Genotype-phenotype correlations in MYCN-related Feingold syndrome
Genotype-phenotype correlations in MYCN-related Feingold syndrome
复制标题
DOI：
10.1002/humu.20750
复制
发表时间：
2008-09-01
期刊：
影响因子：
3.9
通讯作者：
de Brouwer, Arjan P. M.
中科院分区：
文献类型：
--
作者：
Marcelis, Carlo L. M.;Hol, Frans A.;de Brouwer, Arjan P. M.
法因戈尔德综合征（FS）是家族性综合征性胃肠闭锁最常见的原因，遵循常染色体显性遗传。FS由MYCN基因的种系突变或缺失引起。此前，研究人员描述了12个不同的杂合MYCN突变和2个包含包括MYCN在内的多个基因的缺失。所有这些突变都导致典型MYCN蛋白和较短同工型Delta MYCN的单倍性不足。我们报告了11个新的突变，包括7个外显子2突变，导致MYCN长转录本中的过早终止密码子（PTC）。此外，我们在外显子1中发现了一个PTC，它只影响MYCN亚型，没有表型效应。这表明只有Delta MYCN的突变不会导致FS。此外，我们还发现了三个包含MYCN的新缺失。加上我们之前的报告，我们现在在DNA结合域共有4个错义突变，其中19个ptc中有6个使转录本受到无义介导的衰变（NMD），总共77例患者中有5个较大的缺失。我们回顾了这些患者的临床特征，发现指征异常，如短管状趾和趾并指是最一致的特征，分别出现在100%和97%的患者中。89%的病例头围小。胃肠道闭锁仍然是最重要的先天性异常（55%），但心脏和肾脏异常也很常见。我们认为，短食管和趾并趾合并小头畸形的存在足以证明MYCN分析的合理性。
Feingold syndrome (FS) is the most frequent cause of familial syndromic gastrointestinal atresia and follows autosomal dominant inheritance. FS is caused by germline mutations in or deletions of the MYCN gene. Previously, 12 different heterozygous MYCN mutations and two deletions containing multiple genes including MYCN were described. All these mutations result in haploinsufficiency of both the canonical MYCN protein and the shorter isoform, Delta MYCN. We report 11 novel mutations including seven mutations in exon 2 that result in a premature termination codon (PTC) in the long MYCN transcript. Moreover, we have identified a PTC in exon 1 that only affects the Delta MYCN isoform, without a phenotypic effect. This suggests that mutations in only Delta MYCN do not contribute to the FS. Additionally, we found three novel deletions encompassing MYCN. Together with our previous report we now have a total of four missense mutations in the DNA binding domain, 19 PTCs of which six render the transcript subject to nonsense-mediated decay (NMD), and five larger deletions in a total of 77 patients. We have reviewed the clinical features of these patients, and found that digital anomalies, e.g., brachymesophalangy and toe syndactyly, are the most consistent features, present in 100% and 97% of the patients, respectively. Small head circumference was present in 89% of the cases. Gastrointestinal atresia remains the most important major congenital anomaly (55%), but cardiac and renal anomalies are also frequent. We suggest that the presence of brachymesophalangy and toe syndactyly in combination with microcephaly is enough to justify MYCN analysis.