Screening Consanguineous Families for Hearing Loss Using the MiamiOtoGenes Panel.
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ABSTRACT:
SUBMITTER: Kannan-Sundhari A
PROVIDER: S-EPMC7585618 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC6296877 | biostudies-literature
Project description:BACKGROUND:Hearing loss is the most common sensory defect, and it affects over 6% of the population worldwide. Approximately 50-60% of hearing loss patients are attributed to genetic causes. Currently, more than 100 genes have been reported to cause non-syndromic hearing loss. It is possible and efficient to screen all potential disease-causing genes for hereditary hearing loss by whole exome sequencing (WES). METHODS:We collected 5 consanguineous pedigrees from Pakistan with hearing loss and applied WES in selected patients for each pedigree, followed by bioinformatics analysis and Sanger validation to identify the causal genes. RESULTS:Variants in 7 genes were identified and validated in these pedigrees. We identified single candidate variant for 3 pedigrees: GIPC3 (c.937?T?>?C), LOXHD1 (c.6136G?>?A) and TMPRSS3 (c.941?T?>?C). The remaining 2 pedigrees each contained two candidate variants: TECTA (c.4045G?>?A) and MYO15A (c.3310G?>?T and c.9913G?>?C) for one pedigree and DFNB59 (c.494G?>?A) and TRIOBP (c.1952C?>?T) for the other pedigree. The candidate variants were validated in all available samples by Sanger sequencing. CONCLUSION:The candidate variants in hearing-loss genes were validated to be co-segregated in the pedigrees, and they may indicate the aetiologies of hearing loss in such patients. We also suggest that WES may be a suitable strategy for hearing-loss gene screening in clinical detection.
| S-EPMC7368710 | biostudies-literature
Project description:Hearing loss is a highly heterogeneous disease presented with various phenotypes. Genetic testing of disease-causing mutations plays an important role in precise diagnosis and fertility guidance of heredity hearing loss. Here we reported an effective method employing target enrichment and BGISEQ-500 platform to detect clinically relevant alterations for heredity hearing patients in a single assay.In this study, we designed an array based chip, containing 127 genes related to hearing loss. Then we conducted targeted next-generation sequencing toward 58 patients to make a precise diagnosis using BGISEQ-500 platform.We successfully detected disease-causing mutations in 77.59% (45/58) of the patients with hearing loss. Finally, a total of 62 disease-causing mutations were identified, including 31 missense, 17 Indel, 11 splicing, 2 synonymous, and 1 copy number variant. 58.06% (36/62) of which has never been reported before.To our knowledge, this is the first report using BGISEQ-500 platform to investigate both syndromic and nonsyndromic hearing loss in the Chinese population. The results showed that this method can greatly assist and enhance hearing loss diagnosis and improve molecular diagnostics outcome.
| S-EPMC6709004 | biostudies-literature
Project description:Multilocus analysis of rare or genetically heterogeneous diseases is a distinct advantage of next-generation sequencing (NGS) over conventional single-gene investigations. Recent studies have begun to uncover an under-recognized prevalence of dual molecular diagnoses in patients with a "blended" phenotype that is the result of 2 clinical diagnoses involving 2 separate genetic loci. This blended phenotype could be mistakenly interpreted as a novel clinical extension of a single-gene disorder. In this study, we ascertained a proband from a large consanguineous Iranian family who manifests postlingual, progressive, moderate hearing loss in addition to suspected Ellis-van Creveld syndrome phenotype. NGS with a customized skeletal dysplasia panel containing over 370 genes and subsequent bioinformatics analysis disclosed 2 homozygous mutations in EVC2 (c.2653C>T; p.Arg885*) and COL11A2 (c.966dup; p.Thr323Hisfs*19), respectively. This study highlights a dual molecular diagnosis in a patient with a blending of 2 distinct phenotypes and illustrates the advantage and importance of this staple technology to facilitate rapid and comprehensive genetic dissection of a heterogeneous phenotype. The differentiation between phenotypic expansion of a genetic disorder and a blended phenotype that is due to more than one distinct genetic aberration is essential in order to reduce the diagnostic odyssey endured by patients.
| S-EPMC5803684 | biostudies-literature
Project description:BackgroundThe extremely high genetic heterogeneity of hearing loss due to diverse group of genes encoding proteins required for development, function, and maintenance of the complex auditory system makes the genetic diagnosis of this disease challenging. Up to now, 121 different genes have been identified for nonsyndromic hearing loss (NSHL), of which 76 genes are responsible for the most common forms of NSHL, autosomal recessive nonsyndromic hearing loss (ARNSHL).MethodsAfter excluding mutations in the most common ARNSHL gene, GJB2, by Sanger sequencing, genetic screening for a panel of genes responsible for hereditary hearing impairment performed in 9 individuals with ARNSHL from unrelated Iranian consanguineous pedigrees.ResultsOne compound heterozygote and eight homozygote variants, of which five are novel, were identified: CDH23:p.(Glu1970Lys), and p.(Ala1072Asp), GIPC3:p.(Asn82Ser), and (p.Thr41Lys), MYO7A:p.[Phe456Phe]; p.[Met708Val], and p.(Gly163Arg), TECTA:p.(Leu17Leufs*19), OTOF:c.1392+1G>A, and TRIOBP:p.(Arg1068*). Sanger sequencing confirmed the segregation of the variants with the disease in each family.ConclusionFinding more variants and expanding the spectrum of hearing impairment mutations can increase the diagnostic value of molecular testing in the screening of patients and can improve counseling to minimize the risk of having affected children for at risk couples.
| S-EPMC7755797 | biostudies-literature
Project description:Nonsyndromic hearing loss has been shown to have high genetic heterogeneity. In this report, we aimed to disclose the genetic causes of the subjects from the ten Chinese deaf families who did not have pathogenic common genes/mutation. Next-generation sequencing (NGS) of 142 known deafness genes was performed in the probands of ten families followed by cosegregation analysis of all family members. We identified novel pathogenic variants in six families including p.D1806E/p.R1588W, p.R964W/p.R1588W, and p.G17C/p.G1449D in CDH23; p.T584M/p.D1939N in LOXHD1; p.P1225L in MYO7A; and p.K612X in EYA4. Sanger sequencing confirmed that these mutations segregated with the hearing loss of each family. In four families, no pathogenic variants were identified. Our study provided better understanding of the mutation spectrum of hearing loss in the Chinese population.
| S-EPMC6079373 | biostudies-literature
Project description:BACKGROUND:Recent advances in molecular genetics have enabled to determine the genetic causes of non-syndromic hearing loss, and more than 100 genes have been related to the phenotype. Due to this extraordinary genetic heterogeneity, a large percentage of patients remain without any molecular diagnosis. This condition imply the need for new methodological strategies in order to detect a greater number of mutations in multiple genes. In this work, we optimized and tested a panel of 86 mutations in 17 different genes screened using a high-throughput genotyping technology to determine the molecular etiology of hearing loss. METHODS:The technology used in this work was the MassARRAY iPLEX® platform. This technology uses silicon chips and DNA amplification products for accurate genotyping by mass spectrometry of previous reported mutations. The generated results were validated using conventional techniques, as direct sequencing, multiplex PCR and RFLP-PCR. RESULTS:An initial genotyping of control subjects, showed failures in 20 % of the selected alterations. To optimize these results, the failed tests were re-designed and new primers were synthesized. Then, the specificity and sensitivity of the panel demonstrated values above 97 %. Additionally, a group of 180 individuals with NSHL without a molecular diagnosis was screened to test the diagnostic value of our panel, and mutations were identified in 30 % of the cases. In 20 % of the individuals, it was possible to explain the etiology of the HL. Mutations in GJB2 gene were the most prevalent, followed by other mutations in in SLC26A4, CDH23, MT-RNR1, MYO15A, and OTOF genes. CONCLUSIONS:The MassARRAY technology has the potential for high-throughput identification of genetic variations. However, we demonstrated that optimization is required to increase the genotyping success and accuracy. The developed panel proved to be efficient and cost-effective, being suitable for applications involving the molecular diagnosis of hearing loss.
| S-EPMC4581412 | biostudies-literature
Project description:BACKGROUND:DFNB1, the first locus to have been associated with deafness, has two major genes GJB2 & GJB6, whose mutations have played vital role in hearing impairment across many ethnicities in the world. In our present study we have focused on the role of these mutations in assortative mating hearing impaired families from south India. METHODS:One hundred and six assortatively mating hearing impaired (HI) families of south Indian origin comprising of two subsets: 60 deaf marrying deaf (DXD) families and 46 deaf marrying normal hearing (DXN) families were recruited for this study. In the 60 DXD families, 335 members comprising of 118 HI mates, 63 other HI members and 154 normal hearing members and in the 46 DXN families, 281 members comprising of 46 HI and their 43 normal hearing partners, 50 other HI members and 142 normal hearing family members, participated in the molecular study. One hundred and sixty five (165) healthy normal hearing volunteers were recruited as controls for this study. All the participating members were screened for variants in GJB2 and GJB6 genes and the outcome of gene mutations were compared in the subsequent generation in begetting deaf offspring. RESULTS:The DFNB1 allele frequencies for DXD mates and their offspring were 36.98 and 38.67%, respectively and for the DXN mates and their offspring were 22.84 and 24.38%, respectively. There was a 4.6% increase in the subsequent generation in the DXD families, while a 6.75% increase in the DXN families, which demonstrates the role of assortative mating along with consanguinity in the increase of DFNB1 mutations in consecutive generations. Four novel variants, p.E42D (in GJB2 gene), p.Q57R, p.E101Q, p.R104H (in GJB6 gene) were also identified in this study. CONCLUSION:This is the first study from an Indian subcontinent reporting novel variants in the coding region of GJB6 gene. This is perhaps the first study in the world to test real-time, the hypothesis proposed by Nance et al. in 2000 (intense phenotypic assortative mating mechanism can double the frequency of the commonest forms of recessive deafness [DFNB1]) in assortative mating HI parental generation and their offspring.
| S-EPMC6008914 | biostudies-literature
Project description:To investigate the causative genetic mutations in 12 Pakistani families with nonsyndromic or syndromic hearing loss.Mutations in the most common causative gene for hearing loss, GJB2, were evaluated by Sanger sequencing. Targeted next-generation sequencing or whole-exome sequencing was used to analyze the genomic DNA samples from 11 probands with hearing loss. Sanger sequencing was performed to verify all identified variants.We found pathogenic, or likely to be pathogenic, mutations in all 12 families, including six known mutations in GJB2, SLC26A4, LHFPL5, and USH2A and eight novel mutations in ESPN, MYO7A, LRTOMT, PCDH15, USH2A, or EPS8L2. Notably, four compound heterozygous mutations in the MYO7A and USH2A genes were detected in two consanguineous families. In addition, the novel frameshift mutation in EPS8L2 was first documented in Pakistan.Our study increases the spectrum of mutations associated with hearing loss in the Pakistani population. In addition, our study highlights the fact that compound heterozygous mutations, although rare, can occur in consanguineous families.
| S-EPMC5444417 | biostudies-literature
Project description:Objective:The purpose of this work was to characterize the Met34Thr variant in a group of patients with nonsyndromic hearing loss, in order to establish a genotype-phenotype correlation. Methods:13 cases from 4 unrelated Portuguese families were selected, in which one or more hearing-impaired members had Met34Thr variant. Results:Met34Thr variant was identified in 11/13 cases. Two cases have an additional mutation - Val153Ile and 35delG. Hearing loss was mild in 2 patients (Met34Thr/Val153Ile; Met34Thr/Met34Thr), moderate in 3(Met34Thr/WT; Met34Thr/35delG; Met34Thr/Met34Thr), severe in 2 (2 Met34Thr/WT) and profound in 1 (Met34Thr/WT). Three individuals with Met34Thr had normal hearing thresholds. Conclusion:The present data corroborate the hypothesis that the Met34Thr variant is associated with mild-to-severe forms of deafness and that this variant seems to segregate with a dominant hearing loss with incomplete penetrance and a variable expression of the phenotype. However, other factors are likely to also have a pathologic effect.
| S-EPMC6806946 | biostudies-literature