WFS1 – Wolfram-like syndrome

Wolfram-like syndrome (WFSL, MONDO:0013673) is an autosomal dominant neurodevelopmental disorder characterized by sensorineural hearing loss, diabetes mellitus, and optic atrophy. Heterozygous pathogenic variants in WFS1 (HGNC:12762) underlie WFSL, distinguishing it from recessive Wolfram syndrome. The gene encodes wolframin, an endoplasmic reticulum membrane protein involved in calcium homeostasis and unfolded protein response.

Genetic evidence for WFSL includes multiple de novo and familial missense variants. A de novo c.2425G>A (p.Glu809Lys) variant was first reported in a boy with juvenile-onset diabetes and multisystem anomalies (PMID:27217304). Subsequent de novo heterozygous c.2051C>T (p.Ala684Val) was identified in congenital bilateral deafness with optic atrophy (PMID:36330437), and the novel c.2508G>T (p.Lys836Asn) segregated in a mother–son pair with hearing loss and mild vision loss (PMID:35450504). A recurrent hotspot, c.2590G>A (p.Glu864Lys), was described across multiple families (PMID:29529044). A systematic review encompassed 86 unrelated WFSL patients from 35 studies, confirming missense variants as the predominant class (PMID:36764396).

Segregation data are limited but include transmission in five multigenerational families and at least three additional affected relatives carrying the same variant. Variant spectrum is dominated by missense mutations (e.g., p.Glu809Lys, p.Ala684Val, p.Lys836Asn), with few splice or truncating alleles reported, and no founder mutations outside hotspot positions.

Functional studies support a haploinsufficiency mechanism. Patient-derived induced pluripotent stem cells carrying p.Ala684Val exhibit impaired differentiation and increased endoplasmic reticulum stress, recapitulating key WFSL features (PMID:36933359). Concordant animal and cellular models demonstrate wolframin’s role in ER calcium regulation and stress response, aligning with human phenotypes.

No significant conflicting evidence has been reported. All identified variants co-segregate with disease, and no benign heterozygotes with identical alleles have been documented in large population cohorts.

In sum, heterozygous WFS1 missense variants cause autosomal dominant WFSL with high penetrance for hearing loss, diabetes, and optic atrophy. Genetic testing for WFS1 should be considered in early-onset syndromic deafness or optic atrophy. Early molecular diagnosis enables anticipatory management and genetic counseling.

Key take-home: WFS1 heterozygous missense mutations are a validated cause of autosomal dominant Wolfram-like syndrome with clear implications for diagnosis and management.

References

• Journal of clinical research in pediatric endocrinology • 2016 • A p.(Glu809Lys) Mutation in the WFS1 Gene Associated with Wolfram-like Syndrome: A Case Report. PMID:27217304
• Frontiers in genetics • 2022 • Case report: De novo pathogenic variant in WFS1 causes Wolfram-like syndrome debuting with congenital bilateral deafness. PMID:36330437
• Ophthalmic genetics • 2022 • Novel missense WFS1 variant causing autosomal dominant atypical Wolfram syndrome. PMID:35450504
• Stem cell research • 2023 • Generation of induced pluripotent stem cells (IBMSi027-A) from a patient with hearing loss carrying WFS1 c.2051C>T (p.Ala684Val) variant. PMID:36933359
• Survey of ophthalmology • 2023 • Delineating Wolfram-like syndrome: A systematic review and discussion of the WFS1-associated disease spectrum. PMID:36764396

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