Homozygous Splice Mutation in CWF19L1 in Two Brothers with Autosomal Recessive Cerebellar Ataxia

Background: Primary ataxias with onset in childhood can have variable associated findings and are usually due to autosomal recessive mutations in one of ~20 genes known to date. Since 2014, four children with pathogenic variants in a novel gene (CWF19L1) have been published. We report on two brothers with a novel homozygous splice mutation in the CWF19L1 gene.

Methods: Two brothers (8 and 3.5 years), third and fourth offsprings of Swiss parents from a small valley without reported consanguinity, presented with late walking at 18 and 16 months, respectively, and moderate speech delay. During childhood, both showed mild cognitive impairment, broad-based gait, truncal ataxia, mild dysmetria, and dysarthria. Head circumference was P10–25 and P25–50, respectively. The older brother had mild progression of truncal ataxia but improvement of active speech and speech flow until the age of 8 years.

Results: Cranial MRI of the elder brother at 4 years showed isolated cerebellar atrophy with progression and volume reduction of the brain stem and cervical myelon at 7.5 years. MRI in the younger brother is pending. Metabolic testing and microarray analysis were normal. Whole-exome sequencing revealed a homozygous splice mutation in the CWF19L1 gene.

Conclusion: This report on siblings with a novel splice mutation confirms the CWF19L1 gene as a new locus of autosomal recessive ataxia. All six patients known to date have mild cognitive impairment and some have progression of ataxia over time. Genetic testing is recommended in primary ataxia with symptom onset in childhood to enable genetic counseling and prenatal testing.

No conflict of interest has been declared by the author(s).