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

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.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0618-5) contains supplementary material, which is available to authorized users.

<i>GJB2</i> Gene Related Nonsyndromic Hearing Loss in Mazandaran Province, North of Iran

“…Because hearing loss is heterogeneous, so it is a good candidate for digenic inheritance [46]. Several examples of digenic inheritance have been reported for hearing loss, such as PCDH15 and CDH23, SLC26A4 and FOX1, SLC26A4 and KCNJ10, MYO7A and PCDH15, PCDH and USH1G [47].…”

Gene Therapy to the Retina and the Cochlea

“…Mice are also widely used as genetic models for hearing loss. Mouse models of hearing loss have been created using a variety of genetic approaches, ranging from traditional knockouts to modern gene-edited germline models (see for example Charizopoulou et al, 2011 ; Michel et al, 2017 ; Schrauwen et al, 2018 ; Zhang H. et al, 2018 ). The major difference between the mouse and human auditory system is the timeline of development.…”

Identification of autosomal recessive nonsyndromic hearing impairment genes through the study of consanguineous and non-consanguineous families: past, present, and future

“…For each family, if DNA samples from all family members have not undergone NGS, the segregation of the identified variant with the affection status of the family members needs to be verified using, for example, Sanger sequencing. Lastly, due to the high interaction among proteins of the ear sensory epithelia and hair cells, digenic and polygenic inheritance have also been described for HI (Schrauwen et al 2018;Khalil et al 2020). The definition of digenic inheritance in the literature can be variable, but for HI, genes have been often reported in a classic digenic model, for example, where two trans heterozygous variants in two genes are required for the expression of a phenotype (Schrauwen et al 2018).…”