Del Greco Christina, Kuo Molly E, Smith Desiree E C, Mendes Marisa I, Salamons Gajja S, Nemcovic Marek, Kodrikova Rebeka, Sestak Sergej, Stancheva Malina, Antonellis Anthony
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Cellular and Molecular Biology Program, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Mol Genet Genomic Med. 2025 Feb;13(2):e70078. doi: 10.1002/mgg3.70078.
Mutations in cysteinyl-tRNA synthetase (CARS1) have been implicated in a multisystem disease including microcephaly, developmental delay, and brittle hair and nail phenotypes.
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.
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.
This study is the second report of pathogenic CARS1 variants and expands the allelic and phenotypic heterogeneity of CARS1-associated disease.
半胱氨酰 - tRNA合成酶（CARS1）突变与一种多系统疾病有关，该疾病包括小头畸形、发育迟缓以及头发和指甲脆弱的表型。
在此，我们报告一名患有肝病、甲状腺功能减退、身材矮小、发育迟缓、小头畸形、肌张力减退、头发脆弱和共济失调的患者。该患者接受了外显子组测序以鉴定潜在的致病基因变异。此外，使用酵母互补试验评估鉴定出的变异，以确定其功能后果。
外显子组测序确定该患者为CARS1基因p.Arg341His和p.Arg370Trp的复合杂合子。酵母互补试验表明，p.Arg341His变异具有亚效性作用，而p.Arg370Trp变异导致完全功能丧失效应。
本研究是关于致病性CARS1变异的第二篇报道，并扩展了CARS1相关疾病的等位基因和表型异质性。
