Arch Iran Med. 2019;22(4):189-197.
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Original Article

Novel Mutations in KCNQ4, LHFPL5 and COCH Genes in Iranian Families with Hearing Impairment

Hoda Mehregan 1, Marzieh Mohseni 1, Mojdeh Akbari 1, Khadijeh Jalalvand 1, Sanaz Arzhangi 1, Nooshin Nikzat 1, Kimia Kahrizi 1, Hossein Najmabadi 1 *

1 Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Evin, Tehran 19834, Iran
1 Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Evin, Tehran 19834, Iran
*Corresponding Author: Hossein Najmabadi, PhD; Genetics Research Center, Director, University of Social Welfare and Rehabilitation Sciences, Daneshjoo Blvd, Koodakyar Avenue, Evin, Tehran, Iran, 1985713834, Tel: +98-21-22180138, Fax: +98-21-22180138, E-mail: Email: hnajm12@yahoo.com

Abstract

Background: Hearing loss (HL) is the most common sensory deficit in humans, and genetic factors contribute to about half of the cases. With 112 causative genes identified so far and a disproportionate share of the genes within different ethnic groups, HL has proven to be quite heterogeneous.

Methods: Twenty Iranian families having at least 2 children with hereditary HL were initially verified to be GJB2-negative and were then subjected to whole exome sequencing (WES). Sanger sequencing was used to confirm segregation of the variant identified in each family.

Results: In 3 families, WES revealed 3 novel variants in KCNQ4, LHFPL5 and COCH genes. The KCNQ4 gene (DFNA2A) encodes a potassium channel (KV7.4) and the heterozygous variant identified (c.1647C>G, p.F549L) resulted in the substitution of Phe549 residing in the KV7.4 cytoplasmic region. The homozygous variant (c.34A>T, p.K12X) was identified in the LHFPL5 gene (DFNB67) which encodes a transmembrane protein, and another variant in a homozygous state (c.116T>A, p.L39X) was identified in the COCH gene which encodes a secretory protein. Pathogenic variants in the COCH gene are associated with late onset autosomal dominant hearing loss (DFNA9) but the affected individuals displayed early onset HL with a recessive mode of inheritance.

Conclusions: The 16% contribution of GJB2 to HL in the Iranian population necessitates the discovery of the remaining causal factors. This study is the first to report KCNQ4 and COCH related HL in the Iranian population and the second study, globally, to report HL due to biallelic inactivation of the COCH gene.

Cite this article as: Mehregan H, Mohseni M, Akbari M, Jalalvand K, Arzhangi S, Nikzat N, et al. Novel mutations in KCNQ4, LHFPL5 and COCH genes in Iranian families with hearing impairment. Arch Iran Med. 2019;22(4):189–197.
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Submitted: 26 Nov 2018
Accepted: 13 Feb 2019
First published online: 01 Apr 2019
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