Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Eur J Hum Genet. 2019 Dec;27(12):1845-1857. doi: 10.1038/s41431-019-0473-7. Epub 2019 Jul 22.
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.
并指（趾）畸形（SHFM）是一种临床表现和遗传异质性都很强的疾病。我们先后对新招募的 41 个有非综合征型和综合征型 SHFM 的日本家族进行了先前确定的日本 17p13.3 重复/三重复涉及 BHLHA9 的筛查、比较基因组杂交和外显子组测序（WES），以及对我们之前对 56 个家族的研究中未发现潜在遗传原因的 7 个有非综合征型和综合征型 SHFM 的家族进行了 WES。结果，我们不仅发现了已知的致病性 CNVs（17p13.3 重复/三重复[21 例]、2q31 缺失[1 例]和 10q24 重复[3 例]）和已知致病基因中的罕见变异（TP63[3 例]、DLX5[1 例]、IGF2[1 例]、WNT10B[3 例]、WNT10B/PORCN[1 例]和 PORCN[1 例]），还发现了一个新的 19q13.11 缺失导致 UBA2 失活（1 例）和可能影响 LRP6（1 例）和 UBA2（1 例）功能的变异。因此，连同我们之前基于对 56 个家族的测试数据，对总共 97 个 SHFM 家族的分子研究揭示了 75 个家族的潜在遗传原因，对这 75 个家族的临床研究表明遗传原因与表型之间存在一定程度的相关性。结果表明，SHFM 主要是一种具有基因型-表型相关性的遗传疾病。此外，这些结果与 Lrp6 基因敲除小鼠中出现 SHFM、涉及 UBA2 的 19q13 缺失的两个患者中存在 SHFM 以及发育中的肢芽中强烈的小鼠 Uba2 表达等先前数据一起，提示 LRP6 和 UBA2 可能是 SHFM 的候选基因。
