A NOVEL DE NOVO LIKELY PATHOGENIC VARIANT OF WFS-1 GENE IN A PAKISTANI CHILD WITH NON-CLASSIC WFS-1 SPECTRUM DISORDER.

ABSTRACT: Wolfram syndrome is a progressive neurodegenerative disorder caused by an alteration in the WFS-1 gene, located on chromosome 4p16.1 and is characterized by the acronym DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness). WFS-1 gene encodes for a transmembrane protein termed Wolframin found in the membrane of the endoplasmic reticulum. Although Wolfram Syndrome is generally considered an autosomal recessive disorder, a milder non-classic autosomal dominant form has been reported in association with a single pathogenic or likely pathogenic variant in WFS-1 gene. Objective was to date more than 200 variants have been identified in the WFS-1 gene. This case report aims to highlight and explain a novel de-novo likely pathogenic variant of the WFS-1 gene in a Pakistani child, which is highly plausible to induce non-classic WFS-1 spectrum disorder (MedGen UID: 481988).

CASE DISCUSSION: Our patient, a seven-year-old boy, initially sought medical attention at our endocrine clinic for diabetic control. Besides diabetes, other notable features included short stature, sensorineural deafness and a history of bilateral cataracts. Family history was significant for parental consanguinity. A clinical diagnosis of Wolfram Syndrome was suspected and a multi gene panel test which included the WFS-1 gene was ordered. Initial report noted a variant of uncertain significance in the WFS-1 gene at c.2586G>T (p.Lys862Asn), which was later reclassified as a likely pathogenic variant by the laboratory based on the patient's clinical presentation.

CONCLUSIONS

Access to genetic testing is not readily available in Pakistan and our population is under studied and these complex diagnoses are often missed. In this study, we present a novel de novo likely pathogenic variant in the WFS-1 gene that causes non-classic WFS-1 spectrum disorder in a child from our population.