Clinical and molecular spectrum associated with Polymerase-γ related disorders
Ruchika Jha1, Harshkumar Patel2, Rachana Dubey3
1Department of Pediatrics, 29590Armed Forces Medical College, Pune, India.
Insights
Pathogenic variants in the POLG gene are a common cause of inherited mitochondrial disease. This study links specific POLG gene variants to clinical outcomes in pediatric patients, aiding future management.
Area of Science:
- Genetics
- Neurology
- Pediatrics
Background:
- Pathogenic variants in the DNA polymerase gamma (POLG) gene are the most frequent monogenic cause of inherited mitochondrial diseases.
- Limited data exists on the clinicogenetic associations of POLG-related disorders, particularly in pediatric populations.
Purpose of the Study:
- To map the clinicogenetic spectrum of POLG-related disorders in Indian children.
- To identify associations between specific POLG gene variants/domains and clinical phenotypes.
Main Methods:
- Retrospective study of pediatric patients diagnosed with pathogenic or likely pathogenic POLG variants (onset <15 years) across 6 Indian centers.
- Phenotypic classification into established syndromes and analysis of clinical manifestations.
- Identification and domain mapping of POLG variants.
Main Results:
- Twenty-two pediatric patients were identified with pathogenic POLG variants.
- Alpers-Huttenlocher syndrome and progressive external ophthalmoplegia were the most common phenotypes (36.4% each).
- Developmental delay, neuroregression, encephalopathy, and epilepsy were prominent clinical features. Variants in the linker or polymerase domains were associated with severe outcomes like neuroregression, epilepsy, encephalopathy, and hepatic dysfunction.
Conclusions:
- This study delineates the clinical subgroups and genotype-phenotype correlations in pediatric POLG-related disorders in India.
- Understanding these associations can inform follow-up and management strategies for affected individuals and presymptomatic cases.
Background:
POLG pathogenic variants are the commonest single-gene cause of inherited mitochondrial disease. However, the data on clinicogenetic associations in POLG-related disorders are sparse. This study maps the clinicogenetic spectrum of POLG-related disorders in the pediatric population.
Methods:
Individuals were recruited across 6 centers in India. Children diagnosed between January 2015 and August 2020 with pathogenic or likely pathogenic POLG variants and age of onset <15 years were eligible. Phenotypically, patients were categorized into Alpers-Huttenlocher syndrome; myocerebrohepatopathy syndrome; myoclonic epilepsy, myopathy, and sensory ataxia; ataxia-neuropathy spectrum; Leigh disease; and autosomal dominant / recessive progressive external ophthalmoplegia.
Results:
A total of 3729 genetic reports and 4256 hospital records were screened. Twenty-two patients with pathogenic variants were included. Phenotypically, patients were classifiable into Alpers-Huttenlocher syndrome (8/22; 36.4%), progressive external ophthalmoplegia (8/22; 36.4%), Leigh disease (2/22; 9.1%), ataxia-neuropathy spectrum (2/22; 9.1%), and unclassified (2/22; 9.1%). The prominent clinical manifestations included developmental delay (n = 14; 63.7%), neuroregression (n = 14; 63.7%), encephalopathy (n = 11; 50%), epilepsy (n = 11; 50%), ophthalmoplegia (n = 8; 36.4%), and liver dysfunction (n = 8; 36.4%). Forty-four pathogenic variants were identified at 13 loci, and these were clustered at exonuclease (18/44; 40.9%), linker (13/44; 29.5%), polymerase (10/44; 22.7%), and N-terminal domains (3/44; 6.8%). Genotype-phenotype analysis suggested that serious outcomes including neuroregression (odds ratio [OR] 11, 95% CI 2.5, 41), epilepsy (OR 9, 95% CI 2.4, 39), encephalopathy (OR 5.7, 95% CI 1.4, 19), and hepatic dysfunction (OR 4.6, 95% CI 21.3, 15) were associated with at least 1 variant involving linker or polymerase domain.
Conclusions:
We describe the clinical subgroups and their associations with different POLG domains. These can aid in the development of follow-up and management strategies of presymptomatic individuals.
More Related Videos
10:41Wild-type Blocking PCR Combined with Direct Sequencing as a Highly Sensitive Method for Detection of Low-Frequency Somatic Mutations
Published on: March 29, 2017
08:22A Robust Polymerase Chain Reaction-based Assay for Quantifying Cytosine-guanine-guanine Trinucleotide Repeats in Fragile X Mental Retardation-1 Gene
Published on: September 16, 2019
Related Concept Videos
01:31Proofreading
Errors During Replication are Corrected by the DNA Polymerase...
02:10Translesion DNA Polymerases
TLS polymerases are found in all three domains of life - archaea, bacteria, and eukaryotes. Of the different classes of TLS polymerases, members of the Y family are fitted with specialized structures that...
00:58Eukaryotic RNA Polymerases
All three eukaryotic RNAPs require specific transcription factors, of which the...
01:32PCR