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Asparagine synthetase deficiency: A novel case with an unusual molecular mechanism.

ABSTRACT: We report the case of a girl with Asparagine synthetase deficiency, an autosomal recessive metabolic disorder characterized by severe microcephaly and epileptic encephalopathy secondary to pathogenic variants in the ASNS gene. Genetic explorations found a deletion of ASNS and a missense variant on the other allele detected respectively by array comparative genomic hybridization (CGH) and Sanger sequencing. Amino acid analysis provided a biochemical confirmation. Previous cases of Asparagine synthetase deficiency were diagnosed though exome Sequencing. The combination of several techniques (array CGH, sequencing, and biochemical analysis) improves the opportunity to provide accurate diagnosis.

SUBMITTER: Faoucher M

PROVIDER: S-EPMC6838931 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Asparagine synthetase deficiency: A novel case with an unusual molecular mechanism.

Faoucher Marie M Poulat Anne-Lise AL Chatron Nicolas N Labalme Audrey A Schluth-Bolard Caroline C Till Marianne M Vianey-Saban Christine C Portes Vincent Des VD Edery Patrick P Sanlaville Damien D Lesca Gaëtan G Acquaviva Cécile C

Molecular genetics and metabolism reports 20191101

We report the case of a girl with Asparagine synthetase deficiency, an autosomal recessive metabolic disorder characterized by severe microcephaly and epileptic encephalopathy secondary to pathogenic variants in the <i>ASNS</i> gene. Genetic explorations found a deletion of <i>ASNS</i> and a missense variant on the other allele detected respectively by array comparative genomic hybridization (CGH) and Sanger sequencing. Amino acid analysis provided a biochemical confirmation. Previous cases of A ...[more]

PMID: 31720226

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Project description:BackgroundAsparagine synthetase deficiency (ASNSD) is a rare pediatric congenital disorder that clinically manifests into severe progressive microcephaly, global developmental delay, spastic quadriplegia, and refractory seizures. ASNSD is caused by inheritable autosomal recessive mutations in the asparagine synthetase (ASNS) gene.MethodsWe performed whole-exome sequencing using the patient's peripheral blood, and newly discovered mutations were subsequently verified in the patient's parents via Sanger sequencing. Software-based bioinformatics analyses (protein sequence conservation analysis, prediction of protein phosphorylation sites, protein structure modeling, and protein stability prediction) were performed to investigate and deduce their downstream effects.ResultsIn this article, we summarized all the previously reported cases of ASNSD and that of a Chinese girl who was clinically diagnosed with ASNSD, which was later confirmed via genetic testing. Whole-exome sequencing revealed two compound heterozygous missense mutations within the ASNS (c.368T > C, p.F123S and c.1649G > A, p.R550H). The origin of the two mutations was also verified in the patient's parents via Sanger sequencing. The mutation c.368T > C (p.F123S) was discovered and confirmed to be novel and previously unreported. Using software-based bioinformatics analyses, we deduced that the two mutation sites are highly conserved across a wide range of species, with the ability to alter different phosphorylation sites and destabilize the ASNS protein structure. The newly identified p.F123S mutation was predicted to be the most significantly destabilizing and detrimental mutation to the ASNS protein structure, compared to all other previously reported mutations.ConclusionEvidently, the presence of these compound heterozygous mutations could lead to severe clinical phenotypes and serve as a potential indicator for considerably higher risk with less optimistic prognosis in ASNSD patients.

Dataset Information

Asparagine synthetase deficiency: A novel case with an unusual molecular mechanism.

Publications

Asparagine synthetase deficiency: A novel case with an unusual molecular mechanism.

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