Putative TMPRSS3/GJB2 digenic inheritance of hearing loss detected by targeted resequencing

Leone, Maria Pia; Palumbo, Pietro; Ortore, Rocco Pio; Castellana, Stefano; Palumbo, Orazio; Melchionda, Salvatore; Palladino, Teresa; Stallone, Raffaella; Mazza, Tommaso; Cocchi, R; Carella, Massimo

doi:10.1016/j.mcp.2017.03.001

Cited by 10 publications

(13 citation statements)

References 27 publications

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“…Interestingly, none of the subjects was diagnosed with HL. Our data provide strong evidence against TMPRSS3 / GJB2 digenic inheritance of HL that has been proposed by two recent reports [7, 8], which in our opinion are far from being convincing. Both studies rely exclusively on data from only two families with either one [7] or two [8] affected individuals carrying heterozygous GJB2 and TMPRSS3 variants.…”

Section: Discussioncontrasting

confidence: 50%

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Overinterpretation of high throughput sequencing data in medical genetics: first evidence against TMPRSS3/GJB2 digenic inheritance of hearing loss

et al. 2019

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Background Hearing loss (HL) is the most common disability of human senses characterized by a great allelic heterogeneity. GJB2 and TMPRSS3 are two well-known HL genes typically underlying its monogenic form. Recently, TMPRSS3/GJB2 digenic inheritance has been proposed. As results of genetic testing can be easily overinterpreted, we aimed to verify the hypothesis. Methods From genetic database of HL patients with at least one TMPRSS3 pathogenic variants we have selected individuals with additional GJB2 pathogenic variants. All of the available family members were recruited for the study. Segregation analysis of the respective TMPRSS3 and GJB2 pathogenic variants was performed within the families. Results The strategy has allowed to identify four individuals who were double heterozygous for known pathogenic TMPRSS3 and GJB2 variants. Two individuals from different families had GJB2 c.35delG and TMPRSS3 c.208delC and in two other individuals from one family GJB2 c.35delG together with TMPRSS3 c.1343T>C variants were found. None of these subjects has ever reported hearing problems and their hearing status was normal. Conclusions Our data provide evidence against TMPRSS3 / GJB2 digenic inheritance of HL. As high throughput sequencing is increasingly used for genetic testing, particular caution should be taken to provide the patients with accurate genetic counseling.

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Section: Discussioncontrasting

confidence: 50%

“…The first one refers to a combination of GJB2 c.35delG together with TMPRSS3 c.208delC for which only familial evidence (based on one family) has been provided by Battelino et al [7]. The second combination is GJB2 c.487A>G (p.Met163Val) and TMPRSS3 c.1276G>A (p.Ala426Thr) that is supposed to be evidenced by familial and functional data [8].…”

Section: Resultsmentioning

confidence: 99%

Overinterpretation of high throughput sequencing data in medical genetics: first evidence against TMPRSS3/GJB2 digenic inheritance of hearing loss

et al. 2019

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“…However, digenic mutations have also been reported recently [7][8][9][10][11][12]. In our cases, the compound heterozygous for GJB2 variants (p.V37I ) and MYO7A (p.L347I) variant were found in the proband using whole-exome sequencing.…”

Section: Discussionsupporting

confidence: 51%

“…In 2009, Liu et al [8] identi ed heterozygous GJB2 and GJB3 mutations in NHSL patients. Since then, many other digenic inheritance has been reported [7][8][9][10][11][12], such as GJB2/GJB3, GJB2/MITF, and GJB2/ TMPRSS3 (Table 1). Although the digenic inheritance has been increasingly described in NSHL, the prevalence is unknown.…”

Section: Discussionmentioning

confidence: 99%

Putative Digenic GJBI2/MYO7A Inheritance of Hearing Loss Detected in a Patient with 48, XXYY Klinefelter Syndrome

Qin

Zhang

et al. 2020

Preprint

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Background: 48, XXYY Klinefelter syndrome is a rare sex chromosome abnormality. Nonsyndromic hearing loss (NSHL) is the most frequent hereditary type of hearing impairment. There has been no report of NSHL combined with 48XXYY. The purpose of this study was to explore the underlying genetic cause in a three-generation family affected by NSHL. The proband had concomitant NSHL and 48, XXYY syndrome. The whole-exome sequencing was performed in the proband. The candidate pathogenic variants identified by whole-exome sequencing were then confirmed by Sanger sequencing and segregation analysis.Results: The proband was identified to be compound heterozygous for c.109G>A (p.V37I) variant in the GJB2 gene and additional heterozygous for the c.1039C>A (p.L347I) variants in the MYO7A gene. His mother had normal hearing and did not have any form of variant. His father and uncle, both had NSHL, were digenic compound heterozygote for the GJB2 p.V37I and MYO7A p.L347I variants, thus suggesting a possible GJB2/MYO7A digenic inheritance of NSHL in this family consist with the clinical phenotype.Conclusions: Our findings reported a putative GJB2/MYO7A digenic inheritance form of hearing loss, which expands the mutation spectrum of NSHL. This is also the first report of concomitant NSHL and 48, XXYY syndrome.

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“…Other described digenic cases include SLC26A4 and FOXI [ 2 ], which causes Pendred syndrome or HI associated with enlarged vestibular aqueducts (EVA) in humans or EVA in the mouse mutant, and SLC26A4 and KCNJ10 [ 3 ], which have been observed to cause HI and EVA in humans. In addition, some putative digenic inheritances have been suggested but still require further evidence or need to be replicated, such as GJB2 and TMPRSS3 [ 7 ] and MYO7A and PCDH15 [ 8 ], amongst others.…”

Section: Introductionmentioning

confidence: 99%

Novel digenic inheritance of PCDH15 and USH1G underlies profound non-syndromic hearing impairment

et al. 2018

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BackgroundDigenic inheritance is the simplest model of oligenic disease. It can be observed when there is a strong epistatic interaction between two loci. For both syndromic and non-syndromic hearing impairment, several forms of digenic inheritance have been reported.MethodsWe performed exome sequencing in a Pakistani family with profound non-syndromic hereditary hearing impairment to identify the genetic cause of disease.ResultsWe found that this family displays digenic inheritance for two trans heterozygous missense mutations, one in PCDH15 [p.(Arg1034His)] and another in USH1G [p.(Asp365Asn)]. Both of these genes are known to cause autosomal recessive non-syndromic hearing impairment and Usher syndrome. The protein products of PCDH15 and USH1G function together at the stereocilia tips in the hair cells and are necessary for proper mechanotransduction. Epistasis between Pcdh15 and Ush1G has been previously reported in digenic heterozygous mice. The digenic mice displayed a significant decrease in hearing compared to age-matched heterozygous animals. Until now no human examples have been reported.ConclusionsThe discovery of novel digenic inheritance mechanisms in hereditary hearing impairment will aid in understanding the interaction between defective proteins and further define inner ear function and its interactome.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0618-5) contains supplementary material, which is available to authorized users.

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Putative TMPRSS3/GJB2 digenic inheritance of hearing loss detected by targeted resequencing

Cited by 10 publications

References 27 publications

Overinterpretation of high throughput sequencing data in medical genetics: first evidence against TMPRSS3/GJB2 digenic inheritance of hearing loss

Overinterpretation of high throughput sequencing data in medical genetics: first evidence against TMPRSS3/GJB2 digenic inheritance of hearing loss

Putative Digenic GJBI2/MYO7A Inheritance of Hearing Loss Detected in a Patient with 48, XXYY Klinefelter Syndrome

Novel digenic inheritance of PCDH15 and USH1G underlies profound non-syndromic hearing impairment

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