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Identification of Three Novel and One Known Mutation in the WFS1 Gene in Four Unrelated Turkish Families; the Role of Homozygosity Mapping in the Early Diagnosis.

Abstract：

OBJECTIVE:Bi-allelic mutations in wolframin gene (WFS1) cause Wolfram syndrome 1 (WS1 or DIDMOAD) characterized with non-autoimmune diabetes mellitus (DM), optic atrophy (OA), diabetes insipidus (DI), sensorineural deafness (SND), urinary tract abnormalities, and neuropsychiatric disorders. We evaluated patients presented with an incomplete phenotype of WS1 using homozygosity mapping and subsequent whole-exome sequencing. PATIENTS AND METHODS:Four unrelated consanguineous Turkish families (7 affected children), and their unaffected parents and siblings were evaluated. Homozygosity mapping (HZM) was performed, followed by whole-exome sequencing of WFS1. Mutations were classified according to results of "in silico" analyses, protein prediction, and functional consequences. RESULTS:Homozygosity mapping confirmed shared homozygous regions on chromosome 4 (chr4p16.1) between the affected individuals, and absent from their unaffected siblings. Exome sequencing identified three novel (c.1215T>A, c.554G>A, c.1525_1540dup) and one known (c. 1522_1523delTA) mutations in WFS1 gene. All mutations were predicted to cause stop codon leading to early termination of protein synthesis and complete loss-of-function. All patients were found to be homozygous for the change, with parents and other unaffected siblings being carriers. CONCLUSION:Our study expands the mutation spectrum of WSF1 mutations with three novel mutations. Homozygosity mapping may provide enrichment for molecular genetic analysis and early diagnosis of WS1 patients with incomplete phenotype, particularly in consanguineous pedigrees.

journal_name

J Clin Res Pediatr Endocrinol

journal_title

Journal of clinical research in pediatric endocrinology

authors

Sherif M,Demirbilek H,Cayir A,Tahir S,Cavdarli B,Demiral M,Cebeci AN,Vuralli D,Rahman SA,Unal E,Buyukyilmaz G,Baran RT,Ozbek MN,Hussain K

doi

10.4274/jcrpe.galenos.2020.2020.0152

subject

Has Abstract

pub_date

2020-09-17 00:00:00

eissn

1308-5727

issn

1308-5735

pub_type

杂志文章

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Identification of Three Novel and One Known Mutation in the WFS1 Gene in Four Unrelated Turkish Families; the Role of Homozygosity Mapping in the Early Diagnosis.