Heterozygous WNT1 variant causing a variable bone phenotype.

Area of Science:

• Genetics and Molecular Biology
• Pediatric Endocrinology
• Skeletal Dysplasias

Background:

• Osteogenesis imperfecta (OI) encompasses heritable bone fragility disorders, primarily linked to type I collagen gene mutations, but also involving at least 17 other genes.
• Heterozygous missense variants in the WNT1 gene are known to cause early-onset osteoporosis with diverse skeletal phenotypes.
• Biallelic loss-of-function mutations in WNT1 are associated with severe forms of OI.

Observation:

• A third-generation family presented with variable bone phenotypes, including childhood fractures and early-onset osteoporosis without significant fracture history.
• A novel WNT1 variant (c.1051C>G; p.Trp351Arg) was identified and segregated with the bone phenotype in affected family members, indicating autosomal dominant inheritance.
• The proband also carried a de novo 22q11.2 duplication (434 kb), potentially contributing to non-osseous features like hypotonia and developmental delay.

Findings:

• The identified WNT1 variant (p.Trp351Arg) demonstrates variable expressivity, leading to a spectrum of bone fragility phenotypes within the same family.
• This case confirms the role of heterozygous WNT1 mutations in causing a range of osteogenesis imperfecta presentations.
• The co-occurrence of a WNT1 variant and a 22q11.2 duplication in the proband suggests potential complex genetic contributions to phenotype.

Implications:

• This study expands the understanding of the genotypic and phenotypic spectrum of WNT1-associated bone disorders.
• It underscores the importance of genetic testing for WNT1 in individuals with unexplained osteoporosis or bone fragility, even with atypical presentations.
• The findings contribute to the diagnostic framework for rare skeletal dysplasias and highlight the variability in WNT1-related phenotypes.