Abstract
Osteogenesis imperfecta (OI) is a family of heritable disorders of bone fragility. Most individuals with OI have mutations in the genes encoding type I collagen; at least 17 other genes have been associated with OI. Biallelic loss-of-function mutations in
WNT1
cause severe OI. Heterozygous missense variants in
WNT1
are responsible for early-onset osteoporosis with variable bone phenotypes. Herein we report a 3-generation family with four affected individuals, some presenting with multiple low-impact fractures in childhood and others presenting with early-onset osteoporosis without a striking fracture history. A
WNT1
variant (c. 1051>C; p.Trp351Arg) was identified in the proband and segregated with a bone phenotype in three additional family members, consistent with autosomal dominant inheritance. In the proband, whole genome sequencing also revealed a de novo duplication (434 kb) of 22q11.2 that involves 25 genes, 4 of which are associated with human disease when haploinsufficient. Though smaller than the typical (1.5 Mb) 22q11.2 duplication, the duplication in the proband may be responsible for additional non-osseous aspects of his phenotype (hypotonia, developmental delay, small genitalia, strabismus, and depression in pre-adolescence). This case demonstrates the variability of bone phenotype conferred by a
WNT1
variant and extends the spectrum of bone phenotypes associated with heterozygous
WNT1
mutations.