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Molecular diagnosis of Huntington disease in Brazilian patients
T C Lima E Silva1, H G Serra, C S Bertuzzo
1Departamento de Genética Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP).
Insights
Huntington disease (HD) diagnosis can be confirmed by genotyping the IT15 gene for CAG repeat expansions. Not all patients with HD symptoms carry the expansion, highlighting the need for molecular confirmation for genetic counseling.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Huntington disease (HD) is an autosomal dominant neurodegenerative disorder.
- HD is characterized by choreiform movements, cognitive decline, and is linked to CAG repeat expansion in the IT15 gene.
Purpose of the Study:
- To genotype the CAG repeat in the IT15 gene for Huntington disease (HD) in Brazilian individuals.
- To investigate the correlation between CAG repeat size and age of symptom onset in HD patients.
Main Methods:
- CAG repeat genotyping of the IT15 gene was performed on 44 Brazilian individuals (42 patients, 2 controls) from 34 families.
- Control individuals (25) were genotyped to establish normal CAG repeat ranges.
- Statistical analysis was used to determine the correlation between expanded CAG allele size and age at onset.
Main Results:
- An expanded CAG allele was identified in 76% of individuals with suspected HD, with repeat sizes ranging from 43 to 73 units.
- Normal CAG alleles ranged from 18 to 26 units in patients and 16 to 33 units in controls.
- A significant negative correlation (r=0.6, p=0.0001) was found between expanded CAG allele size and age at onset, explaining 40% of variability.
Conclusions:
- Molecular confirmation of Huntington disease (HD) is crucial, as not all clinically diagnosed patients carry the IT15 gene CAG expansion.
- The absence of intermediate-sized alleles facilitates molecular diagnosis.
- Molecular testing enables accurate genetic counseling for suspected HD cases.
Abstract:
Huntington disease (HD) is a progressive neurodegenerative disorder with autosomal dominant inheritance, characterized by choreiform movements and cognitive impairment. Onset of symptoms is around 40 years of age and progression to death occurs in approximately 10 to 15 years from the time of disease onset. HD is associated with an unstable CAG repeat expansion at the 5' and of the IT15 gene. We have genotyped the CAG repeat in the IT15 gene in 44 Brazilian individuals (42 patients and 2 unaffected family members) belonging to 34 unrelated families thought to segregate HD. We found one expanded CAG allele in 32 individuals (76%) belonging to 25 unrelated families. In these HD patients, expanded alleles varied from 43 to 73 CAG units and normal alleles varied from 18 to 26 CAGs. A significant negative correlation between age at onset of symptoms and size of the expanded CAG allele was found (r=0.6; p=0.0001); however, the size of the expanded CAG repeat could explain only about 40% of the variability in age at onset (r2=0.4). In addition, we genotyped 25 unrelated control individuals (total of 50 alleles) and found normal CAG repeats varying from 16 to 33 units. The percentage of heterozigocity of the normal allele in the control population was 88%. In conclusion, our results showed that not all patients with the "HD" phenotype carried the expansion at the IT15 gene. Furthermore, molecular diagnosis was possible in all individuals, since no alleles of intermediate size were found. Therefore, molecular confirmation of the clinical diagnosis in HD should be sought in all suspected patients, making it possible for adequate genetic counseling.