Familial aggregation of "apple peel" intestinal atresia and cardiac left-sided obstructive lesions: A possible causal relationship with NOTCH1 gene mutations

Am J Med Genet A. 2019 Aug;179(8):1570-1574. doi: 10.1002/ajmg.a.61195. Epub 2019 May 20.

Abstract

"Apple peel" intestinal atresia is a rare form of small bowel atresia, in which the duodenum or proximal jejunum ends in a blind pouch and the distal small bowel wraps around its vascular supply, in a spiral resembling an apple peel. The etiology of "apple peel" intestinal atresia is presently unknown, although a congenital or acquired intestinal vascular accident can have a role in the pathogenesis. We report a family in which the proband affected by "apple peel" intestinal atresia, had a sibling (an interrupted pregnancy), and a paternal cousin with cardiac left-sided obstructive lesions. Molecular testing for NOTCH1 gene was carried out in the proband, because pathogenic mutations in this gene have been associated with familial and sporadic cardiac left-sided obstructive lesions and vascular anomalies, both isolated or within the spectrum of the Adams-Oliver syndrome (AOS). The heterozygous c.2734C>T (p.Arg912Trp) NOTCH1 variant was found in the proband with "apple peel" intestinal atresia and in his father. This result argues for a possible causal relationship between NOTCH1 gene mutations and some forms of intestinal defects, through a vascular mechanism. The spectrum of NOTCH1-associated malformations is widened. Genetic counseling should take into account intrafamilial variable clinical expression and incomplete penetrance.

Keywords: NOTCH1 gene; congenital heart defect; intestinal atresia; left-sided obstruction; vascular anomaly.

Publication types

  • Case Reports

MeSH terms

  • Alleles
  • Cardiac Output, Low / diagnosis*
  • Cardiac Output, Low / genetics*
  • Comparative Genomic Hybridization
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Genotype
  • Humans
  • Infant
  • Intestinal Atresia / diagnosis*
  • Intestinal Atresia / genetics*
  • Intestine, Small / abnormalities*
  • Mutation*
  • Pedigree
  • Receptor, Notch1 / genetics*

Substances

  • NOTCH1 protein, human
  • Receptor, Notch1

Supplementary concepts

  • Atresia of small intestine