title: Exome sequencing identifies SLC26A4, GJB2, SCARB2 and DUOX2 mutations in 2 siblings with Pendred syndrome in a Malaysian family.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: UKM Medical Molecular Biology Institute (UMBI), Chancellor Tuanku Muhriz Hospital, UKM Medical Centre, Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur, Malaysia.
authors.forename: Yock-Ping
authors.initials: YP
authors.lastname: Chow
authors.affiliation: UKM Medical Molecular Biology Institute (UMBI), Chancellor Tuanku Muhriz Hospital, UKM Medical Centre, Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur, Malaysia.
authors.forename: Nor Azian
authors.initials: NA
authors.lastname: Abdul Murad
authors.affiliation: UKM Medical Molecular Biology Institute (UMBI), Chancellor Tuanku Muhriz Hospital, UKM Medical Centre, Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur, Malaysia.
authors.forename: Zamzureena
authors.initials: Z
authors.lastname: Mohd Rani
authors.affiliation: Codon Genomics S/B, No 26, Jalan Dutamas 7, Taman Dutamas, Balakong, 43200, Seri Kembangan, Selangor, Malaysia.
authors.forename: Jia-Shiun
authors.initials: JS
authors.lastname: Khoo
authors.affiliation: Codon Genomics S/B, No 26, Jalan Dutamas 7, Taman Dutamas, Balakong, 43200, Seri Kembangan, Selangor, Malaysia.
authors.forename: Pei-Sin
authors.initials: PS
authors.lastname: Chong
authors.affiliation: Department of Pediatrics, Chancellor Tuanku Muhriz Hospital, UKM Medical Centre, Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur, Malaysia.
authors.forename: Loo-Ling
authors.initials: LL
authors.lastname: Wu
authors.affiliation: UKM Medical Molecular Biology Institute (UMBI), Chancellor Tuanku Muhriz Hospital, UKM Medical Centre, Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur, Malaysia. rahmanj@ppukm.ukm.edu.my.|Department of Pediatrics, Chancellor Tuanku Muhriz Hospital, UKM Medical Centre, Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur, Malaysia. rahmanj@ppukm.ukm.edu.my.
authors.forename: Rahman
authors.initials: R
authors.lastname: Jamal
mesh_terms: D000293:Adolescent; D002648:Child; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D000074623:Dual Oxidases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006044:Goiter, Nodular / Q000453:epidemiology / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008296:Malaysia / Q000453:epidemiology; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D051116:Receptors, Scavenger / Q000235:genetics / Q000378:metabolism*; D000076988:Sulfate Transporters; D000073359:Exome Sequencing / Q000379:methods*
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D051907:Lysosomal Membrane Proteins; D026901:Membrane Transport Proteins; D051116:Receptors, Scavenger; C074299:SCARB2 protein, human; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters; D000072259:Connexin 26; D000074623:Dual Oxidases; C431515:DUOX2 protein, human
keywords: Autosomal recessive inheritance; Childhood deafness; Exome sequencing; Pendred syndrome; Syndromic hearing loss