Dataset Information

The clinical significance of A2ML1 variants in Noonan syndrome has to be reconsidered.

ABSTRACT: The RASopathies are a group of clinically and genetically heterogeneous developmental disorders caused by dysregulation of the RAS/MAPK signalling pathway. Variants in several components and regulators of this pathway have been identified as the pathogenetic cause. In 2015, missense variants in A2ML1 were reported in three unrelated families with clinical diagnosis of Noonan syndrome (NS) and a zebrafish model was presented showing heart and craniofacial defects similar to those caused by a NS-associated Shp2 variant. However, a causal role of A2ML1 variants in NS has not been confirmed since. Herein, we report on 15 individuals who underwent screening of RASopathy-associated genes and were found to carry rare variants in A2ML1, including variants previously proposed to be causative for NS. In cases where parental DNA was available, the respective A2ML1 variant was found to be inherited from an unaffected parent. Seven index patients carrying an A2ML1 variant presented with an alternate disease-causing genetic aberration. These findings underscore that current evidence is insufficient to support a causal relation between variants in A2ML1 and NS, questioning the inclusion of A2ML1 screening in diagnostic RASopathy testing.

SUBMITTER: Brinkmann J

PROVIDER: S-EPMC7940614 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The clinical significance of A2ML1 variants in Noonan syndrome has to be reconsidered.

Brinkmann Julia J Lissewski Christina C Pinna Valentina V Vial Yoann Y Pantaleoni Francesca F Lepri Francesca F Daniele Paola P Burnyte Birute B Cuturilo Goran G Fauth Christine C Gezdirici Alper A Kotzot Dieter D Güleç Elif Yılmaz EY Iotova Violeta V Schanze Denny D Ramond Francis F Havlovicová Markéta M Utine Gulen Eda GE Simsek-Kiper Pelin Ozlem PO Stoyanova Milena M Verloes Alain A De Luca Alessandro A Tartaglia Marco M Cavé Hélène H Zenker Martin M

European journal of human genetics : EJHG 20201020 3

The RASopathies are a group of clinically and genetically heterogeneous developmental disorders caused by dysregulation of the RAS/MAPK signalling pathway. Variants in several components and regulators of this pathway have been identified as the pathogenetic cause. In 2015, missense variants in A2ML1 were reported in three unrelated families with clinical diagnosis of Noonan syndrome (NS) and a zebrafish model was presented showing heart and craniofacial defects similar to those caused by a NS-a ...[more]

PMID: 33082526

Similar Datasets

Project description: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.

Dataset Information

The clinical significance of A2ML1 variants in Noonan syndrome has to be reconsidered.

Publications

The clinical significance of A2ML1 variants in Noonan syndrome has to be reconsidered.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets