Genotypic Categorization of Loeys-Dietz Syndrome Based on 24 Novel Families and Literature Data

Genes (Basel). 2019 Sep 28;10(10):764. doi: 10.3390/genes10100764.

Abstract

Loeys-Dietz syndrome (LDS) is a connective tissue disorder first described in 2005 featuring aortic/arterial aneurysms, dissections, and tortuosity associated with craniofacial, osteoarticular, musculoskeletal, and cutaneous manifestations. Heterozygous mutations in 6 genes (TGFBR1/2, TGFB2/3, SMAD2/3), encoding components of the TGF-β pathway, cause LDS. Such genetic heterogeneity mirrors broad phenotypic variability with significant differences, especially in terms of the age of onset, penetrance, and severity of life-threatening vascular manifestations and multiorgan involvement, indicating the need to obtain genotype-to-phenotype correlations for personalized management and counseling. Herein, we report on a cohort of 34 LDS patients from 24 families all receiving a molecular diagnosis. Fifteen variants were novel, affecting the TGFBR1 (6), TGFBR2 (6), SMAD3 (2), and TGFB2 (1) genes. Clinical features were scored for each distinct gene and matched with literature data to strengthen genotype-phenotype correlations such as more severe vascular manifestations in TGFBR1/2-related LDS. Additional features included spontaneous pneumothorax in SMAD3-related LDS and cervical spine instability in TGFB2-related LDS. Our study broadens the clinical and molecular spectrum of LDS and indicates that a phenotypic continuum emerges as more patients are described, although genotype-phenotype correlations may still contribute to clinical management.

Keywords: Ehlers-Danlos syndrome; Loeys-Dietz syndrome; SMAD2; SMAD3; TGFB2; TGFB3.; TGFBR1; TGFBR2; arterial aneurysms; hereditary connective tissue disorders.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Humans
  • Infant
  • Loeys-Dietz Syndrome / classification
  • Loeys-Dietz Syndrome / genetics*
  • Loeys-Dietz Syndrome / pathology
  • Middle Aged
  • Pedigree
  • Receptor, Transforming Growth Factor-beta Type I / genetics
  • Receptor, Transforming Growth Factor-beta Type II / genetics
  • Smad3 Protein / genetics
  • Transforming Growth Factor beta2 / genetics

Substances

  • SMAD3 protein, human
  • Smad3 Protein
  • TGFB2 protein, human
  • Transforming Growth Factor beta2
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • TGFBR1 protein, human
  • TGFBR2 protein, human