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Intellectual disability

Gene: DALRD3

Amber List (moderate evidence)
DALRD3 (DALR anticodon binding domain containing 3)
EnsemblGeneIds (GRCh38): ENSG00000178149
EnsemblGeneIds (GRCh37): ENSG00000178149
DALRD3 is in 2 panels

2 reviews

Arina Puzriakova (Genomics England Curator)

Comment on list classification: Maintaining Amber rating as only 2 families have been reported to date.
Created: 14 Mar 2025, 11:16 a.m. | Last Modified: 14 Mar 2025, 11:16 a.m.
Panel Version: 8.138
Comment on publications: PMID: 39482881 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Created: 14 Mar 2025, 11:13 a.m. | Last Modified: 14 Mar 2025, 11:13 a.m.
Panel Version: 8.137
PMID: 39482881 - second family identified with an individual with a homozygous missense variant in DALRD3 (c.1549C>T, p.(Arg517Cys)) who displayed severe developmental delay, cognitive deficiencies, and multifocal epilepsy. Phenotype was consistent with previously reported cases but less severe which is consistent with the variant types identified. Patient fibroblasts showed reduced levels of DALRD3 protein compared to WT indicating the variant alters the structure of DALRD3.
Created: 14 Mar 2025, 11:12 a.m. | Last Modified: 14 Mar 2025, 11:12 a.m.
Panel Version: 8.136
Comment on list classification: New gene added by Konstantinos Varvagiannis. Rating Amber as this is a good candidate gene but only a single family has been reported to date with variants. Additional evidence needed prior to adding the gene as diagnostic-grade.
Created: 5 Jul 2023, 1:47 p.m. | Last Modified: 5 Jul 2023, 1:47 p.m.
Panel Version: 5.194
Created: 5 Jul 2023, 1:47 p.m.
Last Modified: 14 Mar 2025, 11:12 a.m.
Panel version: 8.136

Konstantinos Varvagiannis (Other)

I don't know

Biallelic pathogenic DALRD3 variants cause ?Developmental and epileptic encephalopathy 86 (# 618910).

Lentini et al (2020 - PMID: 32427860) report 2 sibs born to first cousin parents, homozygous for a DALRD3 pathogenic variant.

Both exhibited hypotonia, severe global DD and epilepsy (onset of seizures at the age 6-7m, poorly controlled by AEDs in one) corresponding overall to an developmental and epileptic encephalopathy. The authors reported subtle dysmorphic features. Other findings included GI concerns (in both) with microcephaly, CHD or renal anomalies in the younger.

WES in both followed by autozygome analysis revealed homozygosity for a DALRD3 stopgain variant (NM_001009996.3:c.1251C>A/pTyr417*) with Sanger sequencing confirming status of the children and carrier state of the parents.

DALRD3 encodes DALR anticodon-binding domain-containing protein 3. A DALR

As the authors demonstrate, and (better) summarized in OMIM, its product is a tRNA-binding protein that interacts with METTL2 to facilitate 3-methylcytosine (m3C) modification - by METTL2 - at position 32 of the anticodon loop in specific arginine tRNAs, namely tRNA-Arg-UCU and tRNA-Arg-CCU. In particular, DALRD3 seems to serve as discrimination factor required for recognition of these specific tRNAs.

In addition to DALRD3, a DALR anticodon-binding domain is also found in arginyl-tRNA synthetases (the cytoplasmic RARS1, and mitochondrial RARS2).

Given the variant type observed, predicting truncation of the protein and/or NMD, in LCLs from the 2 sibs (and comparison with controls) the authors demonstrated that the levels of full-length DALRD3 were decreased in cell lysates, with severe reduction (/loss) of m3C modification of the specific arginine tRNAs, which was not observed for other tRNAs (eg. tRNA-Ser-UGA) or controls. These findings were suggestive of c.1251C>A / pTyr417* being a partial LoF allele.

As the authors discuss, defects in tRNA modification have been associated with numerous human - among others neurological and neurodevelopmental - disorders (cited PMID: 30529455, table 1 of this review summarizing these incl. ADAT3-, PUS3-, TRMT1- related NDDs, etc).

Consider inclusion in the current panel with amber rating.

Sources: Literature
Created: 2 May 2022, 10:12 a.m. | Last Modified: 2 May 2022, 10:14 a.m.
Panel Version: 3.1561

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Developmental and epileptic encephalopathy 86, # 618910

Publications

Created: 2 May 2022, 10:12 a.m.
Last Modified: 2 May 2022, 10:14 a.m.
Panel version: 3.1561

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
Phenotypes
  • ?Developmental and epileptic encephalopathy 86, # 618910
Clinvar variants
Variants in DALRD3
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

14 Mar 2025, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: dalrd3 has been classified as Amber List (Moderate Evidence).

14 Mar 2025, Gel status: 2

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: DALRD3 were set to 32427860

5 Jul 2023, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: dalrd3 has been classified as Amber List (Moderate Evidence).

2 May 2022, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: DALRD3 was added gene: DALRD3 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: DALRD3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DALRD3 were set to 32427860 Phenotypes for gene: DALRD3 were set to ?Developmental and epileptic encephalopathy 86, # 618910 Penetrance for gene: DALRD3 were set to Complete Review for gene: DALRD3 was set to AMBER