Abstract
Background: Asparagine Synthetase Deficiency (ASNSD; OMIM #615574) is a newly described rare autosomal recessive neurometabolic disorder, characterised by congenital microcephaly, severe psychomotor delay, encephalopathy and progressive cerebral atrophy. To date, seven families and seven missense mutations in the ASNSD disease causing gene, ASNS, have been published. Methods: We report two further affected infant sisters from a consanguineous Indian family, who in addition to the previously described features had diaphragmatic eventration. Both girls died within the first 6 months of life. Whole exome sequencing (WES) was performed for both sisters to identify the pathogenic mutation. The clinical and biochemical parameters of our patient are compared to previous reports. Results: WES demonstrated a homozygous novel missense ASNS mutation, c.1019G > A, resulting in substitution of the highly conserved arginine residue by histidine (R340H). Conclusion: This report expands the phenotypic and mutation spectrum of ASNSD, which should be considered in neonates with congenital microcephaly, seizures and profound neurodevelopmental delay. The presence of diaphragmatic eventration suggests extracranial involvement of the central nervous system in a disorder that was previously thought to exclusively affect the brain. Like all previously reported patients, these cases were diagnosed with WES, highlighting the clinical utility of next generation sequencing in the diagnosis of rare, difficult to recognise disorders.
Competing interests: None declared
Please note that Jun Sun and Angela J. McGillivray contributed equally and should be shared first authors. Maya Chopra and Asan should be co-corresponding authors.
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Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE et al (2010) A method and server for predicting damaging missense mutations. Nat Methods 7(4):248–249
Alfadhel M, Alrifai MT, Trujilano D et al (2015) Asparagine synthetase deficiency: new inborn errors of metabolism. JIMD Rep 22:11–16
Balasubramanaian MN, Butterworth EA, Kilberg MS (2013) Asparagine synthetase: regulation by cell stress and involvement in tumour biology. Am J Physiol Endocrinol Metab 304:E789–E799
Bartanusz V, Jezova D, Alajajian B et al (2011) The blood-spinal cord barrier: morphology and clinical implications. Ann Neurol 70(2):194–206
Ben-Salem S, Gleeson JG, Al-Shamsi AM et al (2015) Asparagine synthetase deficiency detected by whole exome sequencing causes congenital microcephaly, epileptic encephalopathy and psychomotor delay. Metab Brain Dis 30:687–694
Biasini M, Bienert S, Waterhouse A et al (2014) SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res 42:W252–W258
Bond J, Roberts E, Mochida GH et al (2002) ASPM is a major determinant of cerebral size. Nat Genet 32:316–320
de Koning TJ, Klomp LW (2004) Serine – deficiency syndromes. Curr Opin Neurol 17:197–204
Ghribi A, Bouden A, Braiki M et al (2015) Diaphragmatic eventration in children. Tunis Med 93:76–78
Gonzalez-Perez A, Lopez-Bigas N (2011) Improving the assessment of the outcome of nonsynonymous SNVs with a consensus deleteriousness score, Condel. Am J Hum Genet 88:440–449
Haberle J, Shahbeck N, Ibrahim K et al (2012) Glutamine supplementation in a child with inherited GS deficiency improves the clinical status and partially corrects the peripheral and central amino acid imbalance. Orphanet J Rare Dis 7:48
Jackson AP, Eastwood H, Bell SM (2002) Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet 71:136–142
Larsen TM, Boehlein SK, Schuster SM et al (2000) Three-dimensional structure of Escherichia coli asparagine synthetase B: a short journey from substrate to product. Biochemistry 39:7330
Palmer EE, Hayner J, Sachdev R et al (2015) Asparagine synthetase deficiency causes reduced proliferation of cells under conditions of limited asparagine. Mol Genet Metab 116(3):178–186
Richards NG, Schuster SM (1998) Mechanistic issues in asparagine synthetase catalysis. Adv Enzymol Relat Areas Mol Biol 72:145–198
Ruzzo EK, Cap-Chichi M, Ben-Zeev B et al (2013) Deficiency of asparagine synthetase causes congenital microcephaly and a progressive form of encephalopathy. Neuron 80:429–441
Tiryaki T, Livanelioglu Z, Atayurt H (2006) Eventration of the diaphragm. Asian J Surg 29(1):8–10
van der Crabben SN, Verhoeven-Duif NM, Brilstra EH (2013) An update on serine deficiency disorders. J Inherit Metab Dis 36(4):613–619
Villar J et al (2014) International standards for newborn weight, length and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of INTERGROWTH – 21st Project. Lancet 384:857–868
Yazici M, Karaca I, Arikan A et al (2003) Congenital eventration of the diaphragm in children: 25 years experience in three pediatric surgery centres. Eur J Pediatr Surg 13:298–301
Zhang YP, Lambert MA, Cairney AE (1989) Molecular structure of the human asparagine synthetase gene. Genomics 4:259–265
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Communicated by: Verena Peters
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Fig. 1
Sequence alignment of the ASNS protein between human and E.coli. AsnB and ASNS (TIFF 925 kb)
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Concise Synopsis
A novel homozygous mutation in ASNS causes asparagine synthetase deficiency in two sisters with microcephaly, severe psychomotor delay, cerebral atrophy and diaphragmatic hernia.
Authors’ Contributions
Jun Sun was responsible for the NGS experiment, interpretation of mutation data and drafting the relevant part of manuscript.
Angela J McGillivray, Jason Pinner, Drago Bratkovic and Elizabeth Thompson drafted the relevant parts of manuscript and critically revised the paper.
Fengxia Liu performed the bioinformatic analysis of the NGS data.
Zhihui Yan and Huifeng Jiang performed and interpreted the protein simulation experiment.
Xiuxiu Wei performed and interpreted the Sanger sequencing experiment.
Asan was responsible for the experiment resign and reviewed the manuscript.
Maya Chopra was responsible for the study conception and design, the drafting of the manuscript.
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Asan.
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Maya Chopra has received a reimbursement from BGI as an invited speaker to a conference sponsored by BGI.
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The parents of the patients have consented to take part in this study. They have consented to the publication of this paper. Consent for photographs was declined. There are no photographs in this paper.
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Sun, J. et al. (2016). Diaphragmatic Eventration in Sisters with Asparagine Synthetase Deficiency: A Novel Homozygous ASNS Mutation and Expanded Phenotype. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 34. JIMD Reports, vol 34. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2016_3
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DOI: https://doi.org/10.1007/8904_2016_3
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