Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disordersGene: HIST1H1E
Comment on list classification: Updated rating from Red to Green now 2017 paper is published (PMID:28475857) and MOI can be completed, and after clinical agreement from Helen Brittain: sufficient unrelated cases to support causation of an overgrowth phenotype.
Created: 18 Sep 2017, 7:44 a.m.
Tatton-Brown 2017 paper is now out: PMID:28475857 reported 5 unrelated patients with mild to severe ID associated with variable somatic overgrowth, including increased height, weight, and/or head circumference. The authors reported 3 heterozygous truncating variants in HIST1H1E. The variants occurred de novo in 4 families- parental DNA wasn't available from the 5th family. Therefore sufficient unrelated cases to promote to green on this panel.
Created: 18 Sep 2017, 7:40 a.m.
Comment on mode of inheritance: Monoallelic MOI supported by OMIM (MIM:617537)
Created: 5 Sep 2017, 9:26 a.m.
Added new-gene-name tag, new approved HGNC gene symbol for HIST1H1E is H1-4
Created: 6 Sep 2019, 3:17 p.m. | Last Modified: 6 Sep 2019, 3:17 p.m.
Panel Version: 1.92
Review and Green rating from Kate Tatton-Brown April 2017 ; Paper in press with AJHG but we only have five cases currently. We need to ascertain more cases before we can say that the gene is an overgrowth gene. We wil be reporting variants in clinical practice soon
Created: 31 May 2019, 11:15 a.m.
Five HIST1H1E OGID causing-mutations have been found clustered significantly to a 12bp region in the carboxy- terminal domain (CTD) resulting in the same shift in reading frame and the generation of a similar truncated mutant protein with significantly reduced net charge compared to wild type protein (7-9 compared to the wild type charge of 44). This mutant protein is less effective at neutralizing negatively charged linker DNA disrupting chromatin modelling. In addition, the loss of the c-terminus is likely to impede DNA binding and protein-protein interactions.
The phenotypes of the five individuals with HIST1H1E mutations were remarkably similar and characterized by a variable intellectual disability; increased height and/or head circumference and a recognizable facial appearance consisting of full cheeks, high hairline and telecanthus. Longitudinal studies are underway to further delineate this phenotype. HIST1H1E joins a growing family of epigenetic regulator overgrowth genes. (From abstract (unpublished) Tatton-Brown et al 2017 'HIST1H1E and a growing family of overgrowth genes: clarifying the genetic architecture of overgrowth syndromes' (http://conf.hinxton.wellcome.ac.uk/advancedcourses/GRD2017Abstactbook.pdf).
Created: 31 Mar 2017, 5:50 p.m.
Recently (2017) Tatton-Brown et al describes a new developmental disorder/OGID gene. 'HIST1H1E and a growing family of overgrowth genes: clarifying the genetic architecture of overgrowth syndromes' (http://conf.hinxton.wellcome.ac.uk/advancedcourses/GRD2017Abstactbook.pdf) has explored the genetic architecture of Human overgrowth syndromes (OGID)
and performed experimental and bioinformatic analyses of 710 individuals with OGID, identifying patients with OGID-causing mutations in genes including NSD1 (240 cases), EZH2 (34 cases), DNMT3A (18 cases), CHD8 (12 cases) and EED (two cases) and HIST1H1E (five cases). Other genes with OGID-causing mutations, identified in the current study, include NFIX (14 cases), GPC3 (two cases) and BRWD3 (seven cases) in addition to the genes encoding components of the PI3K/AKT pathway (PTEN (16 cases); PPP2R5D (three cases); AKT and PIK3CA (one case each).
Created: 31 Mar 2017, 4:23 p.m.
Mode of inheritance
OVERGROWTH SYNDROME WITH INTELLECTUAL DISABILITY
Tag new-gene-name tag was added to gene: HIST1H1E.
This gene has been classified as Green List (High Evidence).
Mode of inheritance for HIST1H1E was changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for HIST1H1E were set to OVERGROWTH SYNDROME WITH INTELLECTUAL DISABILITY; Rahman syndrome, 617537
Publications for HIST1H1E were set to 28475857
HIST1H1E was created by LouiseD
HIST1H1E was added to Beckwith-Wiedemann syndrome (BWS) and other congenital overgrowth disorderspanel. Sources: Research