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Updated: May 27, 2025
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Loss-of-Function CARS1 Variants in a Patient With Microcephaly, Developmental Delay, and a Brittle Hair Phenotype
Christina Del Greco1, Molly E Kuo1,2,3, Desiree E C Smith4
1Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA.
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.
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