A new mutation in the C-SH2 domain of PTPN11 causes Noonan syndrome with multiple giant cell lesions

Abstract

Noonan syndrome (NS), an autosomal dominant multisystem disorder, is caused by the dysregulation of the RAS-MAPK pathway and is characterized by short stature, heart defects, pectus excavatum, webbed neck, learning problems, cryptorchidism and facial dysmorphism. We here present the clinical and molecular characterization of a family with NS and multiple giant cell lesions (MGCLs). The proband is a 12-year-old girl with NS and MGCL. Her mother shows typical NS without MGCL. Whole-exome sequencing of the girl, her mother and her healthy maternal grand parents revealed a previously unobserved mutation in exon 5 of the PTPN11 gene (c.598 A>T; p.N200Y), transmitted from the mother to the proband. As no other modification in the RAS-MAPK pathway genes as related to Rasopathies was detected in the proband, this report demonstrates for the first time that a unique mutation affecting this, otherwise unaffected signaling route, can cause both NS and NS/MGCL in the same family. This observation further confirms that NS/MGCL is not a distinct entity but rather that MGCL represents a rare complication of NS. Moreover, the localization of the p.N200Y mutation suggests an alternative molecular mechanism for the excessive phosphatase activity of the PTPN11-encoded protein.

Phenotype–genotype analysis of 242 individuals with RASopathies: 18‐year experience of a tertiary center in Brazil

“…Karbach et al (2012) noticed that individuals harboring variants in SOS1 were overrepresented in the group with GCL. Since their report, five other cases have been described in the literature (Carapito et al, 2014; Eyselbergs et al, 2014; Lutz et al, 2020; Rodríguez, Castellón, Moreno, Paez, & Aracena Álvarez, 2020; Sinnott & Patel, 2018) and including the present data, there are 16 individuals with variants in PTPN11 and 15 individuals with variants in SOS1 , giving further support to the idea that individuals harboring variants in SOS1 could present a higher risk for the development of GCL compared with the ones with variants in PTPN11 .…”

“…Karbach et al (2012) noticed that individuals harboring variants in SOS1 were overrepresented in the group with GCL. Since their report, five other cases have been described in the literature (Carapito et al, 2014;Eyselbergs et al, 2014;Lutz et al, 2020;Rodríguez, Castellón, Moreno, Paez, & Aracena Alvarez, 2020;Sinnott & Patel, 2018) and (Figure 3). Iliac bone lesions in NS are uncommon.…”

A de novoADCY5 mutation causes early‐onset autosomal dominant chorea and dystonia

“…Exome sequencing was performed as previously described . An average of 8.9 Gb were mapped to the hg19 using Lifescope TM (LifeTechnologies TM ).…”

miRNA Genetic Variants Alter Their Secondary Structure and Expression in Patients With RASopathies Syndromes

“…The WES approach enables studies of the patients within an environmental and clinical context through large-scale cohort trials and data processing with a focus on the associations among molecular biology, disease and health phenotypes to assure a more accurate diagnosis, leading to the establishment of individualized disease prevention and treatment programmes (Tetreault et al, 2015; Collins et al, 2016; Tebani et al, 2016). Moreover, WES has allowed the identification of new genes associated to the clinical description of patients with RASopathies (Niguidula et al, 2018; Matias et al, 2019), such as RIT1 (Aoki et al, 2013), A2ML1 (Vissers et al, 2015), RASA2, SPRY1 (Chen et al, 2014), SOS2, LZTR1 (Yamamoto et al, 2015; Umeki et al, 2019), PPP1CB (Gripp et al, 2016), CBL (Coe et al, 2017), and MRAS (Higgins et al, 2017), as well as new mutations in genes of the RAS/MAPK pathway (Carapito et al, 2014; Sana et al, 2016; Coe et al, 2017; Harms et al, 2018; Valera et al, 2018).…”