Missing the pathological expansion in Huntington disease: de novo c.51C>G variant on the expanded allele causing...

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Huntington disease (HD) is an autosomal dominant neurodegenerative disorder.
• It is characterized by motor, cognitive, and behavioral symptoms.
• Pathological expansion of CAG/CAA repeats in the HTT gene causes HD.

Purpose of the Study:

• To describe the phenotype of a patient with symptoms compatible with HD.
• To investigate the genetic basis of HD in a patient with an atypical genetic test result.
• To identify genetic variants that may interfere with standard HD genetic testing.

Main Methods:

• Clinical phenotyping and family history assessment.
• Standard HD genetic testing for CAG/CAA repeat length in the HTT gene.
• Direct sequencing of the HTT gene to identify variants.
• Polymerase chain reaction (PCR) analysis with alternative primers.

Main Results:

• The proband presented with an HD phenotype but showed homozygosity for a normal HTT CAG/CAA allele (14 repeats).
• HT T gene sequencing revealed heterozygosity for the c.51C>G variant, located before the CAG repeat tract.
• This variant caused primer misannealing and dropout of the expanded allele in standard PCR testing.
• Alternative PCR methods confirmed the presence of a 41 CAG/CAA allele, indicating HD.
• The c.51C>G variant appeared to be a de novo occurrence in the proband.

Conclusions:

• Genetic variants near or within the CAG repeat region of the HTT gene can hinder accurate diagnosis.
• Patients with an HD phenotype and seemingly normal HTT CAG/CAA allele results require further genetic investigation.
• The c.51C>G variant highlights the importance of considering complex genetic scenarios in HD diagnosis.