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Fetal anomalies

Gene: AARS2

Green List (high evidence)
AARS2 (alanyl-tRNA synthetase 2, mitochondrial)
EnsemblGeneIds (GRCh38): ENSG00000124608
EnsemblGeneIds (GRCh37): ENSG00000124608
OMIM: 612035, Gene2Phenotype
AARS2 is in 13 panels

3 reviews

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Created: 10 Oct 2023, 3:39 p.m. | Last Modified: 10 Oct 2023, 3:39 p.m.
Panel Version: 3.111

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Created: 10 Oct 2023, 3:39 p.m.
Last Modified: 10 Oct 2023, 3:39 p.m.
Panel version: 3.111

Stephanie Allen (Birmingham Women's NHS Foundation Trust)

Green List (high evidence)

This gene and phenotype were reviewed during a meeting on 23rd Feb 2023 between representatives of the North Thames and Central & South R21 testing GLHs. Clinical review and curation was performed by Natalie Chandler (North Thames GLH), and Stephanie Allen, Esther Kinning and Megan Horton-Bell (Central & South GLH). Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.
Created: 5 May 2023, 3 p.m. | Last Modified: 5 May 2023, 3 p.m.
Panel Version: 3.8
On 13 panels, inc. IEM, cardiomyopathies (inc. child onset), severe paediatric disorders. Associated with Combined oxidative phosphorylation deficiency 8 (AR) and Leukoencephalopathy, progressive, with ovarian failure (AR). Kiraly-Borri et al., 2019: Px A presented in pregnancy with polyhydramnios and nonimmune hydrops with small pulmonary effusions and significant ascites at 35wks. 19wk scan was normal. Died within first hour. Px B (male sibling of A). Child had no respiratory effort at delivery, required full resuscitation. Pulmonary hypoplasia that wasn't suspected prenatally. Died 90mins post birth. WES: both px were compound het AARS2 c.1774C>T p.(Arg592Trp) and c.647dup p.(Cys219Leufs*6) confirmed by Sanger. Sequencing of mtDNA was not performed for either child.p.(Arg592Trp) has been seen before, with majority presenting with severe cardiomyopathy unlike above patients. Bruwer et al., 2018: 5 NIFH cases were found to be homozygous for c.2027A>C p.(Gln676Pro). Expanded the clinical spectrum of AARS2 variants to include fetal hydrops. Gotz et al., 2011: Px II-6 (family 2): towards end of preg, cardiac recordings showed extrasystolia, otherwise pregnancy was uneventful. Died at 3 days. Px II-3 (family 2) - brother to above): died in utero at 40+1 weeks. Autopsy: hypertrophic heart with cardiomyopathic histology and pulmonary hypoplasia. c.1774C>T (p.Arg592Trp) and c.464T>G (p.Leu155Arg) Calvo et al., 2012: Px P40: stillborn foetus with hypotonia and multiple fractures. c.986G>A, p.R329H and c.1774C>T, p.R592W. Conclusion: linked to prenatal phenotypes (polyhydramnios, NIHF, pulmonary effusions, ascites, cardiac recording anomalies). Relevant.
Created: 5 May 2023, 3 p.m. | Last Modified: 5 May 2023, 3 p.m.
Panel Version: 3.8

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Combined oxidative phosphorylation deficiency 8, OMIM:614096; Leukoencephalopathy, progressive, with ovarian failure, OMIM:615889

Publications

Created: 5 May 2023, 3 p.m.
Last Modified: 5 May 2023, 3 p.m.
Panel version: 3.8

Patrick Campbell (Leeds NHS Hospital Trust)

Green List (high evidence)

This gene is not on R21. It can cause fetal phenotype and early neonatal death with bi-allelic variants. We had a fetus present locally with fetal hydrops from around 28 weeks. The result was discovered on whole genome sequencing after miscarriage (R14). It would not have been identified on R21 for fetal anomalies. The local finding of presentation antenatally is corroborated by recent publication (PMID 30819764) with a case showing polyhydramnios and nonimmune hydrops, with small pulmonary effusions and significant ascites first detected at 35 wk of pregnancy.
Consideration should be given to adding the gene to R21.
Sources: NHS GMS
Created: 6 Apr 2023, 9:27 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
fetal hydrops; polyhydramnios; pulmonary effusion; cardiomyopathy

Publications

Mode of pathogenicity
Other

Created: 6 Apr 2023, 9:27 a.m.

Panel version: 3.1

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
Phenotypes
  • Leukoencephalopathy, progressive, with ovarian failure, OMIM:615889
  • Combined oxidative phosphorylation deficiency 8, OMIM:614096
  • fetal hydrops
  • cardiomyopathy
  • polyhydramnios
  • pulmonary effusion
OMIM
612035
Clinvar variants
Variants in AARS2
Penetrance
Complete
Publications
Mode of Pathogenicity
Other
Panels with this gene

History Filter Activity

10 Oct 2023, Gel status: 3

Removed Tag, Removed Tag

Sarah Leigh (Genomics England Curator)

Tag Q2_23_promote_green was removed from gene: AARS2. Tag Q2_23_NHS_review was removed from gene: AARS2.

10 Oct 2023, Gel status: 3

Added New Source, Status Update

Sarah Leigh (Genomics England Curator)

Source Expert Review Green was added to AARS2. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

5 May 2023, Gel status: 2

Added Tag, Added Tag

Arina Puzriakova (Genomics England Curator)

Tag Q2_23_promote_green tag was added to gene: AARS2. Tag Q2_23_NHS_review tag was added to gene: AARS2.

5 May 2023, Gel status: 2

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: AARS2 were changed from Leukoencephalopathy, progressive, with ovarian failure, OMIM:615889; fetal hydrops; cardiomyopathy; polyhydramnios; Combined oxidative phosphorylation deficiency 8, OMIM:614096; pulmonary effusion to Leukoencephalopathy, progressive, with ovarian failure, OMIM:615889; Combined oxidative phosphorylation deficiency 8, OMIM:614096; fetal hydrops; cardiomyopathy; polyhydramnios; pulmonary effusion

5 May 2023, Gel status: 2

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: AARS2 were set to 30819764

5 May 2023, Gel status: 2

Added New Source, Set Phenotypes, Status Update

Arina Puzriakova (Genomics England Curator)

Source Expert Review Amber was added to AARS2. Added phenotypes Combined oxidative phosphorylation deficiency 8, OMIM:614096; Leukoencephalopathy, progressive, with ovarian failure, OMIM:615889 for gene: AARS2 Rating Changed from No List (delete) to Amber List (moderate evidence)

6 Apr 2023, Gel status: 0

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

Patrick Campbell (Leeds NHS Hospital Trust)

gene: AARS2 was added gene: AARS2 was added to Fetal anomalies. Sources: NHS GMS Mode of inheritance for gene: AARS2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AARS2 were set to 30819764 Phenotypes for gene: AARS2 were set to fetal hydrops; polyhydramnios; pulmonary effusion; cardiomyopathy Penetrance for gene: AARS2 were set to Complete Mode of pathogenicity for gene: AARS2 was set to Other Review for gene: AARS2 was set to GREEN