Abstract
Split-hand/foot malformation (SHFM) is a clinically and genetically heterogeneous condition. We sequentially performed screening of the previously identified Japanese founder 17p13.3 duplication/triplication involving BHLHA9, array comparative genomic hybridization, and whole exome sequencing (WES) in newly recruited 41 Japanese families with non-syndromic and syndromic SHFM. We also carried out WES in seven families with nonsyndromic and syndromic SHFM in which underlying genetic causes including pathogenic copy-number variants (CNVs) remained undetected in our previous studies of 56 families. Consequently, we identified not only known pathogenic CNVs (17p13.3 duplications/triplications [n = 21], 2q31 deletion [n = 1], and 10q24 duplications [n = 3]) and rare variants in known causative genes (TP63 [n = 3], DLX5 [n = 1], IGF2 [n = 1], WNT10B [n = 3], WNT10B/PORCN [n = 1], and PORCN [n = 1]), but also a de novo 19q13.11 deletion disrupting UBA2 (n = 1) and variants that probably affect function in LRP6 (n = 1) and UBA2 (n = 1). Thus, together with our previous data based on testing of 56 families, molecular studies for a total of 97 families with SHFM revealed underlying genetic causes in 75 families, and clinical studies for the 75 families indicated a certain degree of correlation between genetic causes and phenotypes. The results imply that SHFM primarily occurs as a genetic disorder with genotype–phenotype correlations. Furthermore, the results together with previous data such as the development of SHFM in Lrp6 knockout mice, the presence of SHFM in two subjects with 19q13 deletions involving UBA2, and strong mouse Uba2 expression in the developing limb buds, imply that LRP6 and UBA2 represent plausible candidate genes for SHFM.
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Acknowledgements
We are grateful to all patients and their parents for their cooperation. We thank Ms. Aya Kitamoto and Mr. Naoki Adachi for their technical support. We also thank Drs Toshiro Nagai, Hironao Numabe, Seiji Mizuno, Toshiro Nagai, Keisuke Nagasaki, Hiroaki Yagasaki, You Omura, Noriyuki Namba, Satoshi Okada, Sadao Ito, Hiromi Iwata, Yuri Endo, Kaori Hara, Takahito Wada, and Akira Oishi for providing clinical information and patient samples.
Funding
This work was supported by Grants from the Japan Agency for Medical Research and Development (AMED) (JP17ek0109297 and JP18ek0109301) and by Grant-in-Aid for Scientific Research on Innovative Areas (JP17H06428) from the Japan Society for the Promotion of Science (JSPS).
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This study was approved by the Institutional Review Board Committee of Hamamatsu University School of Medicine, and was performed after obtaining written informed consent (IC) from adult subjects (≥20 years old) or parents of nonadult subjects (<20 years old). We also obtained informed assent from children aged ≥6 years.
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Yamoto, K., Saitsu, H., Nishimura, G. et al. Comprehensive clinical and molecular studies in split-hand/foot malformation: identification of two plausible candidate genes (LRP6 and UBA2). Eur J Hum Genet 27, 1845–1857 (2019). https://doi.org/10.1038/s41431-019-0473-7
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DOI: https://doi.org/10.1038/s41431-019-0473-7
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