title: 1p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiency.
abstract: Deletion-induced hemizygosity may unmask deleterious autosomal recessive variants and be a cause of the phenotypic variability observed in microdeletion syndromes. We performed complete exome sequencing (WES) analysis to examine this possibility in a patient with 1p13.2 microdeletion. Since the patient displayed clinical features suggestive of Noonan Syndrome (NS), we also used WES to rule out the presence of pathogenic variants in any of the genes associated with the different types of NS. We concluded that the clinical findings could be attributed solely to the 1p13.2 haploinsufficiency. Retrospective analysis of other nine reported patients with 1p13.2 microdeletions showed that six of them also presented some characteristics of NS. In all these cases, the deleted segment included the NRAS gene. Gain-of-function mutations of NRAS gene are causally related to NS type 6. Thus, it is conceivable that NRAS haploinsufficiency and gain-of-function mutations may have similar clinical consequences. The same phenomenon has been described for two other genes belonging to the Ras/MAPK pathway: MAP2K2 and SHOC2. In conclusion, we here report genotype-phenotype correlations in patients with chromosome 1p13.2 microdeletions and we propose that NRAS may be a critical gene for the NS characteristics in the patients.
authors: Laboratório de Genômica Clínica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.
authors: Natália Duarte
authors: ND
authors: Linhares
authors: Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.
authors: Maíra Cristina Menezes
authors: MC
authors: Freire
authors: Laboratório de Genômica Clínica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.
authors: Raony Guimarães Corrêa do Carmo Lisboa
authors: RG
authors: Cardenas
authors: Laboratório Gene - Núcleo de Genética Médica, Belo Horizonte, MG, Brazil.
authors: Heloisa Barbosa
authors: HB
authors: Pena
authors: Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom.
authors: Katherine
authors: K
authors: Lachlan
authors: Bambino Gesù Children Hospital, Rome, Italy.
authors: Bruno
authors: B
authors: Dallapiccola
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors: Carlos
authors: C
authors: Bacino
authors: Centre de Génétique Chromosomique, GH de l'Institut Catholique de Lille - Hopital Saint Vincent de Paul, Lille, France.
authors: Bruno
authors: B
authors: Delobel
authors: Victorian Clinical Genetics Service, Melbourne, Victoria, Australia.
authors: Paul
authors: P
authors: James
authors: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors: Ann-Charlotte
authors: AC
authors: Thuresson
authors: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors: Göran
authors: G
authors: Annerén
authors: Laboratório de Genômica Clínica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.|Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.|Laboratório Gene - Núcleo de Genética Médica, Belo Horizonte, MG, Brazil.
authors: Sérgio D J
authors: SD
authors: Pena