Whole-exome sequencing diagnosis of two autosomal recessive disorders in one family

T. Takeichi, A. Nanda, S. Aristodemou, J. R. McMillan, J. Lee, M. Akiyama, H. Al-Ajmi, M. A. Simpson, J. A. McGrath

研究成果: Article同行評審

21 引文 斯高帕斯(Scopus)

摘要

Autosomal recessive congenital ichthyosis (ARCI) is a genetically heterogeneous disorder for which subtyping through molecular analysis can help determine the eventual phenotype and prognosis. We used whole-exome sequencing to identify a new homozygous splice-site mutation in ST14 (IVS5+1G>A), encoding matriptase, in a 4-year-old girl with ARCI from a consanguineous Kuwaiti family. Clinically, she also had hypotrichosis, which supported a diagnosis of ARCI type 11. Only four previous examples of pathogenic mutations in ST14 have been reported, and our findings expand the genotype-phenotype correlation for this subtype of ARCI. Our patient was the second child born to these parents; the first (deceased) and third children had congenital brain and eye abnormalities, of uncertain aetiology and with no precise diagnosis. Further analysis of our patient's exome dataset revealed heterozygosity for a splice-site mutation in POMT1 (IVS4+1G>T), encoding the protein O-mannosyltransferase, a gene implicated in Walker-Warburg syndrome. DNA sequencing in the third child showed homozygosity for this mutation in POMT1. The first-cousin parents were both heterozygous for the splice-site mutations in ST14 and POMT1. In this family, whole-exome sequencing provided accurate subtyping of a form of ARCI in one child and provide an explanation for an undiagnosed developmental disorder in two other children, findings that improve the prospects for diagnostic accuracy and genetic counselling, and demonstrate the impact of next-generation sequencing technologies on clinical genetics. What's already known about this topic? Mutations in the suppression of tumorigenicity 14 gene (ST14), encoding matriptase, underlie autosomal recessive congenital ichthyosis type 11 (ARCI11). To date, only four pathogenic mutations in ST14 have been reported. Walker-Warburg syndrome (WWS) is a rare autosomal recessive disorder with developmental malformations, resulting from mutations in POMT1, which encodes O-mannosyltransferase. Next-generation sequencing has the potential to reveal both anticipated and incidental mutations. What does this study add? Using whole-exome sequencing, we identified a new homozygous splice-site mutation in ST14 in a 4-year-old Bedouin girl with ARCI11. Bioinformatics analysis of the exome dataset revealed that this girl was also heterozygous for a mutation in POMT1, providing insight into WWS affecting two other siblings in this family. Whole-exome sequencing can provide both molecular diagnostics for known disorders, and data that can improve clinical diagnosis and genetic counselling.

原文English
頁(從 - 到)1407-1411
頁數5
期刊British Journal of Dermatology
172
發行號5
DOIs
出版狀態Published - 2015 5月 1

All Science Journal Classification (ASJC) codes

  • 皮膚科

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