Molecular and environmental characterization of Noonan syndrome in Morocco reveals a significant association with consanguinity and advanced parental age

• Main Authors: Ihssane El Bouchikhi, Laila Bouguenouch, Fatima Zohra Moufid, Imane Samri, Fatima Abdouss, Moulay Abdelilah Melhouf, Mohammed Iraqui Houssaini, Khadija Belhassan, Samir Atmani, Karim Ouldim
• Format: Article
• Language: English
• Published: SpringerOpen 2020-02-01
• Series: Egyptian Journal of Medical Human Genetics
• Subjects: Noonan syndrome (NS); PTPN11 mutations; Pathogenic effect prediction; Mutation rate; Consanguinity; Paternal age
• Online Access: http://link.springer.com/article/10.1186/s43042-020-0047-9

Abstract Background Noonan syndrome (NS) is one of the most common RASopathies, with an autosomal dominant inheritance. This disorder is caused by a range of genes belonging to the RAS-MAP kinase (rat sarcoma viral oncogene homolog/mitogen-activated protein kinases) pathway, with PTPN11 (protein-tyrosine phosphatase, non-receptor type 11) being the most involved genetic factor. The aim of this study is to report PTPN11 mutations found in a cohort of Moroccans with Noonan syndrome, compare the mutation rate with various studies, and statistically assess involvement of prominent risk factors in manifestation of this disorder. Thirty-one NS patients were screened for PTPN11 mutations using PCR-Sanger sequencing method. Pathogenic effect prediction, for detected variants, was carried out using PROVEAN, MutationTaster2, and HSF programs. Statistical tests were performed with R software. Chi-square and Fisher’s exact tests were used in percentage comparisons, while Student’s test was used in average comparisons. Results We detected five pathogenic mutations, one synonymous variant with a potential altering effect on splicing function, and three novel intronic duplications. PTPN11 mutation rate in our cohort is around 16.13%. Comparison of this rate with the corresponding rates in various populations shows notably significant differences across continents. Conclusions Besides genetic factors, the present study suggests involvement of additional environmental factors. Statistical assessment of clinical data confirms particularly the association of NS manifestation with consanguinity and advanced paternal age, and suggests an eventual implication of advanced maternal age as well.