ESPE Abstracts (2019) 92 P2-91

A Novel Variant of the WFS1 Gene with Dominant Inheritance Causing Wolfram-like Syndrome

Juraj Stanik1,2, Martina Skopkova2, Lukas Varga3, Ivica Masindova2, Emilia Jancova1, Milan Profant3, Daniela Gasperikova2

1Department of Pediatrics, Medical Faculty of Comenius University and National Institute of Children's Diseases, Bratislava, Slovakia. 2DIABGENE Laboratory, Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia. 3Department of Otorhinolaryngology-Head and Neck Surgery, Faculty of Medicine and University Hospital, Comenius University, Bratislava, Slovakia

Aims/hypothesis: The Wolfram syndrome, also known as the DIDMOAD syndrome (Diabetes Insipidus, early-onset Diabetes Mellitus, progressive Optic Atrophy, and Deafness), is mostly associated with recessive mutations in the WFS1 gene. However, dominant mutations in the WFS1 gene were described as causing less severe Wolfram-like syndrome, or isolated optic atrophy, or low-frequency sensorineural hearing loss.

Methods: Here we describe a patient, currently an 20-years old boy, with congenital hearing loss (received cochlear implant in 2.5 years of age), bilateral cataracts, epilepsy, autism, and non-autoimmune insulin-dependent diabetes mellitus diagnosed at 8 years of age. His father is reported as healthy; mother has an undefined hearing impairment, and she underwent an unspecified eye surgery and wears glasses. Genetic testing included Sanger sequencing of the WFS1 gene (promoter region and all 8 exons with exon/intron boundaries) and MLPA (SALSA P163-GJB-WFS1, MRC-Holland) for identifying potential deletions or duplications. All tests were performed in the patient and his parents.

Results: A novel heterozygous in-frame deletion NM_006005.3:c.2608_2619del, p.(870_873del) was identified in the exon 8 of the WFS1 gene in the patient DNA. This variant was not found in the mother. No other rare variant was found by sequencing and no dosage defect was detected using MLPA in both the patient and his mother. No WSF1 mutations were found in his father.

Conclusions/interpretation: The identification of this novel heterozygous variant found in the patient supports the diagnosis of the Wolfram-like syndrome with dominant inheritance in the patient. However, the suspicious phenotype of the mother keep a possibility of a second, yet unidentified, genetic defect open. Variable inheritance pattern together with the progressive character of clinical symptoms complicate the diagnosis and family genetic counseling in Wolfram syndrome.

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