Copy-number variants and candidate gene mutations in isolated split hand/foot malformation

Area of Science:

• Genetics
• Developmental Biology
• Medical Research

Background:

• Split hand/foot malformation (SHFM) is a congenital limb deficiency characterized by missing or shortened central digits.
• While some causative genes are known, the etiology of many SHFM cases remains unclear.
• Understanding the genetic basis of SHFM is crucial for diagnosis and potential therapeutic strategies.

Purpose of the Study:

• To identify novel genetic causes of SHFM in individuals without other congenital anomalies.
• To investigate the role of copy-number variants (CNVs) and gene mutations in SHFM pathogenesis.
• To explore potential regulatory mechanisms underlying limb development defects in SHFM.

Main Methods:

• Single-nucleotide polymorphism (SNP) microarray analysis was performed on 25 SHFM cases from New York State (NYS).
• Copy-number variants (CNVs) absent from population databases were prioritized and validated using quantitative real-time polymerase chain reaction (qPCR).
• Validated CNVs were tested in seven additional cases from Iowa, and 36 candidate SHFM genes were sequenced.

Main Results:

• Seven NYS cases harbored potentially deleterious variants: TP63 mutations (n=2), a 17q25 microdeletion (n=1), a 10q24 microduplication (n=1), and a 17p13.3 microduplication (n=3).
• One Iowa case presented with a de novo 10q24 microduplication.
• The novel 17q25 microdeletion encompassed SHFM candidate genes SUMO2 and GRB2; 10q24 and 17p13.3 CNVs had breakpoints in putative regulatory regions.

Conclusions:

• Novel genetic variants, including a previously unreported 17q25 microdeletion and microduplications in 10q24 and 17p13.3, contribute to SHFM.
• These findings suggest that SHFM can result from gene haploinsufficiency, deletion of regulatory regions, or disruption of regulatory elements controlling limb development genes.
• The study highlights the importance of CNV analysis and investigation of regulatory elements in understanding SHFM etiology.