Abstract
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.
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Acknowledgements
We thank Matthew Shudt and Zhen Zhang at the Wadsworth Center Applied Genomics Technologies Core, New York State Department of Health, for next-generation sequencing; April Atkins and Emily McGrath at the Wadsworth Center, New York State Department of Health, for technical assistance; and Nathan Pankratz, University of Minnesota, and Karl G. Hill, Social Development Research Group, University of Washington, for generously sharing population B-allele frequency and GC content files for PennCNV software. This work was funded by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contracts HHSN275201100001I, HHSN27500005 and N01-DK-73431) and the Iowa Center for Birth Defects Research and Prevention (5U01DD001035).
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Carter, T., Sicko, R., Kay, D. et al. Copy-number variants and candidate gene mutations in isolated split hand/foot malformation. J Hum Genet 62, 877–884 (2017). https://doi.org/10.1038/jhg.2017.56
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DOI: https://doi.org/10.1038/jhg.2017.56
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