A bi‐allelic loss‐of‐function SARS1 variant in children with neurodevelopmental delay, deafness, cardiomyopathy, and decompensation during fever

Abstract

Aminoacyl‐tRNA synthetases (aaRS) are ubiquitously expressed enzymes responsible for ligating amino acids to their cognate tRNA molecules through an aminoacylation reaction. The resulting aminoacyl‐tRNA is delivered to ribosome elongation factors to participate in protein synthesis. Seryl‐tRNA synthetase (SARS1) is one of the cytosolic aaRSs and catalyzes serine attachment to tRNASer. SARS1 deficiency has already been associated with moderate intellectual disability, ataxia, muscle weakness, and seizure in one family. We describe here a new clinical presentation including developmental delay, central deafness, cardiomyopathy, and metabolic decompensation during fever leading to death, in a consanguineous Turkish family, with biallelic variants (c.638G>T, p.(Arg213Leu)) in SARS1. This missense variant was shown to lead to protein instability, resulting in reduced protein level and enzymatic activity. Our results describe a new clinical entity and expand the clinical and mutational spectrum of SARS1 and aaRS deficiencies.

WARS1 and SARS1 : Two tRNA synthetases implicated in autosomal recessive microcephaly

“…We, therefore, concluded that the variant c.397C>T, p.(Arg133Cys) in WARS1 leads to a, possibly incomplete, loss of function. This observation is in line with other reports in the literature, which have shown that biallelic mutations in ARS genes confer loss-of-function effects (Botta et al, 2021;Friedman et al, 2019;Helman et al, 2021;Mendes et al, 2020;Ravel et al, 2021).…”

“…The phenotype observed in individual 5 closely resembles that described by Musante et al, who found the homozygous variant c.514G>A, p.(Asp172Asn) in four individuals from a consanguineous Iranian family who suffered from a severe neurodevelopmental disorder with microcephaly and epilepsy (Table 2) (Musante et al, 2017). Epileptic encephalopathy and neurodevelopmental abnormalities have also been described for four individuals from a consanguineous family in whom the homozygous variant c.638G>T; p.(Arg213Leu) in SARS1 was identified (Ravel et al, 2021; Thevenon et al, 2016). Microcephaly was not a feature in this family.…”

Loss of seryl-tRNA synthetase (SARS1) causes complex spastic paraplegia and cellular senescence

“…In this study, WES identified for the first time a de novo variant in SARS1, challenging the described recessive mode of inheritance, in a patient affected with complex spastic paraparesis with ataxia, seizures and intellectual disability. Two recent articles reported homozygous missense mutations in SARS1 also in close proximity to the active site (c.514G>A, p.Asp172Asn and c.638G>T, p.Arg213Leu), in two families affected by a neurodevelopmental syndrome including microcephaly, ataxia, seizures, moderate intellectual disability and other anomalies such as cardiomyopathy, deafness and decompensation during fever 9 10. Alterations in the central nervous system, such as MRI abnormalities including leucoencephalopathy, ataxia and seizures, have been reported in both cytoplasmic and mitochondrial ARS-related diseases 3 4 19 20…”

“…Two recent articles reported homozygous loss-of-function missense mutations in SARS1 in two independent families exhibiting a neurodevelopmental syndrome including microcephaly, intellectual disability, seizures and ataxia,9 together with other anomalies such as cardiomyopathy, deafness and decompensation during fever 10. In this work, we identified a de novo inherited novel pathogenic variant of SARS1 causing a complex spastic paraplegia and ataxia phenotype, thus confirming the recent implication of mutations in this gene in neurological and movement disorders 9 10. Furthermore, this variant illustrates the concept that dominant negative mutations in ARS genes can give rise to phenotypes similar to those caused by recessive mutations, rather than the neuropathies frequently linked to dominantly inherited variants.…”

Neurodevelopmental disorder with microcephaly, ataxia, and seizures syndrome: expansion of the clinical spectrum

“…NEDMAS (NEDMAS syndrome; 617709) is an extremely rare disorder described only in two families (Musante et al , 2017; Ravel, et al , 2021). The syndrome is characterized by thin body habitus, microcephaly, seizures, ataxia, muscle weakness, speech impairment, aggressive behavior, and moderate ID.…”