Challenges in whole exome sequencing: An example from hereditary deafness

Asli Sirmaci, Yvonne J K Edwards, Hatice Akay, Mustafa Tekin

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Whole exome sequencing provides unprecedented opportunities to identify causative DNA variants in rare Mendelian disorders. Finding the responsible mutation via traditional methods in families with hearing loss is difficult due to a high degree of genetic heterogeneity. In this study we combined autozygosity mapping and whole exome sequencing in a family with 3 affected children having nonsyndromic hearing loss born to consanguineous parents. Two novel missense homozygous variants, c.508C>A (p.H170N) in GIPC3 and c.1328C>T (p.T443M) in ZNF57, were identified in the same ~6 Mb autozygous region on chromosome 19 in affected members of the family. Both variants co-segregated with the phenotype and were absent in 335 ethnicity-matched controls. Biallelic GIPC3 mutations have recently been reported to cause autosomal recessive nonsyndromic sensorineural hearing loss. Thus we conclude that the hearing loss in the family described in this report is caused by a novel missense mutation in GIPC3. Identified variant in GIPC3 had a low read depth, which was initially filtered out during the analysis leaving ZNF57 as the only potential causative gene. This study highlights some of the challenges in the analyses of whole exome data in the bid to establish the true causative variant in Mendelian disease.

Original languageEnglish
Article numbere32000
JournalPLoS One
Volume7
Issue number2
DOIs
StatePublished - Feb 21 2012

Fingerprint

Exome
deafness
Audition
hearing
Deafness
Hearing Loss
mutation
Chromosomes, Human, Pair 19
Mutation
missense mutation
Genetic Heterogeneity
Missense Mutation
Chromosomes
nationalities and ethnic groups
Genes
Parents
chromosomes
Phenotype
phenotype
DNA

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Challenges in whole exome sequencing : An example from hereditary deafness. / Sirmaci, Asli; Edwards, Yvonne J K; Akay, Hatice; Tekin, Mustafa.

In: PLoS One, Vol. 7, No. 2, e32000, 21.02.2012.

Research output: Contribution to journalArticle

Sirmaci, Asli ; Edwards, Yvonne J K ; Akay, Hatice ; Tekin, Mustafa. / Challenges in whole exome sequencing : An example from hereditary deafness. In: PLoS One. 2012 ; Vol. 7, No. 2.
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