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Updated: May 13, 2025
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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
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Novel Synonymous and Deep Intronic Variants Causing Primary and Secondary Pyruvate Dehydrogenase Complex Deficiency
Helene Bruhn1,2, Karin Naess1,2, Sofia Ygberg1,2,3
1Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
Human Mutation
|April 14, 2025
Summary
Pyruvate dehydrogenase complex deficiency (PDCD) is caused by rare genetic variants affecting metabolism. This study identifies novel atypical variants in PDHA1, PDHX, and TPK1 genes, leading to splicing defects and varying disease severity.
Area of Science:
- Genetics
- Biochemistry
- Neurology
Background:
- Pyruvate dehydrogenase complex deficiency (PDCD) results from impaired aerobic carbohydrate metabolism, causing neurological disorders.
- Genetic variations in PDCD lead to diverse clinical presentations.
- Atypical genetic variants, particularly those affecting splicing, are increasingly recognized as causes of PDCD.
Purpose of the Study:
- To investigate the clinical, biochemical, and molecular characteristics of patients with primary and secondary PDCD.
- To identify and characterize novel atypical genetic variants in PDCD.
- To elucidate the impact of these variants on gene splicing and enzyme activity.
Main Methods:
- Whole-genome sequencing (WGS) was employed to identify genetic variants.
- Sanger and RNA sequencing of cDNA from patient blood and fibroblasts were used to analyze splicing defects.
- Biochemical assays were performed to assess pyruvate dehydrogenase (PDH) enzyme activity.
Main Results:
- Novel synonymous variants in PDHA1 and deep intronic variants in PDHX and TPK1 were identified.
- These variants resulted in aberrant splicing, including exon skipping and intronic sequence insertion.
- Splice defects showed tissue-specific variations, being more pronounced in fibroblasts than in blood.
- Mild phenotypes correlated with leaky splicing and residual PDH enzyme activity in some patients.
Conclusions:
- The study expands the known spectrum of pathogenic variants causing PDCD, emphasizing atypical splicing defects.
- Tissue-specific analysis is crucial for understanding the impact of splice defects in PDCD.
- Novel genetic variants and their splicing consequences provide insights into PDCD pathogenesis and clinical variability.
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