Loss-of-Function CARS1 Variants in a Patient With Microcephaly, Developmental Delay, and a Brittle Hair Phenotype.

BACKGROUND

Mutations in cysteinyl-tRNA synthetase (CARS1) have been implicated in a multisystem disease including microcephaly, developmental delay, and brittle hair and nail phenotypes.

METHODS

Here, we present a patient with hepatopathy, hypothyroidism, short stature, developmental delay, microcephaly, muscular hypotonia, brittle hair, and ataxia. The patient underwent exome sequencing to identify potentially pathogenic genetic variants. In addition, identified variants were assessed using yeast complementation assays to determine functional consequences.

RESULTS

Exome sequencing determined that the patient is compound heterozygous for p.Arg341His and p.Arg370Trp CARS1. Yeast complementation assays showed that the p.Arg341His variant has a hypomorphic effect and that the p.Arg370Trp variant causes a complete loss-of-function effect.

CONCLUSION

This study is the second report of pathogenic CARS1 variants and expands the allelic and phenotypic heterogeneity of CARS1-associated disease.