High frequency of hotspot mutation in PTPN11 gene among Moroccan patients with Noonan syndrome

• Published in: Journal of applied genetics Vol. 65; no. 2; pp. 303 - 308
• Main Authors: Ouboukss, Fatima, Adadi, Najlae, Amasdl, Saadia, Smaili, Wiam, Laarabi, Fatima Zahra, Lyahyai, Jaber, Sefiani, Abdelaziz, Ratbi, Ilham
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-05-2024; Springer Nature B.V
• Subjects: Animal Genetics and Genomics; Biomedical and Life Sciences; Cdc42 protein; Exons; Gene sequencing; Genes; Genetic counseling; Genetic screening; Genotype & phenotype; Heterogeneity; High frequencies; Human Genetics; Human Genetics • Original Paper; Life Sciences; Microbial Genetics and Genomics; Mutation hot spots; Noonan's syndrome; Phenotypes; Plant Genetics and Genomics; Protein-tyrosine-phosphatase; SHP-2 protein; Tyrosine; Pathogenic variant; High hotspot frequency; gene; Moroccan; Noonan syndrome
• ISSN: 1234-1983; 2190-3883
• DOI: 10.1007/s13353-023-00803-6

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.