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Variable cardiovascular phenotypes associated with SMAD2 pathogenic variants

Granadillo, J. L., Chung, W. K., Hecht, L., Corsten-Janssen, N., Wegner, D., Bijvank, S. W. A. N., Toler, T. L., Pineda-Alvarez, D. E., Douglas, G., Murphy, J. J., Shimony, J. & Shinawi, M., Dec-2018, In : Human Mutation. 39, 12, p. 1875-1884 10 p.

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  • Variable cardiovascular phenotypes associated with SMAD2 pathogenic variants

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DOI

  • Jorge L. Granadillo
  • Wendy K. Chung
  • Leah Hecht
  • Nicole Corsten-Janssen
  • Daniel Wegner
  • Sebastiaan W. A. Nij Bijvank
  • Tomi L. Toler
  • Daniel E. Pineda-Alvarez
  • Ganka Douglas
  • Joshua J. Murphy
  • Joshua Shimony
  • Marwan Shinawi

SMAD2 is a downstream effector in the TGF-beta signaling pathway, which is important for pattern formation and tissue differentiation. Pathogenic variants in SMAD2 have been reported in association with arterial aneurysms and dissections and in large cohorts of subjects with complex congenital heart disease (CHD). We used whole exome sequencing (WES) to investigate the molecular cause of CHD and other congenital anomalies in three probands and of an arterial aneurysm in an additional patient. Patients 1 and 2 presented with complex CHD, developmental delay, seizures, dysmorphic features, short stature, and poor weight gain. Patient 3 was a fetus with complex CHD and heterotaxy. The fourth patient is an adult female with aortic root aneurysm and physical features suggestive of a connective tissue disorder. WES identified pathogenic truncating variants, a splice variant, and a predicted deleterious missense variant in SMAD2. We compare the phenotypes and genotypes in our patients with previously reported cases. Our data suggest two distinct phenotypes associated with pathogenic variants in SMAD2: complex CHD with or without laterality defects and other congenital anomalies, and a late-onset vascular phenotype characterized by arterial aneurysms with connective tissue abnormalities.

Original languageEnglish
Pages (from-to)1875-1884
Number of pages10
JournalHuman Mutation
Volume39
Issue number12
Publication statusPublished - Dec-2018

    Keywords

  • arterial aneurysm, congenital heart disease, heterotaxy, holoprosencephaly, mutation, SMAD2, OF-FUNCTION MUTATIONS, LATERALITY DEFECTS, HEART-DEFECTS, HETEROTAXY, PREDICTION, ANEURYSMS, PROTEINS, SERVER

ID: 76617589