Molecular diagnostics of Meckel-Gruber syndrome highlights phenotypic differences between MKS1 and MKS3
Molecular diagnostics of Meckel-Gruber syndrome highlights phenotypic differences between MKS1 and MKS3
复制标题
DOI：
10.1007/s00439-007-0341-3
复制
发表时间：
2007-06-01
期刊：
影响因子：
5.3
通讯作者：
Harris, Peter C.
中科院分区：
文献类型：
--
作者：
Consugar, Mark B.;Kubly, Vickie J.;Harris, Peter C.
Meckel-Gruber综合征（MKS）是一种以肾囊性发育不良、枕叶脑膨出、多指（趾）畸形和胆管发育不全为特征的遗传性疾病。MKS具有遗传异质性，其中三个位点被定位，两个位点被鉴定; MKS 1（17 q23）和MKS 3（8q22.1）。MKS 1是芬兰疾病遗传的一部分，而MKS 3仅在近亲亚洲家庭中描述。在这里，我们的目的是建立MKS的分子诊断，确定MKS 1和MKS 3在非血缘人群中的重要性，并研究基因型/表型相关性。在美国或荷兰的17个临床诊断为MKS的家族中，通过直接测序筛选MKS 1和MKS 3的编码区的突变。将临床表型与基因和等位基因效应进行比较。这两种突变在10个家族中被鉴定; 5个MKS 1和5个MKS 3。除了两个是复合杂合子，符合他们的非血缘性质。MKS 1-Fin（主要）突变占7/10 MKS 1突变;另外检测到两种新变化。在MKS 3中发现了7个新的突变，包括3个错义突变。我们的结论是，MKS 1和MKS 3占大多数的MKS在非血缘人群的欧洲血统。多指（趾）畸形通常见于MKS 1，但在MKS 3中罕见。仅在MKS 3中发现了没有或较轻的中枢神经系统表型的病例;亚型错义突变可能与不太严重的中枢神经系统结局相关。这项研究与MKS的进一步遗传异质性是一致的，但强调了已知基因的分子诊断对计划生育决策的价值。
Meckel-Gruber syndrome (MKS) is a recessively inherited, lethal disorder characterized by renal cystic dysplasia, occipital encephalocele, polydactyly and biliary dysgenesis. MKS is genetically heterogeneous with three loci mapped and two identified; MKS1 (17q23) and MKS3 (8q22.1). MKS1 is part of the Finnish disease heritage, while MKS3 has been described exclusively in consanguineous Asian families. Here we aimed to establish molecular diagnostics for MKS, determine the importance of MKS1 and MKS3 in non-consanguineous populations, and study genotype/phenotype correlations. The coding regions of MKS1 and MKS3 were screened for mutations by direct sequencing in 17 families clinically diagnosed with MKS in the US or The Netherlands. The clinical phenotype was compared to genic and allelic effects. Both mutations were identified in ten families; five MKS1 and five MKS3. All but two were compound heterozygotes, consistent with their non-consanguineous nature. The MKS1-Fin(major) mutation accounted for 7/10 MKS1 mutations; two novel changes were additionally detected. Seven novel mutations were found in MKS3, including three missense changes. We concluded that MKS1 and MKS3 account for the majority of MKS in non-consanguineous populations of European origin. Polydactyly is usually found in MKS1 but rare in MKS3. Cases with no, or milder, CNS phenotypes were only found in MKS3; hypomorphic missense mutations may be associated with less severe CNS outcomes. This study is consistent with further genetic heterogeneity of MKS, but underlines the value of molecular diagnostics of the known genes to aid family planning decisions.