Early onset or syndromic epilepsy
Gene: AIMP2
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
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
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
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 AmberCreated: 20 Feb 2019, 5:38 p.m.
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: LiteratureCreated: 14 Dec 2018, 6:19 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Leukodystrophy, hypomyelinating, 17 (MIM 618006)
Publications
Source Wessex and West Midlands GLH was added to AIMP2.
Source NHS GMS was added to AIMP2.
Tag watchlist tag was added to gene: AIMP2.
Phenotypes for gene: AIMP2 were changed from Leukodystrophy, hypomyelinating, 17, 618006; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis to Epileptic Encephalopathy; Infantile Spasms; Leukodystrophy, hypomyelinating, 17, 618006; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis
Publications for gene: AIMP2 were set to 29215095
Gene: aimp2 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: AIMP2 were changed from Leukodystrophy, hypomyelinating, 17 (MIM 618006) to Leukodystrophy, hypomyelinating, 17, 618006; neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis
gene: AIMP2 was added gene: AIMP2 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: AIMP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AIMP2 were set to 29215095 Phenotypes for gene: AIMP2 were set to Leukodystrophy, hypomyelinating, 17 (MIM 618006) Penetrance for gene: AIMP2 were set to Complete Review for gene: AIMP2 was set to AMBER