Department of Medical Genetics, National Health Commission Key Laboratory of Birth Defects Research, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, China.
Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, Changsha, China.
Mol Genet Genomic Med. 2021 Mar;9(3):e1604. doi: 10.1002/mgg3.1604. Epub 2021 Jan 20.
Split hand/foot malformation (SHFM) is a congenital limb developmental disorder, which impairs the fine activities of hand/foot in the affected individuals seriously. SHFM is commonly inherited as an autosomal dominant disease with incomplete penetrance. Chromosomal aberrations such as copy number variations and translocations have been linked to SHFM. This study aimed to identify the genetic cause for three patients with bilateral hand and foot malformation in a Chinese family.
Karyotyping, single-nucleotide polymorphism (SNP) array, whole exome sequencing, whole genome sequencing, and Sanger sequencing were applied to identify the pathogenic variant.
Karyotyping revealed that the three patients had balanced reciprocal translocation, 46, XX, t(3;15) (q29;q22). SNP array identified no pathogenic copy number variation in the proband. Trio-WES (fetus-mother-father) sequencing results revealed no pathogenic variants in the genes related to SHFM. Whole-genome low-coverage mate-pair sequencing (WGL-MPS), breakpoint PCR, and Sanger sequencing identified the breakpoints disrupting TP63 in the patients, but not in healthy family members.
This study firstly reports that a translocation breakpoint disrupting TP63 contributes to the SHFM in a Chinese family, which expands our knowledge of genetic risk and counseling underlying SHFM. It provides a basis for genetic counseling and prenatal diagnosis (preimplantation genetic diagnosis) for this family.
分裂手/足畸形（SHFM）是一种先天性肢体发育障碍，严重影响受影响个体手/足的精细活动。SHFM通常作为不完全外显率的常染色体显性疾病遗传。染色体异常，如拷贝数变异和易位，与 SHFM 有关。本研究旨在鉴定一个中国家庭中 3 例双侧手和足畸形患者的遗传病因。
核型分析、单核苷酸多态性（SNP）微阵列、全外显子组测序、全基因组测序和 Sanger 测序用于鉴定致病变异。
核型分析显示 3 例患者均存在平衡易位，46，XX，t（3；15）（q29；q22）。SNP 微阵列未在先证者中发现致病性拷贝数变异。三亲子全外显子组测序（胎儿-母亲-父亲）结果显示与 SHFM 相关的基因中无致病性变异。全基因组低覆盖度 mate-pair 测序（WGL-MPS）、断点 PCR 和 Sanger 测序鉴定了患者中破坏 TP63 的断点，但在健康家庭成员中未发现。
本研究首次报道了一个破坏 TP63 的易位断点导致中国一个家庭发生 SHFM，这扩展了我们对 SHFM 遗传风险和咨询的认识。它为该家庭的遗传咨询和产前诊断（植入前遗传学诊断）提供了依据。
