Establishing an algorithm for molecular genetic diagnostics in Chinese children with brachydactyly type E

Area of Science:

• Medical Genetics
• Pediatric Endocrinology
• Skeletal Dysplasias

Background:

• Brachydactyly type E (BDE) involves limb shortening and can be isolated or part of syndromes.
• The role of genetic testing in precisely diagnosing BDE requires further clarification.
• Understanding genotype-phenotype correlations is crucial for effective diagnosis.

Purpose of the Study:

• To develop a molecular genetic diagnostic algorithm for Chinese children with BDE.
• To investigate genotype-phenotype correlations in Chinese BDE patients.
• To enhance the precision of BDE diagnosis through genetic analysis.

Main Methods:

• Retrospective review of 60,650 left-hand wrist X-rays to identify 135 BDE cases.
• Whole-exome sequencing (WES) with copy number variation (CNV) analysis in 60 patients.
• Sanger sequencing for validation of single nucleotide variants (SNVs) and indels.

Main Results:

• Causative variants identified in 19 patients (19.1% diagnostic yield in isolated BDE).
• SNVs/indels in 10 genes and CNVs in four genes were detected.
• GNAS mutations were the most frequent cause, followed by EXT1 and ACAN.

Conclusions:

• A diagnostic algorithm for precise molecular diagnosis of BDE in Chinese children is proposed.
• Genotype-phenotype correlations significantly improve diagnostic yield in syndromic BDE cases.
• This study enhances the understanding and diagnosis of BDE in the pediatric population.