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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

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
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
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.
1552-4825
2049-2055
Burkardt, Deepika D'cunha
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Zachariou, Anna
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Loveday, Chey
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Allen, Clare L.
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Amor, David J.
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Ardissone, Anna
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Banka, Siddharth
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Bourgois, Alexia
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Coubes, Christine
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Faivre, Laurence
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Marion, Gerard
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Horton, Rachel
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Kotzot, Dieter
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Low, Karen
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Luk, Ho‐Ming
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Mark, Paul
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Mcconkie‐rosell, Allyn
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McDonald, Marie
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Shears, Deborah
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Skotko, Brian
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Stewart, Fiona
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Stewart, Helen
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Temple, Isabel
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Mau‐Them, Frederic T.
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Verdugo, Ricardo A.
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Weksberg, Rosanna
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Zarate, Yuri A.
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Graham, John M.
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Tatton‐Brown, Katrina
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Burkardt, Deepika D'cunha
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Zachariou, Anna
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Loveday, Chey
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Allen, Clare L.
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Amor, David J.
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Ardissone, Anna
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Banka, Siddharth
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Bourgois, Alexia
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Marion, Gerard
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Lees, Melissa
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Low, Karen
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Luk, Ho‐Ming
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Mark, Paul
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McDonald, Marie
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Phillipe, Christophe
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Shears, Deborah
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Skotko, Brian
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Stewart, Fiona
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Stewart, Helen
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Temple, Isabel
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Zarate, Yuri A.
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Burkardt, Deepika D'cunha, Zachariou, Anna, Loveday, Chey, Allen, Clare L., Amor, David J., Ardissone, Anna, Banka, Siddharth, Bourgois, Alexia, Coubes, Christine, Cytrynbaum, Cheryl, Faivre, Laurence, Marion, Gerard, Horton, Rachel, Kotzot, Dieter, Lay‐Son, Guillermo, Lees, Melissa, Low, Karen, Luk, Ho‐Ming, Mark, Paul, Mcconkie‐rosell, Allyn, McDonald, Marie, Pappas, John, Phillipe, Christophe, Shears, Deborah, Skotko, Brian, Stewart, Fiona, Stewart, Helen, Temple, Isabel, Mau‐Them, Frederic T., Verdugo, Ricardo A., Weksberg, Rosanna, Zarate, Yuri A., Graham, John M. and Tatton‐Brown, Katrina (2019) 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. American Journal of Medical Genetics part A, 179 (10), 2049-2055. (doi:10.1002/ajmg.a.61321).

Record type: Article

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.

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More information

Accepted/In Press date: 27 July 2019
e-pub ahead of print date: 9 August 2019
Published date: 1 October 2019

Identifiers

Local EPrints ID: 436164
URI: http://eprints.soton.ac.uk/id/eprint/436164
ISSN: 1552-4825
PURE UUID: f4a6623f-dce9-4846-9c2c-68edcab72342
ORCID for Isabel Temple: ORCID iD orcid.org/0000-0002-6045-1781

Catalogue record

Date deposited: 29 Nov 2019 17:31
Last modified: 26 Nov 2021 07:13

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Contributors

Author: Deepika D'cunha Burkardt
Author: Anna Zachariou
Author: Chey Loveday
Author: Clare L. Allen
Author: David J. Amor
Author: Anna Ardissone
Author: Siddharth Banka
Author: Alexia Bourgois
Author: Christine Coubes
Author: Cheryl Cytrynbaum
Author: Laurence Faivre
Author: Gerard Marion
Author: Rachel Horton
Author: Dieter Kotzot
Author: Guillermo Lay‐Son
Author: Melissa Lees
Author: Karen Low
Author: Ho‐Ming Luk
Author: Paul Mark
Author: Allyn Mcconkie‐rosell
Author: Marie McDonald
Author: John Pappas
Author: Christophe Phillipe
Author: Deborah Shears
Author: Brian Skotko
Author: Fiona Stewart
Author: Helen Stewart
Author: Isabel Temple ORCID iD
Author: Frederic T. Mau‐Them
Author: Ricardo A. Verdugo
Author: Rosanna Weksberg
Author: Yuri A. Zarate
Author: John M. Graham
Author: Katrina Tatton‐Brown

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