Bertola Débora R, Pereira Alexandre C, Albano Lílian Maria José, De Oliveira Paulo S L, Kim Chong A, Krieger José Eduardo
Clinical Genetics Unit, Instituto da Criança do Hospital das Clínicas, University of São Paulo, São Paulo, Brazil.
Genet Test. 2006 Fall;10(3):186-91. doi: 10.1089/gte.2006.10.186.
Mutations in the PTPN11 gene are known to cause a large fraction of the cases of Noonan syndrome. The objective of this study was to determine the PTPN11 gene mutation rate in a cohort of clinically well-characterized Brazilian patients with Noonan or Noonan-like syndromes and to study the genotype-phenotype correlation. Fifty probands with Noonan syndrome ascertained according to well-established diagnostic criteria, 3 with LEOPARD syndrome, 5 with Noonan-like/multiple giant cell lesion syndrome, and 3 with neurofibromatosis/ Noonan were enrolled in this study. Mutational analysis was performed using denaturing high-performance liquid chromatography (DHPLC) followed by sequencing of amplicons with an aberrant elution profile. We detected missense mutations in the PTPN11 gene in 21 probands with Noonan syndrome (42%), in all 3 patients with LEOPARD syndrome, and in 1 case with Noonan-like/multiple giant cell lesion syndrome. One patient with neurofibromatosis-Noonan syndrome had a mutation in both the PTPN11 and NF1 genes. The only anomalies that reached statistical significance when comparing probands with and without mutations were the hematological abnormalities. Our data confirms that Noonan syndrome is a genetically heterogeneous disorder, with mutations in the PTPN11 gene responsible for roughly 50% of the cases. A definitive genotype-phenotype correlation has not been established, but the T73I mutation seems to predispose to a myeloproliferative disorder. Regarding Noonan-like syndromes, mutation of the PTPN11 gene is the main causal factor in LEOPARD syndrome, and it also plays a role in neurofibromatosis-Noonan syndrome. Noonan- like/multiple giant cell lesion syndrome, part of the spectrum of Noonan syndrome, is also heterogeneous.
已知PTPN11基因突变会导致很大一部分努南综合征病例。本研究的目的是确定一组临床特征明确的巴西努南或努南样综合征患者中PTPN11基因突变率，并研究基因型与表型的相关性。本研究纳入了50例根据既定诊断标准确诊的努南综合征先证者、3例豹皮综合征患者、5例努南样/多发性巨细胞病变综合征患者以及3例神经纤维瘤病/努南综合征患者。采用变性高效液相色谱法（DHPLC）进行突变分析，随后对洗脱图谱异常的扩增子进行测序。我们在21例努南综合征先证者（42%）、所有3例豹皮综合征患者以及1例努南样/多发性巨细胞病变综合征患者中检测到PTPN11基因的错义突变。1例神经纤维瘤病 - 努南综合征患者的PTPN11和NF1基因均发生突变。在比较有突变和无突变的先证者时，唯一达到统计学显著差异的异常是血液学异常。我们的数据证实，努南综合征是一种基因异质性疾病，PTPN11基因突变约占病例的50%。尚未建立明确的基因型与表型的相关性，但T73I突变似乎易导致骨髓增殖性疾病。关于努南样综合征，PTPN11基因突变是豹皮综合征的主要致病因素，在神经纤维瘤病 - 努南综合征中也起作用。努南样/多发性巨细胞病变综合征作为努南综合征谱系的一部分，同样具有异质性。
