of inheritance in sporadic mild to moderate sensorineural hearing loss in a pediatric population

PurposeThis study was designed to delineate genetic contributions, if any, to sporadic forms of mild to moderate sensorineural hearing loss (SNHL) not related to GJB2 mutations (DFNB1) in a pediatric population.MethodsWe recruited 11 non-DFNB1 simplex cases of mild to moderate SNHL in children. We applied whole-exome sequencing to all 11 probands. We used a filtering strategy assuming that de novo variants of known autosomal dominant (AD) deafness genes, biallelic mutations in autosomal recessive (AR) genes, monoallelic mutations in X chromosome genes for males, and digenic inheritance could be associated. Candidate variants first were prioritized with allele frequency in public databases and confirmed by a phase or a segregation test in each family. Additional information from the literature or public databases was used to identify strong candidate variants.ResultsStrong candidate variants were detected in 5 of 11 probands (45.4%). A diverse mode of inheritance implicated the sporadic occurrence of the phenotype. AR mutations in OTOGL and SERPINB6 and digenic inheritance involving two deafness genes, GPR98 and PDZ7, were detected. A de novo AD mutation also was detected in TECTA and MYH14. No syndromic feature was detected in individuals with GPR98/PDZ7 or MYH14 variants in our cohort at this moment.ConclusionMild to moderate pediatric SNHL, even if sporadic, features a strong genetic etiology and can manifest via diverse modes of inheritance. In addition, a multidisciplinary approach should be used for a correct diagnosis.Genet Med17 11, 901–911.     

湖州地区聋哑学校68名聋哑学生耳聋易感基因突变分析研究

目的研究4个耳聋易感基因GJB2、GJB3、SLC26A4、线粒体12SrRNA在湖州市聋哑学校68名聋哑学生中的突变类型分布情况。方法应用飞行时间质谱技术,对68名聋哑学生进行GJB2、GJB3、SLC26A4、线粒体12SrRNA 4个耳聋易感基因检测,检测位点包含以上基因的20个热点突变。结果68名聋哑学生中共检出耳聋基因突变27例,阳性率39.71％,其中GJB2基因突变19例,占70.37％;GJB3基因突变l例,占3.7％;SLC26A4基因突变5例,占18.52％;线粒体12SrRNA基因突变2例,占7.41％。结论在湖州市聋哑学校中,GJB2是最常见的耳聋突变基因,235delC是GJB2基因最常见的突变位点。     

Newborn genetic screening for hearing impairment: a population-based longitudinal study

PurposeThe feasibility of genetic screening for deafness-causing mutations in newborns has been reported in several studies. The aim of this study was to investigate the long-term results in those who screened positive for deafness mutations; these results are crucial to determine the cost-effectiveness to justify population-wide genetic screening.MethodsWe performed simultaneous hearing screening and genetic screening targeting four common deafness mutations (p.V37I and c.235delC of GJB2, c.919-2A>G of SLC26A4, and the mitochondrial m.1555A>G) in 5173 newborns at a tertiary hospital between 2009 and 2015. Serial audiometric results up to 6 years old were then analyzed in children with conclusive genotypes.ResultsNewborn genetic screening identified 82 (1.6%) babies with conclusive genotypes, comprising 62 (1.2%) with GJB2 p.V37I/p.V37I, 16 (0.3%) with GJB2 p.V37I/c.235delC, and 4 (0.1%) with m.1555A>G. Of these, 46 (56.1%) passed hearing screening at birth. Long-term follow-up demonstrated progressive hearing loss in children with the GJB2 p.V37I/p.V37I and p.V37I/c.235delC genotypes; this hearing loss deteriorated by approximately 1 decibel hearing level (dBHL) per year.ConclusionsWe delineated the longitudinal auditory features of the highly prevalent GJB2 p.V37I mutation on a general population basis and confirmed the utility of newborn genetic screening in identifying infants with late-onset or progressive hearing impairment undetectable by newborn hearing screening.     

SLC26A4 c.919-2A>G varies among Chinese ethnic groups as a cause of hearing loss

PurposeMutations in the SLC26A4 gene are second only to GJB2 mutations as a currently identifiable genetic cause of sensorineural hearing loss. In most areas of China, genetic testing for sensorineural hearing loss is unavailable because of limited knowledge of the mutation spectrum. Although SLC26A4 c.919-2A>G (IVS7–2A>G) is a common mutation among some Asian populations, the mutation prevalence among various ethnic groups within China has not been studied.MethodsDNA specimens from 3271 subjects with moderate to profound sensorineural hearing loss from 27 regions of China were genotyped for the c.919-2A>G mutation by polymerase chain reaction/restriction-fragment-length polymorphism. Normal hearing controls from Han (n = 185) and Uigur (n = 152) populations were also tested.ResultsOverall, 408 subjects with sensorineural hearing loss (12.5%) carried at least one c.919-2A>G allele, with 158 (4.8%) homozygotes and 250 (7.6%) heterozygotes. Within the subpopulations examined, the rate varies from 0% to 12.2% for c.919-2A>G homozygotes and from 0% to 17.6% for heterozygotes. Based on this cohort, Chinese subjects with sensorineural hearing loss seem to have a relatively higher c.919-2A>G frequency than that of other Asian populations.ConclusionThese results demonstrate that a simple and efficient genetic test for the c.919-2A>G mutation alone would identify the molecular cause in up to 8–12% of individuals with sensorineural hearing loss in a few eastern and central regions of China. Those who are negative for the c.919-2A>G mutation would be candidates for further mutational analysis of SLC26A4 or other deafness-related genes. This would greatly improve genetic diagnosis and counseling for a huge number of Chinese individuals and family members with sensorineural hearing loss in China, and many more ethnic Chinese in other countries, which might be up to one million.     

Spectrum and Frequency of SLC26A4 Mutations Among Czech Patients with Early Hearing Loss with and without Enlarged Vestibular Aqueduct (EVA)

Mutations in SLC26A4 cause Pendred syndrome (PS) – hearing loss with goitre – or DFNB4 – non‐syndromic hearing loss (NSHL) with inner ear abnormalities such as Enlarged Vestibular Aqueduct (EVA) or Mondini Dysplasia (MD). We tested 303 unrelated Czech patients with early hearing loss (298 with NSHL and 5 with PS), all GJB2‐negative, for SLC26A4 mutations and evaluated their clinical and radiological phenotype. Among 115 available HRCT/MRI scans we detected three MD (2.6%), three Mondini‐like affections (2.6%), 16 EVA (13 bilateral – 19.2% and 15.6% respectively) and 61 EVA/MD‐negative scans (73.4%). We found mutation(s) in 26 patients (8.6%) and biallelic mutations in eight patients (2.7%) out of 303 tested. In 18 of 26 (69%) patients, no second mutation could be detected even using MLPA. The spectrum of SLC26A4 mutations in Czech patients is broad without any prevalent mutation. We detected 21 different mutations (four novel). The most frequent mutations were p.Val138Phe and p.Leu445Trp (18% and 8.9% of pathogenic alleles respectively). Among 13 patients with bilateral EVA, six patients (50%) carry biallelic mutations. In EVA ‐negative patients no biallelic mutations were found but 4.9% had monoallelic mutations. SLC26A4 mutations are present mostly in patients with EVA/MD and/or progressive HL and those with affected siblings.     

Genomic diagnostics within a medically underserved population: efficacy and implications

PurposeWe integrated whole-exome sequencing (WES) and chromosomal microarray analysis (CMA) into a clinical workflow to serve an endogamous, uninsured, agrarian community.MethodsSeventy-nine probands (newborn to 49.8 years) who presented between 1998 and 2015 remained undiagnosed after biochemical and molecular investigations. We generated WES data for probands and family members and vetted variants through rephenotyping, segregation analyses, and population studies.ResultsThe most common presentation was neurological disease (64%). Seven (9%) probands were diagnosed by CMA. Family WES data were informative for 37 (51%) of the 72 remaining individuals, yielding a specific genetic diagnosis (n = 32) or revealing a novel molecular etiology (n = 5). For five (7%) additional subjects, negative WES decreased the likelihood of genetic disease. Compared to trio analysis, “family” WES (average seven exomes per proband) reduced filtered candidate variants from 22 ± 6 to 5 ± 3 per proband. Nineteen (51%) alleles were de novo and 17 (46%) inherited; the latter added to a population-based diagnostic panel. We found actionable secondary variants in 21 (4.2%) of 502 subjects, all of whom opted to be informed.ConclusionCMA and family-based WES streamline and economize diagnosis of rare genetic disorders, accelerate novel gene discovery, and create new opportunities for community-based screening and prevention in underserved populations.     

PNPT1, MYO15A,PTPRQ, and SLC12A2-associated genetic and phenotypic heterogeneity among hearing impaired assortative mating families in Southern India

The study was conducted between 2018 and 2020. From a cohort of 113 hearing impaired (HI), five non-DFNB12 probands identified with heterozygous CDH23 variants were subjected to exome analysis. This resolved the etiology of hearing loss (HL) in four South Indian assortative mating families. Six variants, including three novel ones, were identified in four genes: PNPT1 p.(Ala46Gly) and p.(Asn540Ser), MYO15A p.(Leu1485Pro) and p.(Tyr1891Ter), PTPRQ p.(Gln1336Ter), and SLC12A2 p.(Pro988Ser). Compound heterozygous PNPT1 variants were associated with DFNB70 causing prelingual profound sensorineural hearing loss (SNHL), vestibular dysfunction, and unilateral progressive vision loss in one family. In the second family, MYO15A variants in the myosin motor domain, including a novel variant, causing DFNB3, were found to be associated with prelingual profound SNHL. A novel PTPRQ variant was associated with postlingual progressive sensorineural/mixed HL and vestibular dysfunction in the third family with DFNB84A. In the fourth family, the SLC12A2 novel variant was found to segregate with severe-to-profound HL causing DFNA78, across three generations. Our results suggest a high level of allelic, genotypic, and phenotypic heterogeneity of HL in these families. This study is the first to report the association of PNPT1, PTPRQ, and SLC12A2 variants with HL in the Indian population.     

Congenital Middle Ear Malformation with Common Deafness Gene Mutation Analysis: A Review of 813 Profound Sensorineural Hearing Loss Child Patients

Deafness gene variants play a key role in inner ear malformations. However, the relationship between congenital middle ear malformations and common deafness genes (GJB2, SLC26A4, and mtDNA) in profound sensorineural hearing loss (SNHL) child patients remains poorly investigated. Here we showed that there was no statistical significance in the total mutation frequency of the three common deafness genes in the middle ear malformation group (21.2%, 41/193) in comparison with the normal middle ear and inner ear group (21.0%, 116/553) (χ² = 0.0061, p = 0.940). Moreover, the mutation ratio of GJB2 and SLC26A4 in the middle ear malformation group (18.7%, 36/193; 2.6%, 5/193) was not significantly different from that in the normal middle ear and inner ear group (17.7%, 98/553; 2.4%, 13/553) (χ² = 0.084, p = 0.772; χ² = 0.0000, p = 1.000). The mutation ratio of GJB2 235delC and GJB2 79G>A in the middle ear malformation group (8.8%, 17/193; 8.8%, 17/193) was almost the same to that in the normal middle ear and inner ear group (8.6%, 48/553; 6.7%, 37/553) (χ² = 0.0030, p = 0.957; χ² = 0.9556, p = 0.328). The high jugular bulb subgroup analysis also showed the same results. Our findings suggested that GJB2, SLC26A4, and mtDNA mutations might not be related to the middle ear malformations in profound SNHL child patients. Anat Rec, 303:594–599, 2020. © 2019 American Association for Anatomy     

Exome sequencing identifies rare variants in multiple genes in atrioventricular septal defect

PurposeThe genetic etiology of atrioventricular septal defect (AVSD) is unknown in 40% cases. Conventional sequencing and arrays have identified the etiology in only a minority of nonsyndromic individuals with AVSD.MethodsWhole-exome sequencing was performed in 81 unrelated probands with AVSD to identify potentially causal variants in a comprehensive set of 112 genes with strong biological relevance to AVSD.ResultsA significant enrichment of rare and rare damaging variants was identified in the gene set, compared with controls (odds ratio (OR): 1.52; 95% confidence interval (CI): 1.35–1.71; P = 4.8 × 10⁻¹¹). The enrichment was specific to AVSD probands, compared with a cohort without AVSD with tetralogy of Fallot (OR: 2.25; 95% CI: 1.84–2.76; P = 2.2 × 10⁻¹⁶). Six genes (NIPBL, CHD7, CEP152, BMPR1a, ZFPM2, and MDM4) were enriched for rare variants in AVSD compared with controls, including three syndrome-associated genes (NIPBL, CHD7, and CEP152). The findings were confirmed in a replication cohort of 81 AVSD probands.ConclusionMutations in genes with strong biological relevance to AVSD, including syndrome-associated genes, can contribute to AVSD, even in those with isolated heart disease. The identification of a gene set associated with AVSD will facilitate targeted genetic screening in this cohort.     

Targeted Resequencing of Deafness Genes Reveals a Founder MYO15A Variant in Northeastern Brazil

Identifying the genetic etiology in a person with hearing loss (HL) is challenging due to the extreme genetic heterogeneity in HL and the population‐specific variability. In this study, after excluding GJB2 variants, targeted resequencing of 180 deafness‐related genes revealed the causative variants in 11 of 19 (58%) Brazilian probands with autosomal recessive HL. Identified pathogenic variants were in MYO15A (10 families) and CLDN14 (one family). Remarkably, the MYO15A p.(Val1400Met) variant was identified in eight families from the city of Monte Santo in the northeast region of Brazil. Haplotype analysis of this variant was consistent with a single founder. No other cases with this variant were detected among 105 simplex cases from other cities of northeastern Brazil, suggesting that this variant is confined to a geographical region. This study suggests that it is feasible to develop population‐specific screening for deafness variants once causative variants are identified in different geographical groups.