VARS1 – Neurodevelopmental Disorder with Microcephaly, Seizures, and Cortical Atrophy

Autosomal recessive variants in VARS1 have been implicated in neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy. This disorder is characterized by early‐onset microcephaly, global developmental delay, seizures, and progressive cerebral atrophy.

In the first family, two male siblings aged 15 and 10 years presented with intellectual disability, global developmental delay, severe speech impairment, microcephaly, and prematurity. Exome sequencing revealed compound heterozygous missense variants c.65C>A (p.Ala22Asp) and c.3214T>C (p.Phe1072Leu) in trans in VARS1 (PMID:30275004).

In a second unrelated non-consanguineous family, two siblings exhibited severe early-onset microcephaly, intractable seizures, and progressive cerebral atrophy. They harbored compound heterozygous variants c.3192G>A (p.Met1064Ile) and c.1577-2A>G, with the splice variant causing nonsense-mediated decay of VARS1 transcripts (PMID:29691655).

These findings establish an autosomal recessive inheritance pattern, with biallelic missense, splice‐site, and frameshift loss-of-function variants underlying the phenotype. No heterozygous carriers showed clinical features, and co-segregation was observed in both sib pairs.

Functional assays in patient-derived fibroblasts demonstrated markedly reduced VARS1 mRNA and protein levels, profoundly diminished valyl-tRNA synthetase activity, and pathogenic structural disruption of the anticodon-binding domain (PMID:29691655). These data support a loss-of-function mechanism.

Some patients lack seizures or cortical atrophy, and one neonatal case with co-existing congenital adrenal hyperplasia carrying a VARS1 variant of uncertain significance underscores phenotype variability and the need for careful interpretation in multi-genic contexts (PMID:36204440).

Collectively, genetic and experimental evidence support a moderate level of clinical validity for VARS1 in this neurodevelopmental disorder. Inclusion of VARS1 in diagnostic panels for autosomal recessive microcephaly syndromes facilitates early diagnosis and management.

References

• Cold Spring Harbor Molecular Case Studies • 2018 • Biallelic variants in VARS in a family with two siblings with intellectual disability and microcephaly: case report and review of the literature. PMID:30275004
• Human Genetics • 2018 • Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy. PMID:29691655
• Iranian Journal of Child Neurology • 2022 • Hypertonia, Microcephaly and Hyperkalaemia in a Neonate: Coexistence of Neurodevelopmental Disorder and Adrenal Insufficiency. PMID:36204440

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