Intellectual disability - microarray and sequencing
Gene: THUMPD1Comment on mode of inheritance: Adding the mode of inheritance of biallelic as this was missing. Autosomal recessive MOI in OMIM for a relevant phenotype.Created: 7 Feb 2023, 11:56 a.m. | Last Modified: 7 Feb 2023, 11:56 a.m.
Panel Version: 4.59
The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.Created: 30 Jan 2023, 5:50 p.m. | Last Modified: 30 Jan 2023, 5:50 p.m.
Panel Version: 4.53
Not associated with a phenotype in OMIM or MONDO, but as moderate Gen2Phen gene for THUMPD1 neurodevelopment disorder. At least 8 variants have been reported in at least 7 unrelated cases, together with supportive functional studies (PMID: 35196516).Created: 19 May 2022, 1:29 p.m. | Last Modified: 19 May 2022, 1:47 p.m.
Panel Version: 3.1576
Comment on phenotypes: Phenotype name based on Gen2Phen entry (https://www.ebi.ac.uk/gene2phenotype/gfd?dbID=4827).Created: 19 May 2022, 1:25 p.m. | Last Modified: 19 May 2022, 1:25 p.m.
Panel Version: 3.1576
Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.Created: 19 May 2022, 1:23 p.m. | Last Modified: 19 May 2022, 1:23 p.m.
Panel Version: 3.1575
Thirteen individuals from eight families and biallelic loss-of-function THUMPD1 variants. Frameshift, nonsense, in-frame deletion and missense variants described.
Common phenotypic findings included global developmental delay, speech delay, moderate to severe intellectual deficiency, behavioral abnormalities such as angry outbursts, facial dysmorphism, and ophthalmological abnormalities.Created: 9 May 2022, 2:33 p.m. | Last Modified: 9 May 2022, 2:33 p.m.
Panel Version: 3.1564
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Intellectual disability; Microcephaly; Seizures
Publications
Variants in this GENE are reported as part of current diagnostic practice
THUMPD1 was identified as a candidate gene for AR ID in the study by Maddirevula et al (2019 - PMID: 30237576) carrying out exome following autozygome analysis in a cohort of affected individuals. The subject initially reported (15DG1395) was included in a recent study discussed below.
Broly et al (2022 - PMID: 35196516) describe the phenotype of 13 individuals (belonging to 8 families - 5/8 consanguineous) harboring biallelic THUMPD1 variants.
Global DD and ID were universal features among those evaluated (12/12 - ranging from mild to severe, suppl.). Other features included microcephaly (4-5/10 each belonging to different families), mild-severe hearing loss (6/8 - 4 fam), variable ophthalmological anomalies (11/13). Brain MRI abnormalities were present in 3/7 evaluated (2 with abnormal CC). Behavioral traits were reported in 7/9 (hyperactivity, aggressive behavior and angry outburst). Febrile seizures in 6/11. The authors also report (rather) variable facial/other physical features.
All were investigated by WES. Previous investigations (CMA and/or determination of stretches of hmz) are available for 4 individuals from 2 consanguineous families.
6 pLoF and 1 missense variants were identified, in almost all cases in homozygosity (the missense SNV in cmp htz with a pLoF one). The authors did not include 3 sibs from a 9th family, with similar phenotype, though harboring a hmz missense variant classified as VUS.
THUMPD1 functions as an adaptor protein in the process of N4-acetylcitidine (ac4C) a modification of serine and leucine tRNAs at the wobble position, catalyzed by N-acetyltransferase 10 (NAT10).
tRNA modifications play roles in tRNA stability, folding, recognition, rate and fidelity of translation as well as many cellular processes. Several genes involved in tRNA modifications incl. NSUN2, PUS3, ADAT3, etc have been associated with NDD.
Using lymphoblasts from an individual hmz for c.706C>T/p.Gln236* the authors demonstrated absence of the protein upon Western Blot and significant decrease of mRNA levels upon RT-qPCR (20% of control). Despite reduction in mature mRNA there was no significant difference in pre-mRNA levels, suggesting that variants lying within this penultimate exon (for NM_001304550.1) may be sensitive to NMD.
Analysis of small RNAs in lymphoblasts from the same individual compared to ctrl indicated no detectable level of ac4C despite normal level of other normal and modifed nucleosides. Specifically purified tRNA-Ser-CGA exhibited >100 fold loss of ac4C compared to ctrl.
THUMPD1 KO HEK293T and HeLa cell lines exhibited similar W.Blot/RT-qPCR results to those of patient lymphoblasts (above) with complete loss of ac4C modifications specific to small RNAs (not affecting 18S rRNA species). NAT10 KO Hela cells displayed loss of ac4C though affecting both rRNA and tRNA. Despite loss of ac4C modification, the steady state levels of tRNA-Ser-CGA where not significantly different compared to ctrl.
p.Pro164Ser was the single missense variant within the cohort (identified in trans of a truncating one), affecting a highly conserved residue within the THUMP RNA-binding domain. The variant is absent from gnomAD. Recombinant Pro164 was shown to result in marked decrease in protein thermal stability and significant loss in RNA binding capacity.
There is currently no THUMPD1-associated phenotype in OMIM/G2P. The gene is listed in SysID as a candidate for ID based on the initial report by Maddirevula et al. THUMPD1 is rated green for ID (also for hearing loss, microcephaly, growth failure) in PanelApp Australia.
Consider inclusion in the current panel (as well as relevant others) with green rating.Created: 12 Mar 2022, 8:58 a.m. | Last Modified: 12 Mar 2022, 8:58 a.m.
Panel Version: 3.1518
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Global developmental delay; Intellectual disability; Microcephaly; Hearing abnormality; Abnormality of the eye; Febrile seizures; Behavioral abnormality; Abnormality of brain morphology; Abnormality of the face
Publications
Variants in this GENE are reported as part of current diagnostic practice
No clear ID link.Created: 31 Oct 2017, 9:24 a.m.
Mode of inheritance for gene: THUMPD1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: THUMPD1 were changed from THUMPD1 neurodevelopment disorder to Neurodevelopmental disorder with speech delay and variable ocular anomalies, OMIM:619989
Tag Q2_22_rating was removed from gene: THUMPD1. Tag Q2_22_NHS_review was removed from gene: THUMPD1.
Source NHS GMS was added to THUMPD1. Source Expert Review Green was added to THUMPD1. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Phenotypes for gene: THUMPD1 were changed from to THUMPD1 neurodevelopment disorder
Gene: thumpd1 has been classified as Amber List (Moderate Evidence).
Tag Q2_22_rating tag was added to gene: THUMPD1. Tag Q2_22_NHS_review tag was added to gene: THUMPD1.
Publications for gene: THUMPD1 were set to
12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
THUMPD1 was added to Intellectual disabilitypanel. Sources: Expert Review Red
THUMPD1 was created by ellenmcdonagh