title: A novel fibrillin-1 gene missense mutation associated with neonatal Marfan syndrome: a case report and review of the mutation spectrum.
abstract: Marfan syndrome (MFS) is a heritable disorder of connective tissue resulting from pathogenic variants of the fibrillin-1 gene (FBN1). Neonatal Marfan syndrome (nMFS) is rare and the most severe form of MFS, involving rapidly progressive cardiovascular dysfunction leading to death during early childhood. The constant enrichment of the nMFS mutation spectrum is helpful to improve our understanding of genotype-phenotype correlations in the disease. Herein, we report a novel dominant mutation in exon 26 of FBN1 (c.3331 T > C) in a sporadic case with nMFS.
  
  
  
  An 8-month-old Han Chinese girl presented with the classic nMFS phenotype, including prominent manifestations of bone overgrowth, aortic root dilatation, and multiple cardiac valve dysfunctions. Genetic analysis revealed that she was heterozygous for a de novo FBN1 missense mutation (c.3331 T > C). The mutation leads to the substitution of a highly conserved FBN1 cysteine residue (p.Cys1111Arg), which is likely to severely perturb the FBN1 structure because of an alteration of the disulfide bond pattern in the calcium-binding epidermal growth factor-like (cbEGF) 12 domain. This variant was absent in 208 ethnically matched controls, providing further evidence that it may be causative of nMFS. An analysis of nMFS-associated mutations from the UMD-FBN1 database indicates that those de novo mutations altering disulfide bonds or Ca(2+) binding sites of the cbEGF domains encoded by exons 25-33, and a lack of phenotypic heterogeneity may be associated with an increased risk for nMFS.
  
  
  
  We diagnosed an infant with rare nMFS showing rapidly progressive cardiovascular dysfunction and widely systemic features. As the only causal FBN1 mutation identified in the patient, the missense mutation c.3331 T > C (p.Cys1111Arg) was associated with the severe phenotype of MFS. However, the pathogenicity of the novel mutation needs further confirmation in other patients with nMFS. Our review of the prominent characteristics of nMFS mutations relative to classic or incomplete MFS-related mutations will be helpful for the recognition of novel nMFS-associated variants.
authors.affiliation: Department of Pediatric Cardiology, West China Second University Hospital/West China Women's and Children's Hospital, West China School of Medicine, Sichuan University, Chengdu, 610041, China.|Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, China.|Department of Pediatrics, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, 610072, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Peng
authors.affiliation: Department of Cardiovascular Ultrasound and Non-invasive Cardiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, 610072, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Medical Genetics, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, 610041, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pediatric Cardiology, West China Second University Hospital/West China Women's and Children's Hospital, West China School of Medicine, Sichuan University, Chengdu, 610041, China. liuhscu@163.com.|Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, China. liuhscu@163.com.
authors.forename: Hanmin
authors.initials: H
authors.lastname: Liu
mesh_terms: D005260:Female; D000071838:Fibrillin-1 / Q000235:genetics*; D005819:Genetic Markers; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008382:Marfan Syndrome / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense; D010641:Phenotype; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D005819:Genetic Markers; C000605722:FBN1 protein, human; D054392:Adipokines
keywords: Calcium-binding EGF-like domain; Cysteine substitution; Disulfide bond; FBN1; Neonatal Marfan syndrome