A novel de novo missense mutation in TP63 underlying germline mosaicism in AEC syndrome: Implications for recurrence risk and prenatal diagnosis
A novel de novo missense mutation in TP63 underlying germline mosaicism in AEC syndrome: Implications for recurrence risk and prenatal diagnosis
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DOI：
10.1002/ajmg.a.35414
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发表时间：
2012-08-01
影响因子：
2
通讯作者：
Di Iorio, Enzo
中科院分区：
文献类型：
--
作者：
Barbaro, Vanessa;Nardiello, Paola;Di Iorio, Enzo
踝睑外胚层缺陷唇/腭裂（AEC）综合征是一种罕见的常染色体显性外胚层发育不良综合征。它是由编码 p53 家族转录因子的 TP63 杂合突变引起的。 TP63 突变（主要是编码不育 α 基序 (SAM) 和反式激活抑制 (TI) 结构域的外显子 13 和 14 的错义）占 AEC 综合征个体突变的 99%。其中，70% 是新生突变，存在于受影响的患者中，但不存在于父母或健康的兄弟姐妹中。然而，当突变从头出现时，不可能区分父母中的散发突变或种系嵌合体。在后一种情况下，存在产生更多受影响后代的风险。我们描述了患有 AEC 综合征的两姐妹，她们的父母未受影响。两名患者在 TP63 外显子 13 中均携带杂合性 c.1568T>C 取代，导致该蛋白 SAM 结构域中的 p.L523P 发生变化。对父母血细胞、精液（来自父亲）和母体细胞（口腔、阴道和宫颈）的 DNA 进行分析，没有发现这种突变，这表明嵌合体可能涉及非常低比例的细胞（非常低级别的体细胞嵌合体），或更可能是母体性腺嵌合体。在 AEC 综合征遗传咨询期间评估复发风险时必须考虑嵌合现象，并且应向所有夫妇提供植入前/产前基因诊断，即使突变明显是新发的。 (C) 2012 年 Wiley 期刊公司。
Ankyloblepharonectodermal defectscleft lip/palate (AEC) syndrome is a rare autosomal dominant ectodermal dysplasia syndrome. It is caused by heterozygous mutations in TP63, encoding a transcriptional factor of the p53 family. Mutations in TP63, mainly missense in exons 13 and 14 encoding the sterile alpha motif (SAM) and the transactivation inhibitory (TI) domains, account for 99% of mutations in individuals with AEC syndrome. Of these, =70% are de novo mutations, present in the affected patient, but not in parents nor in healthy siblings. However, when a mutation appears de novo, it is not possible to differentiate between a sporadic mutation, or germline mosaicism in the parents. In this latter case, there is a risk of having additional affected offspring. We describe two sisters with AEC syndrome, whose parents were unaffected. Both patients carried the heterozygous c.1568T>C substitution in exon 13 of TP63, resulting in a p.L523P change in the SAM domain of the protein. Analyses of DNA from parental blood cells, seminal fluid (from the father) and maternal cells (buccal, vaginal, and cervical) did not reveal the mutation, suggesting that the mosaicism may involve a very low percentage of cells (very low grade somatic mosaicism) or, more likely, maternal gonadal mosaicism. Mosaicism must be considered for the assessment of recurrence risk during genetic counseling in AEC syndrome, and pre-implantation/prenatal genetic diagnosis should be offered to all couples, even when the mutation is apparently de novo. (C) 2012 Wiley Periodicals, Inc.