A Novel Homozygous Loss-of-Function Variant in SPRED2 Causes Autosomal Recessive Noonan-like Syndrome
Author:
Onore Maria Elena1ORCID, Caiazza Martina2ORCID, Farina Antonella1, Scarano Gioacchino23ORCID, Budillon Alberto1ORCID, Borrelli Rossella Nicoletta1, Limongelli Giuseppe24ORCID, Nigro Vincenzo15, Piluso Giulio1ORCID
Affiliation:
1. Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy 2. Inherited and Rare Cardiovascular Diseases Unit, Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Monaldi Hospital, 80131 Naples, Italy 3. Medical Genetics Unit, AORN “San Pio”, Hospital “G. Rummo”, 82100 Benevento, Italy 4. Institute of Cardiovascular Science, University College London and St. Bartholomew’s Hospital, London E1 4NS, UK 5. Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy
Abstract
Noonan syndrome is an autosomal dominant developmental disorder characterized by peculiar facial dysmorphisms, short stature, congenital heart defects, and hypertrophic cardiomyopathy. In 2001, PTPN11 was identified as the first Noonan syndrome gene and is responsible for the majority of Noonan syndrome cases. Over the years, several other genes involved in Noonan syndrome (KRAS, SOS1, RAF1, MAP2K1, BRAF, NRAS, RIT1, and LZTR1) have been identified, acting at different levels of the RAS-mitogen-activated protein kinase pathway. Recently, SPRED2 was recognized as a novel Noonan syndrome gene with autosomal recessive inheritance, and only four families have been described to date. Here, we report the first Italian case, a one-year-old child with left ventricular hypertrophy, moderate pulmonary valve stenosis, and atrial septal defect, with a clinical suspicion of RASopathy supported by the presence of typical Noonan-like facial features and short stature. Exome sequencing identified a novel homozygous loss-of-function variant in the exon 3 of SPRED2 (NM_181784.3:c.325del; p.Arg109Glufs*7), likely causing nonsense-mediated decay. Our results and the presented clinical data may help us to further understand and dissect the genetic heterogeneity of Noonan syndrome.
Subject
Genetics (clinical),Genetics
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