Department of Medical Genetics and Prenatal Diagnosis, Hospital Affiliated 5 to Nantong University (Taizhou People's Hospital), Taizhou, Jiangsu, China.
BMC Med Genomics. 2021 Feb 23;14(1):53. doi: 10.1186/s12920-021-00903-4.
Cleft lip with or without cleft palate (CL/P) is the most common craniofacial anomaly with a high incidence of live births. The specific pathogenesis of CL/P is still unclear, although plenty of studies have been conducted. Variations of tumor protein 63 (TP63) was reported to be related to the phenotype of CL/P. The case discussed in this report involves a pedigree with mutation at TP63 gene, and the variation was not reported before.
A Chinese pedigree with CL/P was collected in this study. The proband is a 3-year-old boy with the phenotype of CL/P, while his global development and intelligence are normal. After two CL/P repair operations, he looks almost normal. The proband's uncle and grandmother both have the phenotype of CL/P. Cytogenetic analysis and chromosomal microarray analysis (CMA) were performed, followed by whole exome sequencing (WES) and sanger validation. Analysis of WES revealed a variant of C>T at nucleotide position 1324 (1324C>T) of TP63 gene, possibly producing a truncated protein with a premature stop codon at amino acid position 442 (p.Q442*). This mutation was localized at the oligomerization domain (OD) of TP63 and might impair the capacity of p63 oligomerization.
The mutation in TP63 was recognized to be the possible cause of the phenotype of CL/P in this pedigree. This report provides some evidence for the clinical diagnosis of CL/P. And our study also provides clinical evidence for the molecular mechanism of TP63 gene causing nonsyndromic cleft lip with or without cleft palate (NSCL/P).
唇裂伴或不伴腭裂（CL/P）是最常见的颅面畸形，活产儿发病率较高。CL/P 的具体发病机制尚不清楚，尽管已经进行了大量研究。肿瘤蛋白 63（TP63）的变异与 CL/P 的表型有关。本报告讨论的病例涉及一个携带 TP63 基因突变的家系，该变异以前尚未报道过。
本研究收集了一个具有 CL/P 表型的中国家系。先证者是一名 3 岁男孩，表现为 CL/P，但其整体发育和智力正常。经过两次 CL/P 修复手术后，他看起来几乎正常。先证者的叔叔和祖母都有 CL/P 的表型。进行了细胞遗传学分析和染色体微阵列分析（CMA），随后进行了全外显子组测序（WES）和 Sanger 验证。WES 分析显示 TP63 基因第 1324 位核苷酸的 C>T 变异（1324C>T），可能导致第 442 位氨基酸处产生一个提前终止密码子的截短蛋白（p.Q442*）。该突变定位于 TP63 的寡聚化结构域（OD），可能会损害 p63 寡聚化的能力。
TP63 中的突变被认为是该家系 CL/P 表型的可能原因。本报告为 CL/P 的临床诊断提供了一些证据。我们的研究还为 TP63 基因引起非综合征性唇裂伴或不伴腭裂（NSCL/P）的分子机制提供了临床证据。
