Dominant ER Stress–Inducing WFS1 Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts

Abstract

Neonatal diabetes is frequently part of a complex syndrome with extrapancreatic features: 18 genes causing syndromic neonatal diabetes have been identified to date. There are still patients with neonatal diabetes who have novel genetic syndromes. We performed exome sequencing in a patient and his unrelated, unaffected parents to identify the genetic etiology of a syndrome characterized by neonatal diabetes, sensorineural deafness, and congenital cataracts. Further testing was performed in 311 patients with diabetes diagnosed before 1 year of age in whom all known genetic causes had been excluded. We identified 5 patients, including the initial case, with three heterozygous missense mutations in WFS1 (4/5 confirmed de novo). They had diabetes diagnosed before 12 months (2 before 6 months) (5/5), sensorineural deafness diagnosed soon after birth (5/5), congenital cataracts (4/5), and hypotonia (4/5). In vitro studies showed that these WFS1 mutations are functionally different from the known recessive Wolfram syndrome–causing mutations, as they tend to aggregate and induce robust endoplasmic reticulum stress. Our results establish specific dominant WFS1 mutations as a cause of a novel syndrome including neonatal/infancy-onset diabetes, congenital cataracts, and sensorineural deafness. This syndrome has a discrete pathophysiology and differs genetically and clinically from recessive Wolfram syndrome.

Trisomy 21 Is a Cause of Permanent Neonatal Diabetes That Is Autoimmune but Not HLA Associated

“…All individuals diagnosed in the first 6 months of life were tested for mutations either by rapid Sanger sequencing of ABCC8, KCNJ11, and INS or, if no mutation was identified, via targeted DNA sequencing through next-generation sequencing (tNGS) of all 24 genes (1)(2)(3)(4)9). This assay can detect single nucleotide variants, insertion-deletions, copy number variation, and structural variation (9).…”

“…Permanent neonatal diabetes (PNDM) is diagnosed before the age of 6 months, and a genetic diagnosis is possible for .82% of cases (1). Twenty-four causative PNDM genes have been identified (1)(2)(3)(4), and four of these cause monogenic autoimmune PNDM that results from destruction of the b-cells very early in life (FOXP3, IL2RA, LRBA, and STAT3). Identifying novel causes of autoimmune neonatal diabetes can provide key insights into the development of autoimmunity and can provide new targets for therapeutic intervention.…”

Proteasome subunitPSMC3variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress

“…These features have not yet been related to this group of disorders to date. Moreover this association has only been reported twice in larger syndromic forms such as the dominant form of WFS1 but in the context of neonatal/infancy -onset diabetes (De Franco et al, 2017) and the Aymé-Gripp syndrome (including also intellectual disability, seizures and Down syndrome like facies) with de novo pathogenic variants in the MAF gene (Niceta et al, 2015). Variations in the later one were shown to impair in vitro MAF phosphorylation, ubiquitination and proteasomal degradation.…”

Congenital Diabetes: Comprehensive Genetic Testing Allows for Improved Diagnosis and Treatment of Diabetes and Other Associated Features

“…In the heterozygous state, cases with isolated features such as diabetes or deafness have been reported. However, a recent paper demonstrated a distinct type of severe, heterozygous mutations which caused infancy-onset diabetes (median diagnosis age 35 weeks, range 13–50 weeks), deafness, cataracts, and hypotonia by inducing a significant level of ER stress [64]. …”