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Bi-Allelic Splicing Variant, c.153-2A > C in TOMM7 Is Associated With Leigh Syndrome

Mayuri Yeole1, Purvi Majethia1, Shahyan Siddiqui2

  • 1Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.

American Journal of Medical Genetics. Part A
|September 27, 2024
PubMed

Insights

A novel splice variant in the TOMM7 gene causes a severe mitochondrial disease in an infant. This finding expands the known spectrum of TOMM7-related disorders and highlights aberrant splicing as a disease mechanism.

Area of Science:

  • Mitochondrial biology
  • Genetics
  • Molecular medicine

Background:

  • The Translocase of the Outer Mitochondrial Membrane (TOMM) complex is crucial for protein import into mitochondria.
  • TOMM7, a subunit of the TOMM complex, regulates its assembly and stability.
  • Previous studies linked bi-allelic TOMM7 variants to diverse phenotypes including short stature, lipodystrophy, progeria, developmental delay, hypotonia, and skeletal dysplasia.

Observation:

  • A 4-month-old female infant presented with severe neonatal-onset hypotonia, lactic acidosis, optic atrophy, and neuroimaging consistent with Leigh disease.
  • Genetic analysis identified a novel canonical splice variant, c.153-2A>C, in the TOMM7 gene (NM_019059.5).

Findings:

  • The identified TOMM7 splice variant led to aberrant splicing and the production of shorter transcripts, as confirmed by parental cDNA analysis.
  • This variant is presumed to be disease-causing, contributing to the infant's severe clinical presentation.

Implications:

  • This case expands the genotypic and phenotypic spectrum of TOMM7-related disorders.
  • It underscores the importance of investigating canonical splice variants and aberrant splicing in unexplained genetic disorders.
  • Understanding the functional consequences of such variants is critical for diagnosis and potential therapeutic strategies.
Keywords:
Garg‐Mishra progeroid syndromeTOMM complexelevated lactatemitochondria

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