EFTUD2 haploinsufficiency leads to syndromic oesophageal atresia
EFTUD2 haploinsufficiency leads to syndromic oesophageal atresia
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DOI：
10.1136/jmedgenet-2012-101173
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发表时间：
2012-12-01
影响因子：
4
通讯作者：
Amiel, Jeanne
中科院分区：
文献类型：
--
作者：
Gordon, Christopher T.;Petit, Florence;Amiel, Jeanne
背景：食道闭锁(OA)和颌面部发育不良(MFD)是两种先天性畸形，其综合征形式的分子基础正在迅速被识别。特别是，在MFD和小头畸形患者(MIM610536)中发现了编码剪接体复合体蛋白的EFTUD2基因突变。结果：我们报告了10例MFD患者，其中8例为OA，要么是由于EFTUD2及其邻近基因的17q21.31缺失，要么是由于EFTUD2杂合性功能丧失突变。在一系列孤立性骨性关节炎或孤立性眼耳颈椎谱(OAVS)患者中没有发现EFTUD2缺失或突变。结论：这些数据排除了与MFD和OA相关的邻近基因综合征，拓宽了归因于EFTUD2单倍性不足的临床特征谱，定义了一个新的综合征性OA实体，并强调了通过剪接体复合体在胚胎发育过程中的特定区域内通过剪接体复合体实现mRNA成熟的必要性。重要的是，这里报告的大多数EFTUD2病变的患者以前被诊断为Feingold或Charge综合征或表现为OAVS加OA，这突显了表达的多样性和广泛的鉴别诊断。
Background: Oesophageal atresia (OA) and mandibulofacial dysostosis (MFD) are two congenital malformations for which the molecular bases of syndromic forms are being identified at a rapid rate. In particular, the EFTUD2 gene encoding a protein of the spliceosome complex has been found mutated in patients with MFD and microcephaly (MIM610536). Until now, no syndrome featuring both MFD and OA has been clearly delineated.Results: We report on 10 cases presenting with MFD, eight of whom had OA, either due to de novo 17q21.31 deletions encompassing EFTUD2 and neighbouring genes or de novo heterozygous EFTUD2 loss-of-function mutations. No EFTUD2 deletions or mutations were found in a series of patients with isolated OA or isolated oculoauriculovertebral spectrum (OAVS).Conclusions: These data exclude a contiguous gene syndrome for the association of MFD and OA, broaden the spectrum of clinical features ascribed to EFTUD2 haploinsufficiency, define a novel syndromic OA entity, and emphasise the necessity of mRNA maturation through the spliceosome complex for global growth and within specific regions of the embryo during development. Importantly, the majority of patients reported here with EFTUD2 lesions were previously diagnosed with Feingold or CHARGE syndromes or presented with OAVS plus OA, highlighting the variability of expression and the wide range of differential diagnoses.