Split hand/foot malformation (SHFM) is a congenital limb deficiency with missing or shortened central digits. Some SHFM genes have been identified but the cause of many SHFM cases is unknown. We used single-nucleotide polymorphism (SNP) microarray analysis to detect copy-number variants (CNVs) in 25 SHFM cases without other birth defects from New York State (NYS), prioritized CNVs absent from population CNV databases, and validated these CNVs using quantitative real-time polymerase chain reaction (qPCR). We tested for the validated CNVs in seven cases from Iowa using qPCR, and also sequenced 36 SHFM candidate genes in all the subjects. Seven NYS cases had a potentially deleterious variant: two had a p.R225H or p.R225L mutation in TP63, one had a 17q25 microdeletion, one had a 10q24 microduplication and three had a 17p13.3 microduplication. In addition, one Iowa case had a de novo 10q24 microduplication. The 17q25 microdeletion has not been reported previously in SHFM and included two SHFM candidate genes (SUMO2 and GRB2), while the 10q24 and 17p13.3 CNVs had breakpoints within genomic regions that contained putative regulatory elements and a limb development gene. In SHFM pathogenesis, the microdeletion may cause haploinsufficiency of SHFM genes and/or deletion of their regulatory regions, and the microduplications could disrupt regulatory elements that control transcription of limb development genes.Journal of Human Genetics advance online publication, 25 May 2017; doi:10.1038/jhg.2017.56.
This research output has an Altmetric Attention Score of 4. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 27 September 2017.
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