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

Isabelle Schrauwen,Khadim Shah,Deborah A Nickerson,Michael J Bamshad,Suzanne M Leal,Irfanullah Irfanullah,Anushree Acharya,Khurram Liaqat,Wasim Ahmad,Imen Chakchouk

doi:10.1186/s12881-018-0618-5

Isabelle Schrauwen, Khadim Shah + Show 8 more

Open Access

https://doi.org/10.1186/s12881-018-0618-5

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Abstract

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.

Highlights

Digenic inheritance is the simplest model of oligenic disease
Schrauwen et al BMC Medical Genetics (2018) 19:122 this example should be considered as monogenic GJB2 autosomal recessive Non-syndromic Hearing Impairment (NSHI) and not truly digenic in its underlying molecular nature, since the GJB6 deletion inactivates GJB2 [10, 11], which is its neighboring gene on chromosome 13
Reads were aligned to the Human genome (Hg19/GRC37) using the Burrows-Wheeler transform (BWA-MEM), Polymerase Chain Reaction (PCR) duplicates were removed with Picard MarkDuplicates, and indel realignment was performed (GATK IndelRealigner)

Summary

Introduction

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. The simplest model of multifactorial inheritance is digenic, where in its original definition, two loci are necessary to express or extremely modify the severity of a phenotype. Schrauwen et al BMC Medical Genetics (2018) 19:122 this example should be considered as monogenic GJB2 autosomal recessive NSHI and not truly digenic in its underlying molecular nature, since the GJB6 deletion inactivates GJB2 [10, 11], which is its neighboring gene on chromosome 13

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