Loss‐of‐Function CARS1 Variants in a Patient With Microcephaly, Developmental Delay, and a Brittle Hair Phenotype
ABSTRACT 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,...
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Wiley
2025-02-01
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| Series: | Molecular Genetics & Genomic Medicine |
| Online Access: | https://doi.org/10.1002/mgg3.70078 |
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| author | Christina Del Greco Molly E. Kuo Desiree E. C. Smith Marisa I. Mendes Gajja S. Salamons Marek Nemcovic Rebeka Kodrikova Sergej Sestak Malina Stancheva Anthony Antonellis |
| author_facet | Christina Del Greco Molly E. Kuo Desiree E. C. Smith Marisa I. Mendes Gajja S. Salamons Marek Nemcovic Rebeka Kodrikova Sergej Sestak Malina Stancheva Anthony Antonellis |
| author_sort | Christina Del Greco |
| collection | DOAJ |
| description | ABSTRACT 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. |
| format | Article |
| id | doaj-art-9b5bc64f0144482f9d1a5a7cf865a718 |
| institution | OA Journals |
| issn | 2324-9269 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj-art-9b5bc64f0144482f9d1a5a7cf865a7182025-08-20T02:01:19ZengWileyMolecular Genetics & Genomic Medicine2324-92692025-02-01132n/an/a10.1002/mgg3.70078Loss‐of‐Function CARS1 Variants in a Patient With Microcephaly, Developmental Delay, and a Brittle Hair PhenotypeChristina Del Greco0Molly E. Kuo1Desiree E. C. Smith2Marisa I. Mendes3Gajja S. Salamons4Marek Nemcovic5Rebeka Kodrikova6Sergej Sestak7Malina Stancheva8Anthony Antonellis9Department of Human Genetics University of Michigan Medical School Ann Arbor Michigan USADepartment of Human Genetics University of Michigan Medical School Ann Arbor Michigan USALaboratory Genetic Metabolic Diseases, Amsterdam UMC University of Amsterdam Amsterdam the NetherlandsLaboratory Genetic Metabolic Diseases, Amsterdam UMC University of Amsterdam Amsterdam the NetherlandsLaboratory Genetic Metabolic Diseases, Amsterdam UMC University of Amsterdam Amsterdam the NetherlandsInstitute of Chemistry, Department of Glycobiology Slovak Academy of Sciences Bratislava SlovakiaInstitute of Chemistry, Department of Glycobiology Slovak Academy of Sciences Bratislava SlovakiaInstitute of Chemistry, Department of Glycobiology Slovak Academy of Sciences Bratislava SlovakiaMedico‐Dental Center Mediva Sofia BulgariaDepartment of Human Genetics University of Michigan Medical School Ann Arbor Michigan USAABSTRACT 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.https://doi.org/10.1002/mgg3.70078 |
| spellingShingle | Christina Del Greco Molly E. Kuo Desiree E. C. Smith Marisa I. Mendes Gajja S. Salamons Marek Nemcovic Rebeka Kodrikova Sergej Sestak Malina Stancheva Anthony Antonellis Loss‐of‐Function CARS1 Variants in a Patient With Microcephaly, Developmental Delay, and a Brittle Hair Phenotype Molecular Genetics & Genomic Medicine |
| title | Loss‐of‐Function CARS1 Variants in a Patient With Microcephaly, Developmental Delay, and a Brittle Hair Phenotype |
| title_full | Loss‐of‐Function CARS1 Variants in a Patient With Microcephaly, Developmental Delay, and a Brittle Hair Phenotype |
| title_fullStr | Loss‐of‐Function CARS1 Variants in a Patient With Microcephaly, Developmental Delay, and a Brittle Hair Phenotype |
| title_full_unstemmed | Loss‐of‐Function CARS1 Variants in a Patient With Microcephaly, Developmental Delay, and a Brittle Hair Phenotype |
| title_short | Loss‐of‐Function CARS1 Variants in a Patient With Microcephaly, Developmental Delay, and a Brittle Hair Phenotype |
| title_sort | loss of function cars1 variants in a patient with microcephaly developmental delay and a brittle hair phenotype |
| url | https://doi.org/10.1002/mgg3.70078 |
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