A Novel Combination of Biallelic Variants in the VARS2 Gene: A Severe Phenotype

Joana Capela; Mariana Reis; Inês Almeida; Marta Novo; Ana Ramalho; Patrícia Lipari; Márcia

doi:10.20344/amp.23831

Autores

Joana Capela Pediatrics Department. Unidade Local de Saúde do Algarve. Faro. https://orcid.org/0000-0002-5081-5481
Mariana Reis Pediatrics Department. Unidade Local de Saúde do Algarve. Faro. https://orcid.org/0000-0002-0776-8819
Inês Almeida Pediatrics Department. Unidade Local de Saúde do Algarve. Faro. https://orcid.org/0009-0001-9128-3469
Marta Novo Neonatal and Pediatric Intensive Care Unit. Unidade Local de Saúde do Algarve. Faro. https://orcid.org/0000-0001-5522-0914
Ana Ramalho Neonatal and Pediatric Intensive Care Unit. Unidade Local de Saúde do Algarve. Faro.
Patrícia Lipari Reference Center for Hereditary Metabolic Disorders. Pediatrics Department. Unidade Local de Saúde Santa Maria. Lisbon. & University Pediatric Clinic. Faculty of Medicine. Universidade de Lisboa. Lisbon. https://orcid.org/0000-0001-9197-7586
Márcia University Pediatric Clinic. Faculty of Medicine. Universidade de Lisboa. Lisbon. & Medical Genetics Department. Pediatrics Department. Unidade Local de Saúde Santa Maria. Lisbon. https://orcid.org/0000-0001-6174-2524

DOI:

https://doi.org/10.20344/amp.23831

Palavras-chave:

Cardiomiopatia Hipertrófica, Doenças Mitocondriais, Epilepsia, Valina-tRNA Ligase

Resumo

Do que se conhece, estão descritos na literatura apenas 29 indivíduos com variantes patogénicas em homozigotia ou heterozigotia composta no gene valil-tRNA sintetase 2 (VARS2), responsável por alterações nos complexos da cadeia respiratória mitocondrial. Descrevemos dois irmãos com uma nova combinação de variantes bialélicas no gene VARS2 (c.1079C>T p.Ala360Val, provavelmente patogénica, e c.1258G>A p.Ala420Thr, provavelmente patogénica). Ambos apresentavam cardiomiopatia hipertrófica e acidose láctica, com desfecho fatal no primeiro ano de vida. O primeiro manifestava também restrição do crescimento fetal e defeito do septo interventricular; o segundo apresentava epilepsia, insuficiência respiratória e atraso do desenvolvimento psicomotor. Este genótipo poderá associar-se a um fenótipo cardíaco grave. Estes casos ampliam o espetro clínico e genético da doença mitocondrial relacionada com o gene VARS2, evidenciam a variabilidade fenotípica e reforçam a importância do diagnóstico molecular precoce na cardiomiopatia. A confirmação genética permite um aconselhamento preciso e a consideração do diagnóstico pré-natal ou pré-implantação em gravidezes futuras.

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