title: Asparagine synthetase deficiency detected by whole exome sequencing causes congenital microcephaly, epileptic encephalopathy and psychomotor delay.
abstract: 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.
authors.affiliation: Department of Pathology, College of Medicine and Heath Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates, salmabs@uaeu.ac.ae.
authors.forename: Salma
authors.initials: S
authors.lastname: Ben-Salem
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
authors.forename: Aisha M
authors.initials: AM
authors.lastname: Al-Shamsi
authors.forename: Barira
authors.initials: B
authors.lastname: Islam
authors.forename: Jozef
authors.initials: J
authors.lastname: Hertecant
authors.forename: Bassam R
authors.initials: BR
authors.lastname: Ali
authors.forename: Lihadh
authors.initials: L
authors.lastname: Al-Gazali
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D001217:Aspartate-Ammonia Ligase / Q000172:deficiency* / Q000235:genetics*; D001927:Brain Diseases / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000150:complications / Q000175:diagnosis / Q000235:genetics; D008297:Male; D008831:Microcephaly / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D008969:Molecular Sequence Data; D010375:Pedigree; D017433:Protein Structure, Secondary; D011596:Psychomotor Disorders / Q000150:complications / Q000175:diagnosis / Q000235:genetics*
chemical_list: D001217:Aspartate-Ammonia Ligase