Gene Validity Curation

ASNS - congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome

Gene: ASNS (HGNC:753)
Classification - 06/29/2020
Disease: congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome (MONDO_0014258)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Aminoacidopathy EP
Evidence Summary: ASNS was first reported in relation to autosomal recessive asparagine synthetase deficiency in 2013 (Ruzzo et al., PMID: 24139043). Individuals with mutations in the ASNS gene exhibit developmental delays, intellectual disability, microcephaly, intractable seizures, and progressive brain atrophy. Currently, the disease requires molecular diagnosis as some, but not all, affected individuals have a measurable decrease in the amount of asparagine in their serum or cerebrospinal fluid, which limits this analysis as a preliminary screen in suspected cases. At least 24 unique variants (primarily missense but also frameshift and nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in 22 probands in 15 publications (PMIDs: 29375865, 25663424, 25227173, 29405484, 28776279, 30315573, 26318253, 24139043, 29279279, 30057589, 27422383, 27711071, 27469131, 27743885, 26395554). Variants in this gene segregated with disease in 10 additional family members. Molecular modeling using the Escherichia coli ASNS-B structure has revealed that most of the reported ASD substitutions are located near catalytic sites or within highly conserved regions of the protein (Reviewed in PMID: 29084849). This gene-disease association is supported by its biochemical function in asparagine synthesis, the functional alteration in patient cells resulting in decreased proliferation, the pattern of expression in the brain similar to that of known microcephaly genes, and a hypomorphic mouse model which recapitulates the human brain phenotypes. In summary, ASNS is definitively associated with autosomal recessive inheritance of asparagine synthetase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 2
3.5
11.2
Seidahmed MZ et al. 2016 Jul 15 (PMID:27422383); Schleinitz D et al. 2018 July 13 (PMID:30057589);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 20
7.7
Ruzzo EK et al. 2013 Oct 16 (PMID:24139043); Ben-Salem S et al. 2015 Jun (PMID:25227173); Alfadhel M et al. 2015 Feb 8 (PMID:25663424); Palmer EE et al. 2015 Nov (PMID:26318253); Zillhardt JL et al. 2016 Apr (PMID:26395554); Seidahmed MZ et al. 2016 Jul 15 (PMID:27422383); Yamamoto T et al. 2017 Mar (PMID:27743885); Shamseldin HE et al. 2017 May (PMID:27711071); Sun J et al. 2016 July 27 (PMID:27469131); Abhyankar A et al. 2018 Jan (PMID:29375865); Gupta N et al. 2017 Dec (PMID:28776279); Sacharow SJ et al. 2018 Mar (PMID:29279279); Galada C et al. 2018 Sep (PMID:29405484); Kahrizi K et al. 2019 Jan (PMID:30315573);
Segregation Evidence   Summed LOD Family Count 0 0  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region 1.45 1
Ruzzo EK et al. 2013 Oct 16 (PMID:24139043);
Total Summed LOD Score 1.45    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 11.2
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
1.5
2
Patterson MK et al. 1968 Jan 25 (PMID:4295091);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Ruzzo EK et al. 2013 Oct 16 (PMID:24139043);
Functional Alteration Patient cells 1 0 - 2 2 1
1
1
Palmer EE et al. 2015 Nov (PMID:26318253);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 1.5 1.5
Ruzzo EK et al. 2013 Oct 16 (PMID:24139043);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 4.5

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 11.2 4.5 15.7 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
04/24/2020
EXPERT CURATION (DATE)
Definitive
06/29/2020
EVIDENCE SUMMARY
ASNS was first reported in relation to autosomal recessive asparagine synthetase deficiency in 2013 (Ruzzo et al., PMID: 24139043). Individuals with mutations in the ASNS gene exhibit developmental delays, intellectual disability, microcephaly, intractable seizures, and progressive brain atrophy. Currently, the disease requires molecular diagnosis as some, but not all, affected individuals have a measurable decrease in the amount of asparagine in their serum or cerebrospinal fluid, which limits this analysis as a preliminary screen in suspected cases. At least 24 unique variants (primarily missense but also frameshift and nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in 22 probands in 15 publications (PMIDs: 29375865, 25663424, 25227173, 29405484, 28776279, 30315573, 26318253, 24139043, 29279279, 30057589, 27422383, 27711071, 27469131, 27743885, 26395554). Variants in this gene segregated with disease in 10 additional family members. Molecular modeling using the Escherichia coli ASNS-B structure has revealed that most of the reported ASD substitutions are located near catalytic sites or within highly conserved regions of the protein (Reviewed in PMID: 29084849). This gene-disease association is supported by its biochemical function in asparagine synthesis, the functional alteration in patient cells resulting in decreased proliferation, the pattern of expression in the brain similar to that of known microcephaly genes, and a hypomorphic mouse model which recapitulates the human brain phenotypes. In summary, ASNS is definitively associated with autosomal recessive inheritance of asparagine synthetase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.