Intellectual disability
Gene: ASNS

ASNS (asparagine synthetase (glutamine-hydrolyzing))
EnsemblGeneIds (GRCh38): ENSG00000070669
EnsemblGeneIds (GRCh37): ENSG00000070669
OMIM: 108370, Gene2Phenotype
ASNS is in 4 panels

2 reviews

Louise Daugherty (Genomics England Curator)

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 Green. From PMID: 29375865 (2018) A. Abhyankar et al. summarised Ruzzo et al. (PMID:24139043) studied nine children from four families presenting with similar phenotypes and reported two missense mutations‐c.1084T>G (p.F362V; NM_183356) and c.1648C>T (p.R550C; NM_183356) in the asparagine synthetase domain that dramatically reduce ASNS protein abundance. The authors concluded that accumulation of aspartate/glutamate secondary to ASNS depletion in the brain resulted in the neurologic impairment. One of the two mutations reported in that study, c.1084T>G (p.F362V; NM_183356), is four residues upstream of NP_001664.3:p.Gly366Glu seen in our patient. HEK293 cells expressing c.1084T>G (p.F362V; NM_183356) mutant allele showed dramatic reduction in protein abundance. Additionally, Ruzzo et al. reported a hypomorphic ASNS mouse knockout with structural brain abnormalities and deficits in learning/memory. Subsequently, eight more cases of ASNSD have been reported in the literature PMID: 2566342,27422383, 27469131, 27743885.
Created: 20 Feb 2019, 6:31 p.m.

Comment on publications: Added GeneReview PMID: 30234940 (2018) for Asparagine Synthetase Deficiency and PMID:27743885 (2017) first two cases (related) Japanese patients with ASNS deficiency with developmental delay and PMID: 29375865 (2017) reports two novel compound heterozygous missense variants in asparagine synthetase gene as the likely cause of fatal asparagine synthetase deficiency in a single neonate case.
Created: 20 Feb 2019, 6:23 p.m.

Comment on publications: Added GeneReview PMID: 30234940 (2018) for Asparagine Synthetase Deficiency and PMID:27743885 (2017) first two cases (related) Japanese patients with ASNS deficiency with developmental delay
Created: 20 Feb 2019, 6:11 p.m.

Comment on phenotypes: added phenotypes to indicate relevance to panel
Created: 20 Feb 2019, 5:54 p.m.

Created: 20 Feb 2019, 5:54 p.m.

Panel version: 2.705

Konstantinos Varvagiannis (Other)

I don't know

Homozygous or compound heterozygous mutations in the ASNS gene result in asparagine synthase deficiency (# 615574). A total of 5 such families have been described to date.

PMID 24139043 describes 9 individuals from 4 families (two of Iranian Jewish origin, one Bangladeshi and one French Canadian) all presenting with congenital microcephaly, profound intellectual disability and progressive cerebral atrophy. Individuals from the 2 Iranian families were unrelated but homozygous for a missense vaiant, considered to be a founder mutation in this population. The siblings from the Bangladeshi family were born to consanguineous parents and homozygous for a further missense variant. Subjects from the French Canadian family were compound heterozygous for two missense variants. Reduction in protein abundance was demonstrated in HEK293 cells expressing two of the identified variants but was not the case for a third one. In two of these subjects plasma asparagine were decreased whereas individuals from one family demonstrated increased levels of glutamine and aspartic acid (precursors in the ASNS-mediated synthesis of asparagine), consistent with a possible functional effect of these variants. An ASNS mouse model was thought to recapitulate the human brain phenotype.

One further affected child born to consanguineous parents from the United Arab Emirates is reported in PMID 25227173. This individual had a similar presentation consisting of congenital microcephaly, epileptic encephalopathy as well as severe psychomotor delay. Brain MRI demonstrated reduced cerebral and cerebellar volume and ventricular dilatation. Plasma amino acids, including asparagine levels were normal.

All the 4 missense variants in these individuals are (extremely) rare with no homozygotes in gnomAD.
Created: 12 Aug 2018, 1:16 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Asparagine synthetase deficiency, 615574

Publications

Created: 12 Aug 2018, 1:16 p.m.

Panel version: 2.361

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Green

Phenotypes

Asparagine synthetase deficiency, 615574
congenital microcephaly, intellectual disability, progressive cerebral atrophy, intractable seizures

OMIM

108370

Clinvar variants

Variants in ASNS

Penetrance

Complete

Publications

Panels with this gene