ISSN: 1308-5727 | E-ISSN: 1308-5735
Volume : 13 Issue : 1 Year : 2023
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Turkish Society for Pediatric Endocrinology and Diabetes
Identification of Three Novel and One Known Mutation in the Gene in Four Unrelated Turkish Families: The Role of Homozygosity Mapping in the Early Diagnosis [J Clin Res Pediatr Endocrinol]
J Clin Res Pediatr Endocrinol. 2021; 13(1): 34-43 | DOI: 10.4274/jcrpe.galenos.2020.2020.0152

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

Maha Sherif1, Hüseyin Demirbilek1, Atilla Çayır2, Sophia Tahir1, Büşra Çavdarlı3, Meliha Demiral4, Ayşe Nurcan Cebeci5, Doğuş Vurallı6, Sofia Asim Rahman1, Edip Unal4, Gönül Büyükyılmaz7, Riza Taner Baran8, Mehmet Nuri Özbek9, Khalid Hussain10
1University College London, Institute of Child Health, Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, London, United Kingdom
2Regional Training and Research Hospital, Clinic of Paediatric Endocrinology, Erzurum, Turkey
3Ankara City Hospital, Clinic of Medical Genetics, Ankara, Turkey
4Gazi Yaşargil Training and Research Hospital, Clinic of Pediatric Endocrinology, Diyarbakır, Turkey
5Derince Training and Research Hospital, Clinic of Paediatric Endocrinology, Kocaeli, Turkey
6Hacettepe University Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey
7Ankara City Hospital, Clinic of Pediatric Endocrinology, Ankara, Turkey
8Diyarbakır Children’s Hospital, Clinic of Paediatric Endocrinology, Diyarbakır, Turkey
9Diyarbakır Children’s Hospital, Clinic of Paediatric Endocrinology, Diyarbakır, Turkey & Gazi Yaşargil Training and Research Hospital, Clinic of Pediatric Endocrinology, Diyarbakır, Turkey
10University College London, Institute of Child Health, Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, London, United Kingdom & Sidra Medicine, Department of Pediatrics, Division of Endocrinology, Doha, Qatar

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.

Keywords: Wolfram syndrome, WFS1, diabetes mellitus, diabetes insipidus, optic atrophy, sensorineural deafness

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. Identification of Three Novel and One Known Mutation in the Gene in Four Unrelated Turkish Families: The Role of Homozygosity Mapping in the Early Diagnosis. J Clin Res Pediatr Endocrinol. 2021; 13(1): 34-43
Manuscript Language: English
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