# Example of Intrafamilial Clinical Polymorphism in a Family with Osteogenesis Imperfecta

## TL;DR

This study examines a family with osteogenesis imperfecta and finds significant variation in symptoms across generations, highlighting the importance of genetic testing for accurate diagnosis and counseling.

## Contribution

The study presents a case of intrafamilial clinical polymorphism in a large family with OI, emphasizing the role of molecular diagnosis in risk assessment.

## Key findings

- A heterozygous pathogenic variant in the COL1A1 gene (c.1243C>T, p.Arg415*) was identified and confirmed to co-segregate with OI in the family.
- Clinical symptoms varied widely among affected family members, influenced by age and lineage.
- Molecular diagnosis enabled accurate risk assessment and informed treatment with bisphosphonate therapy for pediatric patients.

## Abstract

Background/Objectives: According to the International Classification of Hereditary Skeletal Diseases (2019), osteogenesis imperfecta (OI) is classified as a disorder resulting from impaired formation of the cortical layer density of diaphyses and metaphyseal modeling. OI comprises a heterogeneous group of genetic diseases, with most cases inherited in an autosomal dominant manner, while others follow autosomal recessive or X-linked recessive inheritance patterns. Accurate DNA testing is essential for precise medical and genetic counseling, ensuring reliable prognostic assessments for patients’ descendants and siblings. As part of a medical genetic study of the population of the Republic of the North Ossetia Alania, specifically in the Mozdok district, specialists from the Laboratory of Genetic Epidemiology at the Research Centre for Medical Genetics (RCMG) examined a family with 13 affected individuals with OI across four generations. Methods: A comprehensive clinical assessment was performed, followed by molecular genetic analysis using whole-exome sequencing (WES). Segregation analysis within the family was conducted via Sanger sequencing. Results: Clinical evaluation suggested a diagnosis of OI, which was subsequently confirmed by genetic testing. The severity and spectrum of symptoms varied considerably among affected family members and were influenced by age and specific nuclear family lineage. Molecular analysis in the proband identified a heterozygous pathogenic variant in the COL1A1 gene variant (c.1243C>T, p.(Arg415*)), confirming a diagnosis of OI type IV. The variant was found to co-segregate with the disease within the family. Conclusions: Molecular diagnosis enabled precise risk assessment for affected offspring in family members with mild phenotypic manifestations. Additionally, pediatric patients were referred for standard bisphosphonate therapy to manage the condition effectively.