Clinical whole exome sequencing from dried blood spot identifies novel genetic defect underlying asparagine synthetase deficiency

Abhyankar, Avinash; Lamendola-Essel, Michelle F.; Brennan, Kelly; Giordano, Jessica L.; Esteves, Cecilia; Felice, Vanessa; Wapner, Ronald J.; Jobanputra, Vaidehi

doi:10.1002/ccr3.1284

Cited by 14 publications

(14 citation statements)

References 13 publications

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“…Originally in 2013, three causative mutations in the gene coding for asparagine synthetase ( ASNS ) have been identified in patients suffering from microcephaly in four families ( Ruzzo et al, 2013 ; ASNS deficiency, ASNSD; OMIM #615574). Since then several mutations were reported in patients with microcephaly in scientific publications ( Ruzzo et al, 2013 ; Alfadhel et al, 2015 ; Ben-Salem et al, 2015 ; Palmer et al, 2015 ; Gataullina et al, 2016 ; Seidahmed et al, 2016 ; Gupta et al, 2017 ; Sacharow et al, 2017 ; Sun et al, 2017 ; Yamamoto et al, 2017 ; Abhyankar et al, 2018 ; Galada et al, 2018 ; for an overview see Gupta et al, 2017 ; Lomelino et al, 2017 and Table 1 ) and three others have been reported in poster form or in the internet ( Table 1 ) from almost all around the world.…”

Section: Introductionmentioning

confidence: 99%

Novel Mutations in the Asparagine Synthetase Gene (ASNS) Associated With Microcephaly

et al. 2018

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Microcephaly is a devastating condition defined by a small head and small brain compared to the age- and sex-matched population. Mutations in a number of different genes causative for microcephaly have been identified, e.g., MCPH1, WDR62, and ASPM. Recently, mutations in the gene encoding the enzyme asparagine synthetase (ASNS) were associated to microcephaly and so far 24 different mutations in ASNS causing microcephaly have been described. In a family with two affected girls, we identified novel compound heterozygous variants in ASNS (c.1165G > C, p.E389Q and c.601delA, p.M201Wfs∗28). The first mutation (E389Q) is a missense mutation resulting in the replacement of a glutamate residue evolutionary conserved from Escherichia coli to Homo sapiens by glutamine. Protein modeling based on the known crystal structure of ASNS of E. coli predicted a destabilization of the protein by E389Q. The second mutation (p.M201Wfs∗28) results in a premature stop codon after amino acid 227, thereby truncating more than half of the protein. The novel variants expand the growing list of microcephaly causing mutations in ASNS.

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Section: Introductionmentioning

confidence: 99%

Novel Mutations in the Asparagine Synthetase Gene (ASNS) Associated With Microcephaly

et al. 2018

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“…Since 2013, exome sequencing has led to the identification of 31 ASNSD cases in 21 unrelated families 1,5–17 . To date, 26 disease-causing variants have been identified in ASNS , with most of them due to recessive missense mutations in the C-terminal domain (Tables 1 and 2).…”

Section: Discussionmentioning

confidence: 99%

“…A list of variants, including those found in our siblings and all cases reported so far, was assembled and is shown in Table 1, which describes the major clinical symptoms and MRI findings observed in patients with ASNSD 1,5–17 .…”

Section: Discussionmentioning

confidence: 99%

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Clinical outcomes of two patients with a novel pathogenic variant in ASNS: response to asparagine supplementation and review of the literature

et al. 2019

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Asparagine synthetase deficiency (ASNSD, OMIM #615574) is a rare autosomal recessive neurometabolic inborn error that leads to severe cognitive impairment. It manifests with microcephaly, intractable seizures, and progressive cerebral atrophy. Currently, there is no established treatment for this condition. In our pediatric cohort, we discovered, by whole-exome sequencing in two siblings from Turkey, a novel homozygous missense mutation in asparagine synthetase at NM_133436.3 ( ASNS _v001): c.1108C>T that results in an amino acid exchange p.(Leu370Phe), in the C-terminal domain. After identification of the metabolic defect, treatment with oral asparagine supplementation was attempted in both patients for 24 months. Asparagine supplementation was well tolerated, and no further disease progression was observed during treatment. One of our patients showed mild developmental progress with increased levels of attention and improved nonverbal communication. These results support our hypothesis that asparagine supplementation should be further investigated as a treatment option for ASNSD. We further reviewed all previously reported ASNSD cases with regard for their clinical phenotypes and brain imaging findings to provide an essential knowledge base for rapid diagnosis and future clinical studies.

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“…Cases of ASNSD reported from a variety of ethnic origins in the past few years (Abhyankar et al, 2018; Alfadhel et al, 2015; Ben‐Salem et al, 2015; Chen, Li, Wang, Chen, & Hong, 2019; Galada et al, 2018; Gataullina et al, 2016; Gupta et al, 2017; Palmer et al, 2015; Radha Rama Devi & Naushad, 2019; Ruzzo et al, 2013; Sacharow et al, 2018; Schleinitz et al, 2018; Seidahmed et al, 2016; Sprute et al, 2019; Sun et al, 2017; Yamamoto et al, 2017), have been summarized in Table 1 with information on nucleotide changes, amino acid changes, and the corresponding genotypes. ASNSD is considered ultrarare in China, with only one case reported in July 2019 (Chen et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

A novel compound heterozygous missense mutation in ASNS broadens the spectrum of asparagine synthetase deficiency

Wang

He²,

et al. 2020

Molec Gen & Gen Med

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Background Asparagine 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. Methods We 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. Results In 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. Conclusion Evidently, 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.

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Clinical whole exome sequencing from dried blood spot identifies novel genetic defect underlying asparagine synthetase deficiency

Cited by 14 publications

References 13 publications

Novel Mutations in the Asparagine Synthetase Gene (ASNS) Associated With Microcephaly

Novel Mutations in the Asparagine Synthetase Gene (ASNS) Associated With Microcephaly

Clinical outcomes of two patients with a novel pathogenic variant in ASNS: response to asparagine supplementation and review of the literature

A novel compound heterozygous missense mutation in ASNS broadens the spectrum of asparagine synthetase deficiency

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