Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome
Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome
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DOI：
10.1136/jmedgenet-2015-103018
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发表时间：
2015-06-01
影响因子：
4
通讯作者：
Bertola, Debora Romeo
中科院分区：
文献类型：
--
作者：
Yamamoto, Guilherme Lopes;Aguena, Meire;Bertola, Debora Romeo
努南综合征是一种常染色体显性、多系统疾病，由RAS/丝裂原活化蛋白激酶（MAPK）通路失调引起。11种已知基因的杂合致病性变异约占病例的80%。鉴定与努南综合征相关的新基因已变得越来越具有挑战性，因为它们可能是极少数病例的原因。方法采用全外显子组测序方法，对50例已知努南综合征相关基因致病性变异阴性的巴西先证者及其家族病例亲属进行检测。随后，来自美国和波兰的具有新发现基因突变的家庭也被纳入研究。结果我们在50个巴西先证中分别鉴定出4%和8%的SOS2和LZTR1罕见、分离或新生错义变异。SOS2和LZTR1变异也在一个美国家庭和一个波兰家庭中分离。值得注意的是，与SOS1突变患者相似，SOS2变异在明显的外胚层受累患者中被发现。我们发现了与Noonan综合征相关的两个新基因SOS2和LZTR1，从而扩大了RASopathies的分子谱。大约3%的努南综合征患者是由这些基因突变引起的。虽然SOS2是一个天然的候选基因，因为它与SOS1具有同源性，但LZTR1在RAS/MAPK通路中的功能作用尚不清楚，如果没有大的谱系，它就不可能被确定。需要进一步的功能研究来阐明LZTR1在RAS/MAPK信号传导和Noonan综合征发病机制中的作用。
Background Noonan syndrome is an autosomal dominant, multisystemic disorder caused by dysregulation of the RAS/mitogen activated protein kinase (MAPK) pathway. Heterozygous, pathogenic variants in 11 known genes account for approximately 80% of cases. The identification of novel genes associated with Noonan syndrome has become increasingly challenging, since they might be responsible for very small fractions of the cases.Methods A cohort of 50 Brazilian probands negative for pathogenic variants in the known genes associated with Noonan syndrome was tested through whole-exome sequencing along with the relatives in the familial cases. Families from the USA and Poland with mutations in the newly identified genes were included subsequently.Results We identified rare, segregating or de novo missense variants in SOS2 and LZTR1 in 4% and 8%, respectively, of the 50 Brazilian probands. SOS2 and LZTR1 variants were also found to segregate in one American and one Polish family. Notably, SOS2 variants were identified in patients with marked ectodermal involvement, similar to patients with SOS1 mutations.Conclusions We identified two novel genes, SOS2 and LZTR1, associated with Noonan syndrome, thereby expanding the molecular spectrum of RASopathies. Mutations in these genes are responsible for approximately 3% of all patients with Noonan syndrome. While SOS2 is a natural candidate, because of its homology with SOS1, the functional role of LZTR1 in the RAS/MAPK pathway is not known, and it could not have been identified without the large pedigrees. Additional functional studies are needed to elucidate the role of LZTR1 in RAS/MAPK signalling and in the pathogenesis of Noonan syndrome.