WFS1 Gene–associated Diabetes Phenotypes and Identification of a Founder Mutation in Southern India

• Published in: The journal of clinical endocrinology and metabolism Vol. 107; no. 5; pp. 1328 - 1336
• Main Authors: Chapla, Aaron, Johnson, Jabasteen, Korula, Sophy, Mohan, Nisha, Ahmed, Anish, Varghese, Deny, Rangasamy, Parthiban, Ravichandran, Lavanya, Jebasingh, Felix, Kumar Agrawal, Krishna, Somasundaram, Noel, Hesarghatta Shyamasunder, Asha, Mathai, Sarah, Simon, Anna, Jha, Sujeet, Chowdry, Subhankar, Venkatesan, Radha, Raghupathy, Palany, Thomas, Nihal
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.05.2022
• Subjects: Analysis; Atrophy; Deafness; Diabetes; Diabetes insipidus; Diagnosis; DNA sequencing; Female; Founder effect; Genes; Genetic aspects; Genetic screening; Haplotypes; Hereditary diseases; Humans; India - epidemiology; Male; Medical screening; Membrane Proteins - genetics; Mutation; Neurodegeneration; Next-generation sequencing; Nucleotide sequencing; Optic atrophy; Phenotype; Phenotypes; Type 2 diabetes; Wolfram Syndrome - diagnosis; Wolfram Syndrome - genetics; Wolfram Syndrome - pathology; India; Wolfram syndrome; next-generation sequencing; founder mutation; DIDMOAD; WFS1
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/clinem/dgac002

Abstract Context Wolfram syndrome (WFS) is a rare autosomal recessive disorder characterized by juvenile-onset diabetes, diabetes insipidus, optic atrophy, deafness, and progressive neurodegeneration. However, due to the progressive nature of the disease and a lack of complete clinical manifestations, a confirmed diagnosis of WFS at the time of onset of diabetes is a challenge. Objective With WFS1 rare heterozygous variants reported in diabetes, there is a need for comprehensive genetic screening strategies for the early diagnosis of WFS and delineating the phenotypic spectrum associated with the WFS1 gene variants in young-onset diabetes. Methods This case series of 11 patients who were positive for WFS1 variants were identified with next-generation sequencing (NGS)–based screening of 17 genemonogenic diabetes panel. These results were further confirmed with Sanger sequencing. Results 9 out of 11 patients were homozygous for pathogenic/likely pathogenic variants in the WFS1 gene. Interestingly, 3 of these probands were positive for the novel WFS1 (NM_006005.3): c.1107_1108insA (p.Ala370Serfs*173) variant, and haplotype analysis suggested a founder effect in 3 families from Southern India. Additionally, we identified 2 patients with young-onset diabetes who were heterozygous for a likely pathogenic variant or a variant of uncertain significance in the WFS1 gene. Conclusion These results project the need for NGS-based parallel multigene testing as a tool for early diagnosis of WFS and identify heterozygous WFS1 variants implicated in young-onset diabetes.