Noonan Syndrome in South Africa: Clinical and Molecular Profiles.

Cedrik Tekendo-Ngongang,Christian Domilongo Bope,Gloudi Agenbag,Ambroise Wonkam,Alina Izabela Esterhuizen

doi:10.3389/fgene.2019.00333

Abstract

Noonan Syndrome (NS) is a common autosomal dominant multisystem disorder, caused by mutations in more than 10 genes in the Ras/MAPK signaling pathway. Differential mutation frequencies are observed across populations. Clinical expressions of NS are highly variable and include short stature, distinctive craniofacial dysmorphism, cardiovascular abnormalities, and developmental delay. Little is known about phenotypic specificities and molecular characteristics of NS in Africa. The present study has investigated patients with NS in Cape Town (South Africa). Clinical features were carefully documented in a total of 26 patients. Targeted Next-Generation Sequencing (NGS) was performed on 16 unrelated probands, using a multigene panel comprising 14 genes: PTPN11, SOS1, RIT1, A2ML1, BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, RAF1, SHOC2, and SPRED1. The median age at diagnosis was 4.5 years (range: 1 month−51 years). Individuals of mixed-race ancestry were most represented (53.8%), followed by black Africans (30.8%). Our cohort revealed a lower frequency of pulmonary valve stenosis (34.6%) and a less severe developmental milestones phenotype. Molecular analysis found variants predicted to be pathogenic in 5 / 16 cases (31.2%). Among these mutations, two were previously reported: MAP2K1-c.389A>G (p.Tyr130Cys) and PTPN11 - c.1510A>G (p.Met504Val); three are novel: CBL-c.2520T>G (p.Cys840Trp), PTPN11- c.1496C>T (p.Ser499Phe), and MAP2K1- c.200A>C (p.Asp67Ala). Molecular dynamic simulations indicated that novel variants identified impact the stability and flexibility of their corresponding proteins. Genotype-phenotype correlations showed that clinical features of NS were more typical in patients with variants in MAP2K1. This first application of targeted NGS for the molecular diagnosis of NS in South Africans suggests that, while there is no major phenotypic difference compared to other populations, the distribution of genetic variants in NS in South Africans may be different.

Highlights

Noonan syndrome (NS; MIM 163950) is a common autosomal dominant condition, with an estimated global incidence of 1:1,000 to 1:2,500 live births (Mendez and Opitz, 1985)
Gross motor milestones were on par for most patients, with ability to walk before the age of 18 months in 61.5% (n = 16/26) of cases
Craniofacial features were widely variable, but more characteristic in infants (2–12 months; 4/26), with widely spaced eyes, epicanthic folds and ptosis found in 75% of cases (Table 1)

Summary

Introduction

Noonan syndrome (NS; MIM 163950) is a common autosomal dominant condition, with an estimated global incidence of 1:1,000 to 1:2,500 live births (Mendez and Opitz, 1985). Affected individuals present with multisystem involvement, including short stature, distinctive craniofacial dysmorphism, congenital heart defects (CHD), skeletal abnormalities, developmental delay, NGS in South Africans With Noonan Syndrome coagulation defects, and other abnormalities (Allanson and Roberts, 2016). Missense variants in PTPN11 alone are found in about 50% of affected individuals (Tartaglia and Gelb, 2005), while SOS1 has been reported to be the second most mutated gene, accounting for 10–20% of PTPN11-negative patients (Roberts et al, 2007). No study investigating the genetic etiology of NS in South Africans has been previously conducted, despite that numerous individuals and families affected with NS were identified in South Africa, largely due to unavailability of molecular diagnostic testing for RASopathies in the state public sector. The present study aimed at characterizing a cohort of South African patients with NS from clinical and molecular perspectives, using targeted NGS approach

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Discussion

Conclusion