Seventeen Novel Mutations in PCCA and PCCB Genes in Indian Propionic Acidemia Patients, and Their Outcomes
Deepti Gupta1,2, Sunita Bijarnia-Mahay1, Sudha Kohli1
11 Center of Medical Genetics, Sir Ganga Ram Hospital , New Delhi, India .
Insights
Genetic mutations in propionic acidemia (PA) genes PCCA and PCCB are distinct in Indian children. This suggests current carrier screening panels may not be effective for this population.
Area of Science:
- Genetics
- Biochemistry
- Pediatrics
Background:
- Propionic acidemia (PA) is a rare genetic metabolic disorder.
- Mutations in propionyl-CoA carboxylase alpha subunit (PCCA) and propionyl-CoA carboxylase beta subunit (PCCB) genes cause PA.
- Understanding genetic variations is crucial for diagnosis and management.
Purpose of the Study:
- To identify PCCA and PCCB gene mutations in Indian PA patients.
- To analyze the impact of these mutations on disease presentation.
- To compare mutation spectrum with other populations.
Main Methods:
- Sanger sequencing of PCCA and PCCB genes in 25 Indian children with PA.
- Bioinformatic analysis to classify genetic variations.
- Clinical data collection on disease onset and outcomes.
Main Results:
- Predominantly early-onset PA (76%) observed.
- Most mutations occurred in the PCCA gene (18/25).
- Identified 26 mutations (20 PCCA, 6 PCCB), with 17 novel variants.
Conclusions:
- The mutation spectrum of PCCA and PCCB genes in Indian PA patients is unique.
- Genetic heterogeneity and admixture in Indian subpopulations contribute to distinct mutation profiles.
- Mutation-based carrier screening panels may require adaptation for Indian populations.
Aims:
The goal of this study was to identify mutations in the propionyl-CoA carboxylase alpha subunit (PCCA) and propionyl-CoA carboxylase beta subunit (PCCB) genes, and to assess their effects on propionic academia (PA) patients.
Methodology:
Twenty-five Indian children with PA were enrolled in this study. Bidirectional Sanger sequencing was performed on both the coding and flanking regions of the PCCA and PCCB genes and the chromatograms were analyzed. Bioinformatic tools were used to classify novel variations into pathogenic or benign.
Results:
The majority of the cases (19/25, 76%) were of the early-onset (<90 days of age) type and 5 were of the late-onset type. The majority of patients had mutations in the PCCA gene (18/25). A total of 26 mutations were noted: 20 in the PCCA gene and 6 in PCCB gene. Seventeen mutations were novel (14 in PCCA and 3 in PCCB). The SNP c.937C>T (p.Arg313Ter), was noted in 9/36 (25%) alleles in the PCCA gene. All of the children were symptomatic and only three survived who are doing well with no major disabilities.
Conclusion:
The spectrum of mutations in the PCCA and PCCB genes among Indians is distinct from other populations. The absence of a common mutation signifies the heterogeneity and admixture of various subpopulations. These findings also suggest that individuals of Indian origin may not benefit from the mutation-based "carrier screening panels" offered by many genetic laboratories.
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