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Early onset or syndromic epilepsy v2.518 DALRD3 Konstantinos Varvagiannis changed review comment from: 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 guided 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

It's DALR anticodon-binding domain is similar to those found in arginyl-tRNA synthetases RARS1/2.

As the authors demonstrate, and (better) summarized in OMIM, it's 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. Specifically, 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 RARS3).

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 lylsates, with severe reduction (/loss) of m3C modification specific to the specific arginine tRNAs, which was not the case for others (eg. tRNA-Ser-UGA). 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 (among others 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; to: 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
Early onset or syndromic epilepsy v1.191 RARS2 Rebecca Foulger Source Wessex and West Midlands GLH was added to RARS2.
Early onset or syndromic epilepsy v1.190 RARS2 Rebecca Foulger Source NHS GMS was added to RARS2.
Early onset or syndromic epilepsy v1.189 RARS2 Rebecca Foulger reviewed gene: RARS2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Early onset or syndromic epilepsy v1.188 RARS2 Tracy Lester reviewed gene: RARS2: Rating: GREEN; Mode of pathogenicity: ; Publications: 20635367; Phenotypes: Pontocerebellar hypoplasia, 611523; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1152 RARS2 Sarah Leigh Mode of inheritance for gene: RARS2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v0.1151 RARS2 Sarah Leigh Classified gene: RARS2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.1151 RARS2 Sarah Leigh Gene: rars2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v0.1150 RARS2 Sarah Leigh Marked gene: RARS2 as ready
Early onset or syndromic epilepsy v0.1150 RARS2 Sarah Leigh Added comment: Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 5 variants reported in 4 unrelated cases, in which seizures are a phenotypic feature.
Early onset or syndromic epilepsy v0.1150 RARS2 Sarah Leigh Gene: rars2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.1150 RARS2 Sarah Leigh Phenotypes for gene: RARS2 were changed from to Pontocerebellar hypoplasia, type 6, 611523
Early onset or syndromic epilepsy v0.1149 RARS2 Sarah Leigh Publications for gene: RARS2 were set to
Early onset or syndromic epilepsy RARS2 Zornitza Stark reviewed gene: RARS2
Early onset or syndromic epilepsy RARS2 Sarah Leigh Added gene to panel