HIST1H1E heterozygous protein-truncating variants cause a recognizable syndrome with intellectual disability and distinctive facial gestalt: A study to clarify the HIST1H1E syndrome phenotype in 30 individuals

Deepika D.Cunha Burkardt, Anna Zachariou, Chey Loveday, Clare L. Allen, David J. Amor, Anna Ardissone, Siddharth Banka, Alexia Bourgois, Christine Coubes, Cheryl Cytrynbaum, Laurence Faivre, Gerard Marion, Rachel Horton, Dieter Kotzot, Guillermo Lay-Son, Melissa Lees, Karen Low, Ho Ming Luk, Paul Mark, Allyn McConkie-RosellMarie McDonald, John Pappas, Christophe Phillipe, Deborah Shears, Brian Skotko, Fiona Stewart, Helen Stewart, I. Karen Temple, Frederic T. Mau-Them, Ricardo A. Verdugo, Rosanna Weksberg, Yuri A. Zarate, John M. Graham, Katrina Tatton-Brown

Research output: Contribution to journalArticlepeer-review

Abstract

Histone Gene Cluster 1 Member E, HIST1H1E, encodes Histone H1.4, is one of a family of epigenetic regulator genes, acts as a linker histone protein, and is responsible for higher order chromatin structure. HIST1H1E syndrome (also known as Rahman syndrome, OMIM #617537) is a recently described intellectual disability (ID) syndrome. Since the initial description of five unrelated individuals with three different heterozygous protein-truncating variants (PTVs) in the HIST1H1E gene in 2017, we have recruited 30 patients, all with HIST1H1E PTVs that result in the same shift in frame and that cluster to a 94-base pair region in the HIST1H1E carboxy terminal domain. The identification of 30 patients with HIST1H1E variants has allowed the clarification of the HIST1H1E syndrome phenotype. Major findings include an ID and a recognizable facial appearance. ID was reported in all patients and is most frequently of moderate severity. The facial gestalt consists of a high frontal hairline and full lower cheeks in early childhood and, in later childhood and adulthood, affected individuals have a strikingly high frontal hairline, frontal bossing, and deep-set eyes. Other associated clinical features include hypothyroidism, abnormal dentition, behavioral issues, cryptorchidism, skeletal anomalies, and cardiac anomalies. Brain magnetic resonance imaging (MRI) is frequently abnormal with a slender corpus callosum a frequent finding.

Original languageEnglish
Pages (from-to)2049-2055
Number of pages7
JournalAmerican Journal of Medical Genetics, Part A
Volume179
Issue number10
DOIs
Publication statusPublished - Oct 1 2019

Keywords

  • epigenetic regulator gene
  • HIST1H1E
  • intellectual disability
  • Rahman syndrome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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