A Novel Stop-gain Pathogenic Variant in FLT4 and a Nonsynonymous Pathogenic Variant in PTPN11 Associated with Congenital Heart Defects

Overview

Journal Eur J Med Res

Publisher Biomed Central

Specialty General Medicine

Date 2022 Dec 10

PMID 36496429

Authors

Avisa Tabib

Taravat Talebi

Serwa Ghasemi

Maryam Pourirahim

Niloofar Naderi

Majid Maleki

Samira Kalayinia

Affiliations

Soon will be listed here.

Abstract

Background: Congenital heart defects (CHDs) are the most common congenital malformations, including structural malformations in the heart and great vessels. CHD complications such as low birth weight, prematurity, pregnancy termination, mortality, and morbidity depend on the type of defect.

Methods: In the present research, genetic analyses via whole-exome sequencing (WES) was performed on 3 unrelated pedigrees with CHDs. The candidate variants were confirmed, segregated by PCR-based Sanger sequencing, and evaluated by bioinformatics analysis.

Results: A novel stop-gain c.C244T:p.R82X variant in the FLT4 gene, as well as a nonsynonymous c.C1403T:p.T468M variant in the PTPN11 gene, was reported by WES. FLT4 encodes a receptor tyrosine kinase involved in lymphatic development and is known as vascular endothelial growth factor 3.

Conclusions: We are the first to report a novel c.C244T variant in the FLT4 gene associated with CHDs. Using WES, we also identified a nonsynonymous variant affecting protein-tyrosine phosphatase, the non-receptor type 11 (PTPN11) gene. The clinical implementation of WES can determine gene variants in diseases with high genetic and phenotypic heterogeneity like CHDs.

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References

Monaghan R, Page D, Ostergaard P, Keavney B . The physiological and pathological functions of VEGFR3 in cardiac and lymphatic development and related diseases. Cardiovasc Res. 2020; 117(8):1877-1890. PMC: 8262640. DOI: 10.1093/cvr/cvaa291. View

Diab N, Barish S, Dong W, Zhao S, Allington G, Yu X . Molecular Genetics and Complex Inheritance of Congenital Heart Disease. Genes (Basel). 2021; 12(7). PMC: 8307500. DOI: 10.3390/genes12071020. View

Atik T, Aykut A, Hazan F, Onay H, Goksen D, Darcan S . Mutation Spectrum and Phenotypic Features in Noonan Syndrome with PTPN11 Mutations: Definition of Two Novel Mutations. Indian J Pediatr. 2016; 83(6):517-21. DOI: 10.1007/s12098-015-1998-6. View

Ghalamkarpour A, Debauche C, Haan E, Van Regemorter N, Sznajer Y, Thomas D . Sporadic in utero generalized edema caused by mutations in the lymphangiogenic genes VEGFR3 and FOXC2. J Pediatr. 2009; 155(1):90-3. DOI: 10.1016/j.jpeds.2009.02.023. View

Ezquieta B, Santome J, Carcavilla A, Guillen-Navarro E, Perez-Aytes A, Sanchez Del Pozo J . Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. Rev Esp Cardiol (Engl Ed). 2012; 65(5):447-55. DOI: 10.1016/j.recesp.2011.12.016. View

Takahashi K, Kogaki S, Kurotobi S, Nasuno S, Ohta M, Okabe H . A novel mutation in the PTPN11 gene in a patient with Noonan syndrome and rapidly progressive hypertrophic cardiomyopathy. Eur J Pediatr. 2005; 164(8):497-500. DOI: 10.1007/s00431-005-1679-y. View

Hamada K, Oike Y, Takakura N, Ito Y, Jussila L, Dumont D . VEGF-C signaling pathways through VEGFR-2 and VEGFR-3 in vasculoangiogenesis and hematopoiesis. Blood. 2000; 96(12):3793-800. View

Czarny M, Resar J . Diagnosis and management of valvular aortic stenosis. Clin Med Insights Cardiol. 2014; 8(Suppl 1):15-24. PMC: 4213201. DOI: 10.4137/CMC.S15716. View

Narayanan D, Pandey H, Moirangthem A, Mandal K, Gupta R, Puri R . Hotspots in PTPN11 Gene Among Indian Children With Noonan Syndrome. Indian Pediatr. 2017; 54(8):638-643. DOI: 10.1007/s13312-017-1125-z. View

10.

Lertsakulpiriya K, Vijarnsorn C, Chanthong P, Chungsomprasong P, Kanjanauthai S, Durongpisitkul K . Current era outcomes of pulmonary atresia with ventricular septal defect: A single center cohort in Thailand. Sci Rep. 2020; 10(1):5165. PMC: 7083910. DOI: 10.1038/s41598-020-61879-2. View

11.

Arvaniti A, Samakouri M, Keskeridou F, Veletza S . Concurrence of anorexia nervosa and Noonan syndrome. Eur Eat Disord Rev. 2013; 22(1):83-5. DOI: 10.1002/erv.2261. View

12.

Sobreira N, Cirulli E, Avramopoulos D, Wohler E, Oswald G, Stevens E . Whole-genome sequencing of a single proband together with linkage analysis identifies a Mendelian disease gene. PLoS Genet. 2010; 6(6):e1000991. PMC: 2887469. DOI: 10.1371/journal.pgen.1000991. View

13.

Kalayinia S, Goodarzynejad H, Maleki M, Mahdieh N . Next generation sequencing applications for cardiovascular disease. Ann Med. 2017; 50(2):91-109. DOI: 10.1080/07853890.2017.1392595. View

14.

Melikhan-Revzin S, Kurolap A, Dagan E, Mory A, Gershoni-Baruch R . A Novel Missense Mutation in FLT4 Causes Autosomal Recessive Hereditary Lymphedema. Lymphat Res Biol. 2015; 13(2):107-11. DOI: 10.1089/lrb.2014.0044. View

15.

Xu Z, Chen W, Li Y, Suo M, Tian G, Sheng W . PTPN11 Gene Mutations and Its Association with the Risk of Congenital Heart Disease. Dis Markers. 2022; 2022:8290779. PMC: 9013483. DOI: 10.1155/2022/8290779. View

16.

Ueda K, Yaoita M, Niihori T, Aoki Y, Okamoto N . Craniosynostosis in patients with RASopathies: Accumulating clinical evidence for expanding the phenotype. Am J Med Genet A. 2017; 173(9):2346-2352. DOI: 10.1002/ajmg.a.38337. View

17.

Ghalamkarpour A, Morlot S, Raas-Rothschild A, Utkus A, Mulliken J, Boon L . Hereditary lymphedema type I associated with VEGFR3 mutation: the first de novo case and atypical presentations. Clin Genet. 2006; 70(4):330-5. DOI: 10.1111/j.1399-0004.2006.00687.x. View

18.

Ferrero G, Baldassarre G, Delmonaco A, Biamino E, Banaudi E, Carta C . Clinical and molecular characterization of 40 patients with Noonan syndrome. Eur J Med Genet. 2008; 51(6):566-72. DOI: 10.1016/j.ejmg.2008.06.011. View

19.

Wakabayashi Y, Yamazaki K, Narumi Y, Fuseya S, Horigome M, Wakui K . Implantable cardioverter defibrillator for progressive hypertrophic cardiomyopathy in a patient with LEOPARD syndrome and a novel PTPN11 mutation Gln510His. Am J Med Genet A. 2011; 155A(10):2529-33. DOI: 10.1002/ajmg.a.34194. View

20.

Xie D, Wang H, Liu Z, Fang J, Yang T, Zhou S . Perinatal outcomes and congenital heart defect prognosis in 53313 non-selected perinatal infants. PLoS One. 2017; 12(6):e0177229. PMC: 5462529. DOI: 10.1371/journal.pone.0177229. View