Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Jul 20;19(1):122.
doi: 10.1186/s12881-018-0618-5.

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

Isabelle Schrauwen  1 , Imen Chakchouk  1 , Anushree Acharya  1 , Khurram Liaqat  2 , Irfanullah  3 ; University of Washington Center for Mendelian Genomics; Deborah A Nickerson  4 , Michael J Bamshad  4   5 , Khadim Shah  3 , Wasim Ahmad  3 , Suzanne M Leal  6
Collaborators, Affiliations

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

Isabelle Schrauwen et al. BMC Med Genet. .

Abstract

Background: Digenic 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.

Methods: We performed exome sequencing in a Pakistani family with profound non-syndromic hereditary hearing impairment to identify the genetic cause of disease.

Results: We 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.

Conclusions: The 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.

Keywords: Deafness; Digenic inheritance; Hearing impairment; PCDH15; USH1G.

PubMed Disclaimer

Conflict of interest statement

Ethics approval and consent to participate

The study was approved by the Institutional Review Boards of the Quaid-i-Azam University and the Baylor College of Medicine and Affiliated Hospitals (H-17566). Written informed consent was obtained from all participating members.

Competing interests

I.S. and W.A. are members of the BMC Medical Genetics editorial board. All other authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Pedigree drawing for family 4667 and audiograms for the affected family members. Panel a Pedigree drawing displaying family members with NSHI as filled symbols and unaffected family members as clear symbols. Males are represented by squares and females by circles. For the three unaffected and two affected family members genotypes for the PCDH15 variant NM_033056:c.3101G > A and USH1G variant NM_173477:c.1093G > A are shown under each family member and demonstrate digenic inheritance. The DNA sample from Individual IV:4 was exome sequenced. Panel b Audiograms for affected family members IV:3 (top) and IV:4 (bottom). Pure-tone audiometry was performed between 250 and 8000 Hz and x represents the results for the left ear and o for the right ear. Affected individual IV:3 was 34 years old, and affected individual IV:4 was 22 years old at the time of pure-tone audiometry and physical examination
See this image and copyright information in PMC

References

    1. Zheng QY, Yan D, Ouyang XM, Du LL, Yu H, Chang B, et al. Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans. Hum Mol Genet. 2005;14:103–111. doi: 10.1093/hmg/ddi010. - DOI - PMC - PubMed
    1. Yang T, Vidarsson H, Rodrigo-Blomqvist S, Rosengren SS, Enerbäck S, Smith RJH. Transcriptional control of SLC26A4 is involved in Pendred syndrome and nonsyndromic enlargement of vestibular aqueduct (DFNB4) Am J Hum Genet. 2007;80:1055–1063. doi: 10.1086/518314. - DOI - PMC - PubMed
    1. Yang T, Gurrola JG, Wu H, Chiu SM, Wangemann P, Snyder PM, et al. Mutations of KCNJ10 together with mutations of SLC26A4 cause digenic nonsyndromic hearing loss associated with enlarged vestibular aqueduct syndrome. Am J Hum Genet. 2009;84:651–657. doi: 10.1016/j.ajhg.2009.04.014. - DOI - PMC - PubMed
    1. del Castillo I, Villamar M, Moreno-Pelayo MA, del Castillo FJ, Álvarez A, Tellería D, et al. A deletion involving the Connexin 30 gene in nonsyndromic hearing impairment. N Engl J Med. 2002;346:243–249. doi: 10.1056/NEJMoa012052. - DOI - PubMed
    1. Mei L, Chen J, Zong L, Zhu Y, Liang C, Jones RO, et al. A deafness mechanism of digenic Cx26 ( GJB2 ) and Cx30 ( GJB6 ) mutations: reduction of endocochlear potential by impairment of heterogeneous gap junctional function in the cochlear lateral wall. Neurobiol Dis. 2017;108:195–203. doi: 10.1016/j.nbd.2017.08.002. - DOI - PMC - PubMed

Publication types

LinkOut - more resources