title: Diaphragmatic Eventration in Sisters with Asparagine Synthetase Deficiency: A Novel Homozygous ASNS Mutation and Expanded Phenotype.
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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Binhai Genomics Institute, BGI-Tianjin, BGI-Shenzhen, Tianjin, 300308, China.|Tianjin Enterprise Key Laboratory of Clinical molecular diagnostic, BGI-Shenzhen, Tianjin, 300308, China.|BGI-Shenzhen, Shenzhen, 518083, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Newborn Care, Royal Prince Alfred Hospital, Missenden Road, Camperdown, 2050, Sydney, NSW, Australia.
authors.forename: Angela J
authors.initials: AJ
authors.lastname: McGillivray
authors.affiliation: Department of Medical Genomics, Royal Prince Alfred Hospital, Missenden Road, Camperdown, 2050, Sydney, NSW, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Pinner
authors.affiliation: Key Laboratory of Systems Microbial Biotechnology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308, China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Binhai Genomics Institute, BGI-Tianjin, BGI-Shenzhen, Tianjin, 300308, China.|Tianjin Enterprise Key Laboratory of Clinical molecular diagnostic, BGI-Shenzhen, Tianjin, 300308, China.|BGI-Shenzhen, Shenzhen, 518083, China.
authors.forename: Fengxia
authors.initials: F
authors.lastname: Liu
authors.affiliation: Metabolic Clinic, South Australian Clinical Genetics Service, SA Pathology, 5000, Adelaide, SA, Australia.
authors.forename: Drago
authors.initials: D
authors.lastname: Bratkovic
authors.affiliation: Department of Radiology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, Sydney, 2050, NSW, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Thompson
authors.affiliation: Binhai Genomics Institute, BGI-Tianjin, BGI-Shenzhen, Tianjin, 300308, China.|Tianjin Enterprise Key Laboratory of Clinical molecular diagnostic, BGI-Shenzhen, Tianjin, 300308, China.|BGI-Shenzhen, Shenzhen, 518083, China.
authors.forename: Xiuxiu
authors.initials: X
authors.lastname: Wei
authors.affiliation: Key Laboratory of Systems Microbial Biotechnology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308, China.
authors.forename: Huifeng
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Binhai Genomics Institute, BGI-Tianjin, BGI-Shenzhen, Tianjin, 300308, China. asan@genomics.cn.|Tianjin Enterprise Key Laboratory of Clinical molecular diagnostic, BGI-Shenzhen, Tianjin, 300308, China. asan@genomics.cn.|BGI-Shenzhen, Shenzhen, 518083, China. asan@genomics.cn.
authors.lastname: Asan
authors.affiliation: Department of Medical Genomics, Royal Prince Alfred Hospital, Missenden Road, Camperdown, 2050, Sydney, NSW, Australia. Maya.Chopra@sswahs.nsw.gov.au.|Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China. Maya.Chopra@sswahs.nsw.gov.au.|Discipline of Genetic Medicine, University of Sydney, Sydney, 2050, NSW, Australia. Maya.Chopra@sswahs.nsw.gov.au.
authors.forename: Maya
authors.initials: M
authors.lastname: Chopra
keywords: ASNS; ASNSD; Asparagine synthetase deficiency; Cerebral atrophy; Congenital microcephaly; Hyperekplexia