Molecular profiling of organic acidemias in India achieves 95 percent diagnostic yield and maps population-specific variants
Investigators analyzed molecular data from 394 families suspected of organic acidemias between 2010 and 2025 using targeted Sanger sequencing and next-generation sequencing. The cohort achieved a 95.4 percent molecular confirmation rate, with glutaric acidemia type 1 and methylmalonic acidemia being the most frequently identified disorders. Researchers documented 61 novel pathogenic variants across 16 genes and observed a high rate of homozygous mutations, alongside a geographically clustered BCKDHB variant in north-western India. These findings establish a population-specific diagnostic framework that will improve variant interpretation, guide targeted molecular testing, and support prenatal counseling for Indian families.
The original study
Organic Acidemias in India: Clinical and Molecular Spectrum.
- Authors
- Bijarnia-Mahay S, Gupta D, Puri RD, Saxena R, Kohli S, Verma J, et al.
- Journal
- Indian journal of pediatrics
- Type
- Journal Article
- PMID
- 42430061
Original abstract
OBJECTIVES: Organic acidemias (OADs) are inherited disorders of branched chain amino acid catabolism, typically presenting in neonatal or infantile period, with encephalopathy, metabolic acidosis, and seizures. While an early clinical and biochemical recognition is pivotal for immediate survival, molecular characterization is essential for accurate diagnosis, genetic counseling, and future preventive strategies in families. METHODS: A study was performed on 394 patients/families suspected of OADs between year 2010 to 2025. Molecular studies were performed in biochemically diagnosed cases, using targeted Sanger sequencing, or next-generation sequencing. Cases were classified according to age and type of clinical presentations: acute, sub-acute/chronic, or presymptomatic/ newborn screening. RESULTS: A molecular confirmation was achieved in 293 patients from 283 families (95.4% diagnostic yield). Glutaric acidemia type 1 (100 cases) and methylmalonic acidemia (98 cases) were most common disorders identified. One-fourth of variants were novel (61/221, 27.6%) across 16 genes. Homozygosity was observed in 71.5% families. Apart from previously described recurrent variants in GCDH c.1204C>T, MMACHC c.394C>T and BTD c.38_44delGCGCTGinsTCC identified in index study, BCKDHB c.1065delT variant was noted to be geographically clustered in north-western India. High number of variants, including unique novel variants underscores the distinct genetic landscape of the Indian population. The prevalence of homozygous variants, many in the absence of consanguinity, suggests the impact of endogamy. CONCLUSIONS: Molecular characterization of OADs in India provides a critical framework for future studies in addition to clinical care advancements. This study adds 61 new variants to the global scientific record, facilitating improved prenatal diagnosis and early intervention strategies.