Intellectual disability
Gene: WARS2

WARS2 (tryptophanyl tRNA synthetase 2, mitochondrial)
EnsemblGeneIds (GRCh38): ENSG00000116874
EnsemblGeneIds (GRCh37): ENSG00000116874
OMIM: 604733, Gene2Phenotype
WARS2 is in 7 panels

2 reviews

Catherine Snow (Genomics England)

Comment on list classification: Expert review provided by Konstantinos Varvagiannis on WARS2.
WARS2 is associated with ID in OMIM but is not in G2P.
A sufficient number of individuals identified and investigated in a number of publications and a number of functional studies have been performed on WARS2. ID is reported in a majority of cases although clinical phenotypes, age of onset are broad ranging.
Therefore classifying WARS2 as Green.
Created: 28 May 2019, 9:19 a.m. | Last Modified: 27 Jun 2019, 12:17 p.m.

Panel Version: 0.195

Created: 28 May 2019, 9:19 a.m.
Last Modified: 27 Jun 2019, 12:17 p.m.
Panel version: Imported from Intellectual disability update May 2019 panel version 0.83

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Several individuals with biallelic pathogenic WARS2 variants have been published to date. DD and ID have been reported among others in most of the affected individuals (only the respective features are commented on below):

PMID: 28236339 (Musante et al. 2017) : 2 sibs compound heterozygous for NM_201263.2:c.325delA (p.Ser109Alafs*159) and c.37T>G (p.Trp13Gly). DD with ID were features in both.

PMID: 28650581 (Theisen et al. 2017) : The authors report on 1 individual with DD, ID and seizures was found to harbor in the compound heterozygous state NM_0158360.3:c.938A>T (p.K313M) and c.298_300delCTT (p.L100del).

PMID: 28905505 (Wortmann et al. 2017) : Details on 6 individuals from 5 unrelated families are provided. DD and ID were observed in 5 of these individuals (Fam 2-5). Severe, neonatal presentation was the case for an additional subject. Confirmed occurrence of epilepsy was reported for 3 individuals from 2 families (and suspected in a further one). Using NM_0158360.3 variants were the following :
Fam1 : c.91-8725_348+27113del36096 (p.Lys31_Glndel116) in trans with c.1045G>C (p.Val349Leu)
Fam2 : c.797del (p.Pro266Argfs*10) in trans with c.938A>T (p.Lys313met) [in 2 individuals]
Fam3 : c.231C>G (p.His77Gln) in trans with c.1054G>A (p.Glu352Lys)
Fam4 : c.532G>C (p.Val178Leu) in homozygous state
Fam5 : c.134G>T (p.Gly45Val) in trans with c.938A>T (p.Lys313Met)

PMID: 29783990 (Vantroys et al. 2018) : The authors report on 1 individual with DD, ID and seizures (among other features), compound heterozygous for c.797del (p.Pro266Argfs*10) and c.938A>T (p.Lys313met), similar to subjects from family 2 in PMID: 28905505.

PMID: 29120065 (Burke et al. 2018) : One 17-year-old boy with infantile-onset Parkinsonism but not DD/ID is described in this study. This individual was found to harbor the following variants in the compound heterozygous state: NM_015836.3: c.37T>G (p.Trp13Gly) and c.683C>G (p.Ser228Trp).

Probably 7 missense variants, 3 frameshift ones and an intragenic deletion have been reported in individuals with DD/ID (overview in fig 4. - in PMID: 29783990).
- p.Pro266Argfs*10 is located in the last exon of the gene (NM_015836.3).
- p.Trp13Gly (c.37T>G using either NM_201263.2 or NM_015836.3 as ref) has been commented to be a functional polymorphism 'uncovered' by the presence of a LoF allele in trans in affected individuals (AF : 0.003265 and 6 homozygotes in gnomAD)
- p.Lys313Met is possibly the most frequently reported variant as discussed by Vantroys et al.

WARS2 encodes mitochondrial tryptophanyl-tRNA synthetase (a cytoplasmic form is encoded by WARS). As commented in most of the articles, aminoacyl-tRNA synthetases (ARS) are a group of enzymes responsible for ligating amino acids to cognate tRNA molecules. Mutations in mitochondrial ARSs lead to impaired intramitochondrial translation affecting OXPHOS complexes (with mitochondrial-encoded subunits). Mutations in all 19 mitochondrial ARSs have been linked to disorders affecting different organ systems with variable severity and phenotypic presentation (summarized by Vantroys et al.).

Several lines of evidence have been provided to support a role for specific variants (eg. reduced WARS2 amounts upon Western blot, or impaired mitochondrial localization depending on the different variants and their effect) or WARS2 (expression in brain, impaired aminoacylation, abnormalities in OXPHOS enzymes/biosynthesis , etc).

Alternative causes (disorders of the differential diagnosis) have been ruled out on most - if not all - occasions.

As commented by Wortmann et al. the clinical spectrum appears to be broad as for the age of onset, features and clinical course (as happens to be the case for some other disorders due deficiencies of other ARSs). The same authors state that apart from elevated lactate which is suggestive of mitochondrial dysfunction, no specific metabolite was found to be altered in affected individuals.

Phenotypic variability even between individuals with the same genotype has been reported. Eg. severe neonatal presentation with lactic acidosis/hypoglycaemia was the case for 2 sibs in family 2 from Wortmann et al. but the clinical course was different for the subject reported by Vantroys et al. (DD/ID with seizure onset at the age of 6 yrs).

As a result, investigations (and selection of gene panel) may not be straightforward.

In addition consideration of this gene in the epilepsy panel seems to be relevant given that seizures were noted in at least 5 individuals (from 4 families - 28650581, 28905505, 29783990) and severe adverse effects of valproate administration occurred in the subject reported by Vantroys et al.
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The associated phenotype in OMIM is Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (# 617710). WARS2 is not associated with any disorder in G2P.
This gene is included in panels for ID offered by some diagnostic laboratories.
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As a result, WARS2 can be considered for inclusion in the ID and epilepsy panels as green (or amber).
Sources: Literature
Created: 23 Feb 2019, 1:59 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures, 617710

Publications

Variants in this GENE are reported as part of current diagnostic practice

Created: 23 Feb 2019, 1:59 p.m.

Panel version: 2.742

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review
Expert Review Green
Expert Review

Phenotypes

Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures, 617710

OMIM

604733

Clinvar variants

Variants in WARS2

Penetrance

unknown

Publications

Panels with this gene

History Filter Activity

25 Jul 2019, Gel status: 3

Added New Source, Added New Source, Set Phenotypes, Set publications, Status Update

Catherine Snow (Genomics England)

Source Expert Review Green was added to WARS2. Source Expert Review was added to WARS2. Added phenotypes Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures, 617710 for gene: WARS2 Publications for gene WARS2 were changed from 28236339; 28650581; 28905505; 29783990; 29120065 to 29783990; 28236339; 29120065; 28650581; 28905505 Rating Changed from No List (delete) to Green List (high evidence)

23 Feb 2019, Gel status: 0

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

Konstantinos Varvagiannis (Other)

gene: WARS2 was added gene: WARS2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: WARS2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WARS2 were set to 28236339; 28650581; 28905505; 29783990; 29120065 Phenotypes for gene: WARS2 were set to Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures, 617710 Penetrance for gene: WARS2 were set to unknown Review for gene: WARS2 was set to GREEN gene: WARS2 was marked as current diagnostic

Intellectual disability Gene: WARS2