A novel variant in ASNS gene responsible for syndromic intellectual disability and microcephaly: Case report and literature review

• Published in: Molecular genetics & genomic medicine 2024-04, Vol.12 (4), p.e2424-n/a
• Main Authors: Jahanpanah, Mohammad, Mokhtari, Diana, Mokaber, Haleh, Arish, Sara, Ahmadabadi, Farzad, Davarnia, Behzad
• Format: Article
• Language: English
• Subjects: Abnormalities; Adenine; Amino acids; Ammonia; ASNS gene; ASNSD; Asparagine; Aspartate-ammonia ligase; Atrophy; Brain; Brain Diseases - genetics; Case reports; Child; Clinical Report; Clinical Reports; Congenital diseases; Convulsions & seizures; Encephalopathy; Enzymes; Epilepsy; exome sequencing; Female; Genomes; Humans; Hydrogen bonds; Intellectual disabilities; intellectual disability; Intellectual Disability - diagnosis; Intellectual Disability - genetics; Iran; Karyotypes; Literature reviews; Magnetic resonance imaging; Metabolism; Microcephaly; Microcephaly - diagnosis; Microcephaly - genetics; Microencephaly; Nervous System Malformations; Patients; Protein structure; Proteins; Sanger sequencing; Seizures; Signs and symptoms; Thymine
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.2424

Background The ASNS (ASNS, MIM 108370) gene variations are responsible for asparagine synthetase deficiency (ASNSD, MIM 615574), a very rare autosomal recessive disease characterized by cerebral anomalies. These patients have congenital microcephaly, progressive encephalopathy, severe intellectual disability, and intractable seizures. Method Clinical characteristics of the patient were collected. Exome sequencing was used for the identification of variants. Sanger sequencing was used to confirm the variant in the target region. The structure of the protein was checked using the DynaMut2 web server. Results The proband is an 11‐year‐old Iranian‐Azeri girl with primary microcephaly and severe intellectual disability in a family with a consanguineous marriage. Symptoms emerged around the 10–20th days of life, when refractory epileptic gaze and unilateral tonic–clonic seizures initiated without any provoking factor such as fever. A brain MRI revealed no abnormalities except for brain atrophy. The karyotype was normal. Using exome sequencing, we identified a novel homozygous variant of thymine to adenine (NM_001673.5:c.538T>A) in the ASNS gene. Both parents had a heterozygous variant in this location. Subsequently, Sanger sequencing confirmed this variant. We also reviewed the clinical manifestations and MRI findings of the previously reported patients. Conclusion In the present study, a novel homozygous variant was recognized in the ASNS gene in an Iranian‐Azeri girl manifesting typical ASNSD symptoms, particularly intellectual disability and microcephaly. This study expands the mutation spectrum of ASNSD and reviews previously reported patients. A novel alteration of thymine to adenine was identified, using exome sequencing analysis in the ASNS gene. Isoleucine amino acid replacing phenylalanine destabilizes the protein structure. We also reviewed the clinical manifestations and MRI findings of 75 previously reported patients suffering from asparagine synthetase deficiency.