Research Team in Genomics and Molecular Epidemiology of Genetic Diseases, Genomics Center of Human Pathologies, Faculty of Medicine and Pharmacy, University Mohammed V in Rabat, Rabat, Morocco.
Department of Medical Genetics, National Institute of Health in Rabat, BP 769 Agdal, 10 090, Rabat, Morocco.
J Appl Genet. 2024 May;65(2):303-308. doi: 10.1007/s13353-023-00803-6. Epub 2023 Nov 21.
Noonan syndrome (NS; OMIM 163950) is an autosomal dominant RASopathy with variable clinical expression and genetic heterogeneity. Clinical manifestations include characteristic facial features, short stature, and cardiac anomalies. Variants in protein-tyrosine phosphatase, non-receptor-type 11 (PTPN11), encoding SHP-2, account for about half of NS patients, SOS1 in approximately 13%, RAF1 in 10%, and RIT1 each in 9%. Other genes have been reported to cause NS in less than 5% of cases including SHOC2, RASA2, LZTR1, SPRED2, SOS2, CBL, KRAS, NRAS, MRAS, PRAS, BRAF, PPP1CB, A2ML1, MAP2K1, and CDC42. Several additional genes associated with a Noonan syndrome-like phenotype have been identified. Clinical presentation and variants in patients with Noonan syndrome are this study's objectives. We performed Sanger sequencing of PTPN11 hotspot (exons 3, 8, and 13). We report molecular analysis of 61 patients with NS phenotype belonging to 58 families. We screened for hotspot variants (exons 3, 8, and 13) in PTPN11 gene by Sanger sequencing. Twenty-seven patients were carrying heterozygous pathogenic variants of PTPN11 gene with a similar frequency (41.4%) compared to the literature. Our findings expand the variant spectrum of Moroccan patients with NS phenotype in whom the analysis of hotspot variants showed a high frequency of exons 3 and 8. This screening test allowed us to establish a molecular diagnosis in almost half of the patients with a good benefit-cost ratio, with appropriate management and genetic counseling.
努南综合征（NS；OMIM 163950）是一种具有可变临床表型和遗传异质性的常染色体显性 RAS 病。临床表现包括特征性面部特征、身材矮小和心脏异常。编码 SHP-2 的蛋白酪氨酸磷酸酶，非受体型 11（PTPN11）的变异约占 NS 患者的一半，SOS1 约占 13%，RAF1 约占 10%，RIT1 各占 9%。其他基因也被报道在不到 5%的 NS 病例中导致该疾病，包括 SHOC2、RASA2、LZTR1、SPRED2、SOS2、CBL、KRAS、NRAS、MRAS、PRAS、BRAF、PPP1CB、A2ML1、MAP2K1 和 CDC42。还有一些与努南综合征样表型相关的额外基因已被确定。本研究旨在探讨 NS 患者的临床表现和变异情况。我们对 PTPN11 热点（外显子 3、8 和 13）进行了 Sanger 测序。我们报告了属于 58 个家族的 61 名 NS 表型患者的分子分析结果。我们通过 Sanger 测序筛选 PTPN11 基因的热点变异（外显子 3、8 和 13）。27 名患者携带 PTPN11 基因的杂合致病性变异，其频率与文献相似（41.4%）。我们的发现扩展了摩洛哥 NS 表型患者的变异谱，分析热点变异显示外显子 3 和 8 的高频。这种筛选测试使我们能够在近一半的患者中建立分子诊断，具有良好的成本效益比，并进行适当的管理和遗传咨询。
