[Genetic analysis of five pedigrees affected with multiple osteochondromas]

Area of Science:

• Genetics
• Medical Genetics
• Oncology

Background:

• Multiple osteochondromas is a rare genetic disorder characterized by the development of numerous benign bone tumors.
• Mutations in the EXT1 and EXT2 genes are the primary cause of multiple osteochondromas, affecting cartilage growth and bone development.

Purpose of the Study:

• To identify pathogenic variants in the EXT1 and EXT2 genes in five families affected with multiple osteochondromas.
• To offer precise prenatal diagnosis for families carrying identified genetic variants.

Main Methods:

• Targeted next-generation sequencing (NGS) was employed to analyze EXT1 and EXT2 genes in probands.
• Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) were used for variant validation and detection of gross deletions.
• Prenatal diagnosis was performed for two couples with confirmed pathogenic or likely pathogenic variants.

Main Results:

• Five variants were identified, including a novel EXT1 exon 2-3 deletion, c.2084delC, and a novel EXT2 c.187delT variant.
• These three novel variants were absent in unaffected family members and 200 healthy controls.
• Prenatal diagnosis confirmed that the two fetuses carried the same pathogenic variants as their affected probands.

Conclusions:

• Pathogenic variants in EXT1 and EXT2 genes are strongly associated with multiple osteochondromas in the studied pedigrees.
• Genetic testing and subsequent prenatal diagnosis are crucial for preventing the inheritance of multiple osteochondromas.