Non-collagen pathogenic variants resulting in the osteogenesis imperfecta phenotype in children: a single-country...

Area of Science:

• Genetics
• Pediatrics
• Rare Diseases

Background:

• Severe, complex, and atypical osteogenesis imperfecta (OI) in children (0-18 years) in England is managed by a Highly Specialised Service (HSS OI).
• The majority of 'atypical' OI cases managed by the HSS OI have genetic origins not linked to COL1A1 or COL1A2.
• This study assesses the spectrum and frequency of non-collagen pathogenic variants causing OI within this national service.

Purpose of the Study:

• To evaluate the range and frequency of non-collagen pathogenic variants in children with atypical osteogenesis imperfecta (OI).
• To understand the genetic basis of severe and complex OI cases managed by the Highly Specialised Service (HSS OI).

Main Methods:

• Children meeting 'atypical' OI criteria within the HSS OI service database were identified.
• Genetic testing was performed at the Sheffield Diagnostic Genetics Service, and variant data were extracted and matched to patients.
• This service evaluation was registered with the Sheffield Children's Hospital Clinical Governance Department.

Main Results:

• Of 337 children in the HSS OI, 100 met 'atypical' criteria; 80 underwent genetic testing.
• Genetic changes were detected in 72 children, with 67 having variants in 13 known OI-causative genes.
• The most frequent genes affected were IFITM5 (22 children), P3H1 (12), SERPINF1 (8), and BMP1 (6).

Conclusions:

• Approximately 20% of children with severe OI forms have pathogenic variants in non-collagen genes.
• IFITM5 was the most commonly implicated gene, followed by the P3H1 complex genes.
• These findings offer insights into the genetic etiology of OI, potentially guiding clinical management.