{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T14:50:46Z","timestamp":1773327046924,"version":"3.50.1"},"reference-count":27,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,25]],"date-time":"2023-12-25T00:00:00Z","timestamp":1703462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/genes15010032","type":"journal-article","created":{"date-parts":[[2023,12,25]],"date-time":"2023-12-25T03:42:12Z","timestamp":1703475732000},"page":"32","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Novel Homozygous Loss-of-Function Variant in SPRED2 Causes Autosomal Recessive Noonan-like Syndrome"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8329-0215","authenticated-orcid":false,"given":"Maria Elena","family":"Onore","sequence":"first","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3805-4170","authenticated-orcid":false,"given":"Martina","family":"Caiazza","sequence":"additional","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases Unit, Department of Translational Medical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonella","family":"Farina","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5477-0711","authenticated-orcid":false,"given":"Gioacchino","family":"Scarano","sequence":"additional","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases Unit, Department of Translational Medical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital, 80131 Naples, Italy"},{"name":"Medical Genetics Unit, AORN \u201cSan Pio\u201d, Hospital \u201cG. Rummo\u201d, 82100 Benevento, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0889-4784","authenticated-orcid":false,"given":"Alberto","family":"Budillon","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rossella Nicoletta","family":"Borrelli","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8291-9517","authenticated-orcid":false,"given":"Giuseppe","family":"Limongelli","sequence":"additional","affiliation":[{"name":"Inherited and Rare Cardiovascular Diseases Unit, Department of Translational Medical Sciences, University of Campania \u201cLuigi Vanvitelli\u201d, Monaldi Hospital, 80131 Naples, Italy"},{"name":"Institute of Cardiovascular Science, University College London and St. Bartholomew\u2019s Hospital, London E1 4NS, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincenzo","family":"Nigro","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"},{"name":"Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9418-125X","authenticated-orcid":false,"given":"Giulio","family":"Piluso","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1002\/ajmg.c.32012","article-title":"The molecular genetics of RASopathies: An update on novel disease genes and new disorders","volume":"190","author":"Tartaglia","year":"2022","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.bj.2021.06.004","article-title":"RASopathies: From germline mutations to somatic and multigenic diseases","volume":"44","author":"Riller","year":"2021","journal-title":"Biomed. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1210\/er.2017-00232","article-title":"The RASopathy Family: Consequences of Germline Activation of the RAS\/MAPK Pathway","volume":"39","author":"Tajan","year":"2018","journal-title":"Endocr. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1176828","DOI":"10.3389\/fcvm.2023.1176828","article-title":"RASopathies and cardiac manifestations","volume":"10","author":"Hilal","year":"2023","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_5","unstructured":"Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., and Amemiya, A. (2023, November 01). Noonan Syndrome, GeneReviews\u00ae, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/20301303\/."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/ng772","article-title":"Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome","volume":"29","author":"Tartaglia","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1016\/j.ajhg.2021.09.007","article-title":"SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype","volume":"108","author":"Motta","year":"2021","journal-title":"Am. J. Hum. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"104695","DOI":"10.1016\/j.ejmg.2023.104695","article-title":"Autosomal recessive Noonan-like syndrome caused by homozygosity for a previously unreported variant in SPRED2","volume":"66","author":"Markholt","year":"2023","journal-title":"Eur. J. Med. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1038\/35088082","article-title":"Spred is a Sprouty-related suppressor of Ras signalling","volume":"412","author":"Wakioka","year":"2001","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1101\/gad.341222.120","article-title":"SPRED proteins and their roles in signal transduction, development, and malignancy","volume":"34","author":"Lorenzo","year":"2020","journal-title":"Genes Dev."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Lopez, J., Bonsor, D.A., Sale, M.J., Urisman, A., Mehalko, J.L., Cabanski-Dunning, M., Castel, P., Simanshu, D.K., and McCormick, F. (2023). The ribosomal S6 kinase 2 (RSK2)-SPRED2 complex regulates the phosphorylation of RSK substrates and MAPK signaling. J. Biol. Chem., 299.","DOI":"10.1016\/j.jbc.2023.104789"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3124","DOI":"10.1074\/jbc.M115.703710","article-title":"Interaction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1","volume":"291","author":"Hirata","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"107909","DOI":"10.1016\/j.celrep.2020.107909","article-title":"Structural Insights into the SPRED1-Neurofibromin-KRAS Complex and Disruption of SPRED1-Neurofibromin Interaction by Oncogenic EGFR","volume":"32","author":"Yan","year":"2020","journal-title":"Cell Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/S0006-291X(03)00259-6","article-title":"Molecular cloning of mammalian Spred-3 which suppresses tyrosine kinase-mediated Erk activation","volume":"302","author":"Kato","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1038\/ng2113","article-title":"Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype","volume":"39","author":"Brems","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_16","unstructured":"Adam, M.P., Feldman, J., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., and Amemiya, A. (2023, November 01). Legius Syndrome, GeneReviews\u00ae, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK47312\/."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3503","DOI":"10.1093\/eurheartj\/ehad194","article-title":"2023 ESC Guidelines for the management of cardiomyopathies","volume":"44","author":"Arbelo","year":"2023","journal-title":"Eur. Heart J."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"McLaren, W., Gil, L., Hunt, S.E., Riat, H.S., Ritchie, G.R., Thormann, A., Flicek, P., and Cunningham, F. (2016). The Ensembl Variant Effect Predictor. Genome Biol., 17.","DOI":"10.1186\/s13059-016-0974-4"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/s41467-020-20584-4","article-title":"AutoMap is a high performance homozygosity mapping tool using next-generation sequencing data","volume":"12","author":"Quinodoz","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1002\/humu.22981","article-title":"HGVS Recommendations for the Description of Sequence Variants: 2016 Update","volume":"37","author":"Dalgleish","year":"2016","journal-title":"Hum. Mutat."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/gim.2012.94","article-title":"Regions of homozygosity identified by SNP microarray analysis aid in the diagnosis of autosomal recessive disease and incidentally detect parental blood relationships","volume":"15","author":"Sund","year":"2013","journal-title":"Genet. Med."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Correia-Costa, G.R., Sgardioli, I.C., Santos, A.P.D., Araujo, T.K., Secolin, R., Lopes-Cendes, I., Gil-da-Silva-Lopes, V.L., and Vieira, T.P. (2022). Increased runs of homozygosity in the autosomal genome of Brazilian individuals with neurodevelopmental delay\/intellectual disability and\/or multiple congenital anomalies investigated by chromosomal microarray analysis. Genet. Mol. Biol., 45.","DOI":"10.1590\/1678-4685-gmb-2020-0480"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/S0140-6736(12)61023-X","article-title":"Noonan syndrome","volume":"381","author":"Roberts","year":"2013","journal-title":"Lancet"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1136\/jmedgenet-2015-103018","article-title":"Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome","volume":"52","author":"Yamamoto","year":"2015","journal-title":"J. Med. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1038\/gim.2017.249","article-title":"Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants","volume":"20","author":"Johnston","year":"2018","journal-title":"Genet. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1007\/s00418-004-0725-6","article-title":"Expression and subcellular localization of Spred proteins in mouse and human tissues","volume":"122","author":"Engelhardt","year":"2004","journal-title":"Histochem. Cell Biol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/1\/32\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:41:28Z","timestamp":1760132488000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/1\/32"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,25]]},"references-count":27,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["genes15010032"],"URL":"https:\/\/doi.org\/10.3390\/genes15010032","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,25]]}}}