Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations

Abstract

Background: Noonan syndrome (NS), an autosomal dominant developmental genetic disorder, is caused by germline mutations in genes associated with the RAS / mitogen-activated protein kinase (MAPK) pathway. In several studies PTPN11 is one of the genes with a significant number of pathogenic variants in NS-affected patients. Therefore, clinically diagnosed NS individuals are initially tested for pathogenic variants in PTPN11 gene to confirm the relationship before studying genotype-phenotype correlation.

Methods: Individuals (363) with clinically diagnosed NS from four hospitals in South India were recruited and the exons of PTPN11 gene were sequenced.

Results: Thirty-two previously described pathogenic variants in eight different exons in PTPN11 gene were detected in 107 patients, of whom 10 were familial cases. Exons 3, 8 and 13 had the highest number of pathogenic variants. The most commonly identified pathogenic variants in this series were in exon 8 (c.922A > G, c.923A > G), observed in 22 of the affected. Congenital cardiac anomalies were present in 84% of the mutation-positive cohort, the majority being defects in the right side of the heart. The most common facial features were downward-slanting palpebral fissures, hypertelorism and low-set posteriorly rotated ears. Other clinical features included short stature (40%), pectus excavatum (54%) and, in males, unilateral or bilateral cryptorchidism (44%).

Conclusion: The clinical features and mutational spectrum observed in our cohort are similar to those reported in other large studies done worldwide. This is the largest case series of NS-affected individuals with PTPN11 mutations described till date from India.

Keywords: Congenital heart defects; Mutational analysis; Noonan syndrome; PTPN11; RASopathy; SHP-2.

Fig. 1

Location of PTPN11 pathogenic variants shown along with exons and SHP-2 functional protein domains. The bar at top depicts the exons of the PTPN11 gene, with the coding region in pink. The blue boxes above the bar represent the number of patients observed with that particular pathogenic variant. The corresponding functional domains of the SHP-2 protein are shown below and includes the two SH2 domains and the protein tyrosine phosphatase (PTP) domain

Fig. 2

Typical facial features (face front and side) in PTPN11 pathogenic variant positive NS patients. Curly/sparse hair, hooded eyes / ptosis, down-slanting palpebral fissures, hypertelorism and low-set, posteriorly rotated ears seen at ages ranging from 3 months to16years

Fig. 3

Facial features observed in two NS families. Family 1-Mother and daughter with the pathogenic variant c.923A > G in exon 8 of the PTPN11 gene. Family 2- Father and son with the c.922A > G pathogenic variant in exon 8 of the PTPN11 gene