Early onset or syndromic epilepsy
Gene: DALRD3Comment 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, 1:48 p.m. | Last Modified: 5 Jul 2023, 1:48 p.m.
Panel Version: 4.64
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: 4.63
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: LiteratureCreated: 2 May 2022, 10:12 a.m. | Last Modified: 2 May 2022, 10:13 a.m.
Panel Version: 2.518
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
?Developmental and epileptic encephalopathy 86, # 618910
Publications
Gene: dalrd3 has been classified as Amber List (Moderate Evidence).
Gene: dalrd3 has been classified as Amber List (Moderate Evidence).
gene: DALRD3 was added gene: DALRD3 was added to Genetic epilepsy syndromes. 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