Genetic and Clinical Spectrum of Osteogenesis Imperfecta in an Egyptian Cohort With a High Rate of Lethal Phenotypes

Osteogenesis imperfecta (OI) is a genetically heterogeneous connective tissue disorder marked by bone fragility and deformities. This study aimed to define the clinical and molecular characteristics of 21 OI patients from 15 unrelated Egyptian families. Most probands were analyzed by exome sequencing. In three consanguineous cases, variants were identified through SNP array-based homozygosity mapping followed by direct sequencing of a candidate gene. Genotype-phenotype correlations were additionally explored. Parental consanguinity was documented in 66.7% (10/15) of the total cohort and in 100% (8/8) of the families with autosomal recessive OI. Pathogenic or likely pathogenic variants were identified in 14 families, five of which were novel. A variant of uncertain significance was identified in the remaining family. COL1A1 and COL1A2 (n = 7) were the most commonly mutated genes, followed by CRTAP (n = 4), while variants in P3H1, WNT1, CREB3L1, and SEC24D were each identified in a single patient. The present study highlights the molecular heterogeneity of OI. In total, 15 distinct variants in seven OI-related genes were identified. We also report a particularly high number of OI lethal forms affecting 10 patients out of 21. The study adds further evidence for the utility of ES in the genetic diagnosis of OI, which facilitates counseling and personalized care.