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. 2017:34:1-9.
doi: 10.1007/8904_2016_3. Epub 2016 Jul 27.

Diaphragmatic Eventration in Sisters with Asparagine Synthetase Deficiency: A Novel Homozygous ASNS Mutation and Expanded Phenotype

Jun Sun  1   2   3 , Angela J McGillivray  4 , Jason Pinner  5 , Zhihui Yan  6 , Fengxia Liu  1   2   3 , Drago Bratkovic  7 , Elizabeth Thompson  8 , Xiuxiu Wei  1   2   3 , Huifeng Jiang  6 , Asan  9   10   11 , Maya Chopra  12   13   14
Affiliations

Diaphragmatic Eventration in Sisters with Asparagine Synthetase Deficiency: A Novel Homozygous ASNS Mutation and Expanded Phenotype

Jun Sun et al. JIMD Rep. 2017.

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.

Keywords: ASNS; ASNSD; Asparagine synthetase deficiency; Cerebral atrophy; Congenital microcephaly; Hyperekplexia.

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Figures

Fig. 1
Fig. 1
(A) Pedigree and chromatograms of the DNA sequence changes in ASNS. The parents and siblings are heterozygous for the c.1019G > A variant. Patients 1 and 2 are homozygous for this variant. (B–G) MRI brain of Patient 2 at 5 days old. B Sagittal T1 demonstrates small corpus callosum, atrophic brainstem and vermis. C&D Axial T2 images show severe microcephaly and prominence of the lateral ventricles, particularly the temporal horns. E Axial T1 shows wide Sylvian fissure and prominent subarachnoid space overlying the small cerebral hemispheres. F Coronal T2 shows generalised microcephaly, with severe involvement of the temporal lobes. G Coronal T2 demonstrates enlarged trigones of both lateral ventricles. (H) Chest X-ray of Patient 2, showing raised right hemidiaphragm and midline mediastinal shift to the right
Fig. 2
Fig. 2
(A) Allelic spectrum and location by functional domain of reported pathogenic mutations of the ASNS gene. The R340H mutation identified in this study is marked with a black arrow. (B) Evolutionary sequence conservation analysis. Multiplex sequence alignment of the ASNS protein across ten different species from homo sapiens to Salmo salar shows that Arginine (R) at codon 340 is highly conserved among species. The red arrow locates codon 340 of the ASNS protein. (C) ASNS and asnB ASNB structure. The E. coli ASNB is shown in blue. (D) Molecular dynamics simulations on wild type and mutant R340H ASNS protein. The black curve denotes the structural dynamics of the WT protein and the red curve denotes the R340H protein. The root square deviation of backbone atoms (RMSD) reflects a stable protein, allowing for comparison of structure. Radgyr (radius of gyration) reflects the volume of protein structure. The higher Radgyr value in the red curve suggests that the mutant protein is held in a more extended state
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