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

作者：Schrauwen Isabelle; Chakchouk Imen; Acharya Anushree; Liaqat Khurram; Irfanullah; Nickerson Deborah A; Bamshad Michael J; Shah Khadim; Ahmad Wasim; Leal Suzanne M^*

来源：BMC Medical Genetics, 2018, 19(1): 122.

DOI：10.1186/s12881-018-0618-5

• Digenic inheritance
• Hearing impairment
• Deafness
• PCDH15
• USH1G

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.

• 出版日期2018-7-20