Early onset or syndromic epilepsy

Gene: AIMP2

Green List (high evidence)

Comment on list classification: There are at least 6 unrelated individuals reported with biallelic variants in AIMP2, of which 5 presented with seizures / epilepsy. Based on available evidence, this gene should be promoted to Green at the next GMS update.

Created: 19 Jan 2026, 1:59 p.m. | Last Modified: 19 Jan 2026, 1:59 p.m.

Panel Version: 8.93

Additional cases:
PMID: 38374194 Abolhassani et al., 2024
Patient 925, 3yo Iranian female, with NM_006303.4(AIMP2):c.34_35delinsC (p.Gly12ProfsTer?). She presented with: Preterm birth; Low birth weight; Microcephaly; Mild learning difficulty; Developmental delay, speech & motor; Epilepsy; Hypertonia; Limb atrophy & spasticity; Muscle weakness; Strabismus; Ophthalmoplegia; Visual impairment; Anemia. Also homozygous for a VUS SBF1 variant p.Met524Arg (SBF1 is associated with recessive CMT).

PMID: 35140751 Mazaheri et al., 2022
Iranian proband - 7-month-old infant with a complex clinical presentation, including weight loss, severe anemia, skeletal abnormalities, microcephaly and MR imaging features of leukodystrophy. WES revealed a homozygous AIMP2 c.670A>T (p.Lys224Ter) variant, confirmed het in each parent. No mention of seizures. Variant predicted to escape NMD.

PMID: 35568357 Masih et al., 2022
Patient F32.1 - 5yo Indian male - homozygous for NM_006303.4(AIMP2):c.74A>G (p.Tyr25Cys). Clinical presentation: severe DD/ID, generalised tonic-clonic seizures, dysmorphic features, short stature, feeding difficulties, spastic quadriparesis, thin corpus callosum on MRI. Diagnosed with Leukodystrophy, hypomyelinating, 17.

This gene is associated with AR Leukodystrophy, hypomyelinating, 17, MIM:618006 (OMIM accessed 19th Jan 2025). The association between AIMP2 and AR leukodystrophy, hypomyelinating, 17 has been classified as Definitive in ClinGen (Leukodystrophy and Leukoencephalopathy Expert Panel, Sept 2025).

Created: 19 Jan 2026, 1:56 p.m. | Last Modified: 19 Jan 2026, 1:56 p.m.

Panel Version: 8.93

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Leukodystrophy, hypomyelinating, 17, OMIM:618006

Publications

• 35140751
• 35568357
• 38374194

I don't know

Kept rating as Amber based on post-Webex reviews from Helen Lord and Alison Callaway. Added 'watchlist' tag based on PMID:26795593 who report an additional case but there is uncertainty over the clinical significance of the reported variant.

Created: 9 Sep 2019, 9:29 a.m. | Last Modified: 9 Sep 2019, 9:29 a.m.

Panel Version: 1.301

Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

I don't know

AR HLD17. Shukla et al, 2018 (29215095) - 4 children from 2 unrelated consang families of Indian descent with a profound neurodev disorder apparent from early infancy. Early onset multifocal intractable seizures were seen. A hom nonsense variant was identified in both families Y35*. The variant was in a common region of hom in the families suggesting a founder effect. Helbig et al, 2016 (26795593) - compound het - supp data- patient 106: fs and splicing variant classed as likely pathogenic. Patient 106 also has a de novo het nonsense mutation in LRFN2 that they classify as likrly pathogenic but the overal clinicail significance is uncertain.

Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.

Panel Version: 1.261

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

I don't know

Additional report of an AIMP2 compound heterozygote in a patient with Epileptic Encephalopathy, Infantile Spasms in PMID 26795593 (listed in supp table S7) however this case also had a de novo change in another gene which could also explain the phenotype (but listed as uncertain).

Created: 23 Aug 2019, 10:15 a.m. | Last Modified: 23 Aug 2019, 10:15 a.m.

Panel Version: 1.256

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Epileptic Encephalopathy, Infantile Spasms

Publications

• 26795593

Comment on list classification: New gene added by external expert and reviewed by curation team, enough evidence to support gene-disease association and relevance to this panel to rate this gene currently as Amber

Created: 20 Feb 2019, 5:38 p.m.

I don't know

Biallelic pathogenic variants in AIMP2 cause Leukodystrophy, hypomyelinating, 17 (MIM 618006).

3 individuals from 2 unrelated consanguineous families, of Indian origin have been reported (all in PMID: 29215095).

The phenotype consisted of feeding difficulties, lack of development with intellectual disability and seizures (3/3) as well as brain MRI abnormalities (cerebral and cerebellar atrophy, hypo-intensities of the basal ganglia on T2w sequences). Severe microcephaly was observed in 2 patients for whom this information was available (birth measurements not specified).

All patients described to date were homozygous for a nonsense variant [NM_006303.3:c.105C>A or p.(Tyr35Ter)] which appears to be a founder mutation in this population.

Quantitative reverse transcription PCR demonstrated reduced mRNA levels in peripheral lymphocytes, but this decrease was not significant compared to controls (the authors presume low level of NMD).

Previous mouse models provide some - but not substantial - support.

The authors note marked similarity with the phenotype associated with AIMP1 (Leukodystrophy, hypomyelinating, 3 - MIM 260600), another auxiliary protein of the macromolecular multienzyme multi-tRNA synthetase complex. AIMP1 is listed in the current panel as green.

AIMP2 is not associated with any phenotype in G2P.

As a result, this gene can be considered for inclusion in this panel probably as amber.
Sources: Literature

Created: 14 Dec 2018, 6:19 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Leukodystrophy, hypomyelinating, 17 (MIM 618006)

Publications

• 29215095