Pathogenic variants in SARS1 (Seryl-tRNA Synthetase 1) are causative of a spectrum of rare genetic disorders affecting the central and peripheral nervous systems. The primary and most well-described phenotype is Neurodevelopmental Disorder with Microcephaly, Ataxia, and Seizures (NEDMAS, OMIM #617709), which is inherited in an autosomal recessive pattern. More recently, de novo heterozygous variants have been associated with an autosomal dominant presentation of complex spastic paraplegia with ataxia and intellectual disability but without microcephaly. Furthermore, heterozygous missense variants have been implicated in some cases of autosomal dominant Charcot-Marie-Tooth disease, a peripheral neuropathy.
SARS1-related disorders are considered ultra-rare. Precise incidence and prevalence figures have not been established due to the small number of reported patients in the medical literature. As a point of reference for the rarity of related conditions, HUPRA syndrome, which is caused by mutations in the mitochondrial paralog SARS2, has an estimated prevalence of less than 1 in 1,000,000 births.
The inheritance patterns associated with SARS1 variants are crucial for diagnosis and counselling. The classic NEDMAS phenotype is caused by biallelic (homozygous or compound heterozygous) loss-of-function mutations, consistent with autosomal recessive inheritance. In contrast, a distinct phenotype of complex spastic paraplegia has been associated with a de novo splice site deletion. This variant results in a dominant-negative effect, leading to an autosomal dominant mode of inheritance. The existence of both inheritance patterns linked to a single gene signifies a complex relationship between the specific genetic variant, its effect on protein function, and the resulting clinical outcome. This complexity necessitates careful interpretation of genetic testing results; a novel heterozygous SARS1 variant cannot be automatically dismissed as a benign carrier state without thorough consideration of its predicted functional impact and the patient's specific clinical presentation.
SARS1