TY - JOUR
T1 - Asparagine synthetase deficiency detected by whole exome sequencing causes congenital microcephaly, epileptic encephalopathy and psychomotor delay
AU - Ben-Salem, Salma
AU - Gleeson, Joseph G.
AU - Al-Shamsi, Aisha M.
AU - Islam, Barira
AU - Hertecant, Jozef
AU - Ali, Bassam R.
AU - Al-Gazali, Lihadh
N1 - Funding Information:
We are indebted the family members for their participation in this study. We are also grateful to Sheikh Hamdan Bin Rashid Al-Maktoum Award for Medical Sciences for their financial support. Molecular work was funded by NIH grants 1P01HD070494 and R01 NS048453.
Publisher Copyright:
© 2014, Springer Science+Business Media New York.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - Deficiency of Asparagine Synthetase (ASNSD, MIM 615574) is a very rare autosomal recessive disorder presenting with some brain abnormalities. Affected individuals have congenital microcephaly and progressive encephalopathy associated with severe intellectual disability and intractable seizures. The loss of function of the asparagine synthetase (ASNS, EC 6.3.5.4), particularly in the brain, is the major cause of this particular congenital microcephaly. In this study, we clinically evaluated an affected child from a consanguineous Emirati family presenting with congenital microcephaly and epileptic encephalopathy. In addition, whole-exome sequencing revealed a novel homozygous substitution mutation (c.1193A > C) in the ASNS gene. This mutation resulted in the substitution of highly conserved tyrosine residue by cysteine (p.Y398C). Molecular modeling analysis predicts hypomorphic and damaging effects of this mutation on the protein structure and altering its enzymatic activity. Therefore, we conclude that the loss of ASNS function is most likely the cause of this condition in the studied family. This report brings the number of reported families with this very rare disorder to five and the number of pathogenic mutations in the ASNS gene to four. This finding extends the ASNS pathogenic mutations spectrum and highlights the utility of whole-exome sequencing in elucidation the causes of rare recessive disorders that are heterogeneous and/or overlap with other conditions.
AB - Deficiency of Asparagine Synthetase (ASNSD, MIM 615574) is a very rare autosomal recessive disorder presenting with some brain abnormalities. Affected individuals have congenital microcephaly and progressive encephalopathy associated with severe intellectual disability and intractable seizures. The loss of function of the asparagine synthetase (ASNS, EC 6.3.5.4), particularly in the brain, is the major cause of this particular congenital microcephaly. In this study, we clinically evaluated an affected child from a consanguineous Emirati family presenting with congenital microcephaly and epileptic encephalopathy. In addition, whole-exome sequencing revealed a novel homozygous substitution mutation (c.1193A > C) in the ASNS gene. This mutation resulted in the substitution of highly conserved tyrosine residue by cysteine (p.Y398C). Molecular modeling analysis predicts hypomorphic and damaging effects of this mutation on the protein structure and altering its enzymatic activity. Therefore, we conclude that the loss of ASNS function is most likely the cause of this condition in the studied family. This report brings the number of reported families with this very rare disorder to five and the number of pathogenic mutations in the ASNS gene to four. This finding extends the ASNS pathogenic mutations spectrum and highlights the utility of whole-exome sequencing in elucidation the causes of rare recessive disorders that are heterogeneous and/or overlap with other conditions.
KW - ASNS
KW - Asparagine synthetase deficiency
KW - Epileptic encephalopathy
KW - Hypomorphic mutation
KW - Microcephaly
KW - WES
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U2 - 10.1007/s11011-014-9618-0
DO - 10.1007/s11011-014-9618-0
M3 - Article
C2 - 25227173
AN - SCOPUS:84928693524
SN - 0885-7490
VL - 30
SP - 687
EP - 694
JO - Metabolic Brain Disease
JF - Metabolic Brain Disease
IS - 3
ER -