De novo missense variants in the RAP1B gene identified in two patients with syndromic thrombocytopenia

Clin Genet. 2020 Oct;98(4):374-378. doi: 10.1111/cge.13807. Epub 2020 Jul 21.

Abstract

We present two independent cases of syndromic thrombocytopenia with multiple malformations, microcephaly, learning difficulties, dysmorphism and other features. Exome sequencing identified two novel de novo heterozygous variants in these patients, c.35G>T p.(Gly12Val) and c.178G>C p.(Gly60Arg), in the RAP1B gene (NM_001010942.2). These variants have not been described previously as germline variants, however functional studies in literature strongly suggest a clinical implication of these two activating hot spot positions. We hypothesize that pathogenic missense variants in the RAP1B gene cause congenital syndromic thrombocytopenia with a spectrum of associated malformations and dysmorphism, possibly through a gain of function mechanism.

Keywords: Kabuki syndrome; RAP1B; learning difficulties; malformations; microcephaly; pancytopenia; thrombocytopenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / diagnosis
  • Abnormalities, Multiple / genetics
  • Abnormalities, Multiple / pathology
  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Exome / genetics
  • Exome Sequencing
  • Female
  • Heterozygote
  • Humans
  • Intellectual Disability / diagnosis
  • Intellectual Disability / genetics*
  • Intellectual Disability / pathology
  • Male
  • Microcephaly / diagnosis
  • Microcephaly / genetics*
  • Microcephaly / pathology
  • Mutation, Missense / genetics
  • Pedigree
  • Phenotype
  • Thrombocytopenia / diagnosis
  • Thrombocytopenia / genetics*
  • Thrombocytopenia / pathology
  • rap GTP-Binding Proteins / genetics*

Substances

  • RAP1B protein, human
  • rap GTP-Binding Proteins