Exome sequencing identifies SLC26A4, GJB2, SCARB2 and DUOX2 mutations in 2 siblings with Pendred syndrome in a Malaysian family

Yock-Ping Chow,
Nor Azian Abdul Murad,
Zamzureena Mohd Rani,
Jia-Shiun Khoo,
Pei-Sin Chong,
Loo-Ling Wu and
Rahman JamalEmail author

Orphanet Journal of Rare Diseases201712:40

DOI: 10.1186/s13023-017-0575-7

Received: 6 October 2016

Accepted: 20 January 2017

Published: 21 February 2017

Abstract

Background

Pendred syndrome (PDS, MIM #274600) is an autosomal recessive disorder characterized by congenital sensorineural hearing loss and goiter. In this study, we describing the possible PDS causal mutations in a Malaysian family with 2 daughters diagnosed with bilateral hearing loss and hypothyroidism.

Methods and Results

Whole exome sequencing was performed on 2 sisters with PDS and their unaffected parents. Our results showed that both sisters inherited monoallelic mutations in the 2 known PDS genes, SLC26A4 (ENST00000265715:c.1343C > T, p.Ser448Leu) and GJB2 (ENST00000382844:c.368C > A, p.Thr123Asn) from their father, as well as another deafness-related gene, SCARB2 (ENST00000264896:c.914C > T, p.Thr305Met) from their mother. We postulated that these three heterozygous mutations in combination may be causative to deafness, and warrants further investigation. Furthermore, we also identified a compound heterozygosity involving the DUOX2 gene (ENST00000603300:c.1588A > T:p.Lys530* and c.3329G > A:p.Arg1110Gln) in both sisters which are inherited from both parents and may be correlated with early onset of goiter. All the candidate mutations were predicted deleterious by in silico tools.

Conclusions

In summary, we proposed that PDS in this family could be a polygenic disorder which possibly arises from a combination of heterozygous mutations in SLC26A4, GJB2 and SCARB2 which associated with deafness, as well as compound heterozygous DUOX2 mutations which associated with thyroid dysfunction.