CRTAP-Related Osteogenesis Imperfecta: Clinical Variability and a Potential Founder Variant in CRTAP

Area of Science:

• Genetics
• Pediatrics
• Orthopedics

Background:

• Osteogenesis imperfecta (OI) encompasses a group of genetic disorders characterized by bone fragility.
• CRTAP-related osteogenesis imperfecta (OI), specifically OI type VII, is caused by biallelic variants in the CRTAP gene.
• This condition has been reported in approximately 30 cases, with a wide spectrum of severity.

Purpose of the Study:

• To describe the clinical and molecular findings in individuals with CRTAP-related OI.
• To expand the understanding of the phenotypic variability and genetic spectrum of this rare disorder.
• To investigate potential founder effects in specific populations.

Main Methods:

• Molecular confirmation of CRTAP variants in two adult patients and one fetus.
• Detailed clinical phenotyping, including skeletal and extra-skeletal manifestations.
• Variant analysis and population genetics considerations.

Main Results:

• Phenotypic variability ranged from moderate (OI type IV) to severe (OI type III), with diverse fracture patterns.
• Novel CRTAP variants were identified, expanding the known mutational landscape.
• One patient presented with high myopia and retinal detachment, previously unreported in OI type VII.
• A potentially high carrier frequency of a specific CRTAP variant was suggested in the Cape Verdean population.

Conclusions:

• CRTAP-related OI displays significant clinical heterogeneity, with both prenatal and postnatal onset possible.
• The study highlights the importance of considering CRTAP in the genetic diagnosis of OI.
• Further investigation into CRTAP's role in extra-skeletal tissues and population-specific founder effects is warranted.