Pseudodominance in RFC1-Spectrum Disorder

Area of Science:

• Genetics
• Neurology
• Rare Diseases

Background:

• Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and its spectrum are autosomal recessive disorders.
• These conditions are caused by biallelic repeat expansion (RE) in the RFC1 gene.
• A high carrier frequency in the general population can lead to affected individuals across generations.

Purpose of the Study:

• To describe pseudodominance in two families with RFC1-spectrum disorders.
• To illustrate the diagnostic and genetic counseling implications of this inheritance pattern.

Main Methods:

• Case study of two families (Family A and Family B) with RFC1-spectrum disorders.
• Genetic testing for biallelic AAGGG repeat expansion (RE) in the RFC1 gene.
• Carrier screening and analysis of family history.

Main Results:

• Pseudodominance was observed in both families, involving 10 affected and 5 oligo/asymptomatic individuals.
• In Family A, carrier testing of an asymptomatic wife revealed RFC1 RE, leading to diagnoses in offspring.
• In Family B, post-mortem testing confirmed RFC1 RE in a deceased mother, resolving a diagnostic mystery.

Conclusions:

• Pseudodominance is a significant consideration in RFC1-spectrum disorders.
• Genetic counseling is crucial for families affected by RFC1-related conditions.
• Understanding pseudodominance aids in diagnosing and managing these rare genetic disorders.