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
Maha Sherif,
Hüseyin Demirbilek,
Atilla Çayır,
Sophia Tahir,
Büşra Çavdarlı,
Meliha Demiral,
Ayşe Nurcan Cebeci,
Doğuş Vurallı,
Sofia Asim Rahman,
Edip Unal,
Gönül Büyükyılmaz,
Riza Taner Baran,
Mehmet Nuri Özbek,
Khalid Hussain
Affiliations
Maha Sherif
University College London, Institute of Child Health, Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, London, United Kingdom
Hüseyin Demirbilek
University College London, Institute of Child Health, Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, London, United Kingdom
Atilla Çayır
Regional Training and Research Hospital, Clinic of Paediatric Endocrinology, Erzurum, Turkey
Sophia Tahir
University College London, Institute of Child Health, Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, London, United Kingdom
Büşra Çavdarlı
Ankara City Hospital, Clinic of Medical Genetics, Ankara, Turkey
Meliha Demiral
Gazi Yaşargil Training and Research Hospital, Clinic of Pediatric Endocrinology, Diyarbakır, Turkey
Ayşe Nurcan Cebeci
Derince Training and Research Hospital, Clinic of Paediatric Endocrinology, Kocaeli, Turkey
Doğuş Vurallı
Hacettepe University Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey
Sofia Asim Rahman
University College London, Institute of Child Health, Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, London, United Kingdom
Edip Unal
Gazi Yaşargil Training and Research Hospital, Clinic of Pediatric Endocrinology, Diyarbakır, Turkey
Gönül Büyükyılmaz
Ankara City Hospital, Clinic of Pediatric Endocrinology, Ankara, Turkey
Riza Taner Baran
Diyarbakır Children’s Hospital, Clinic of Paediatric Endocrinology, Diyarbakır, Turkey
Mehmet Nuri Özbek
Diyarbakır Children’s Hospital, Clinic of Paediatric Endocrinology, Diyarbakır, Turkey
Khalid Hussain
University College London, Institute of Child Health, Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, London, United Kingdom
Objective:Bi-allelic mutations in the wolframin gene (WFS1) cause Wolfram syndrome 1 (WS1 or DIDMOAD) characterized by non-autoimmune diabetes mellitus, optic atrophy, diabetes insipidus, sensorineural deafness, urinary tract abnormalities, and neuropsychiatric disorders. Patients presenting with an incomplete phenotype of WS1 were evaluated using homozygosity mapping and subsequent whole-exome sequencing.Methods:Four unrelated consanguineous Turkish families, including seven affected children, and their unaffected parents and siblings were evaluated. Homozygosity mapping 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, that was absent in 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. 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.
