Objective: To enrich the limited clinical and genetic data of an extremely rare recessive ataxia subtype.

Background: Advances in NGS techniques led to an increase in the number of genes linked to recessive forms of movement disorders and revealed that numerous genes induce a variable combination of movement disorders. However, due to the extreme rarity of most genetic subtypes, information about the phenotypic spectrum of respective genes is scarce.

Method: Whole exome sequencing of the index patient and consecutive phase verification of the compound-heterozygous variants through Sanger sequencing of identified variants in the parents.

Results: We report a patient from a non-consanguineous family without any family history of neurologic disorders. During infancy, he presented with ataxia combined with dystonic movements. Additional findings included dysarthria, nystagmus, hypotonia, and mild intellectual disability. Imaging studies demonstrated cerebellar atrophy: Research-based exome sequencing identified two undescribed compound-heterozygous variants p.Arg222Gln and p.Gln327* in CWF19L1.

Conclusion: CWF19L1-associated disorders are ultra-rare, with only three families being reported so far and our case being only the second from a non-consanguineous pedigree. Whereas homozygous truncating variants appear to result in severe congenital ataxia and developmental delay, the combination of a missense and a nonsense variant causes an overall milder phenotype. Furthermore, dystonia seems to be a recurrent feature related to compound-heterozygous variants in CWF19L1. We confirm that recessive CWF19L1 variants cause dystonia-ataxia phenotypes.
This abstract has also been presented by one of the authors at the 2020 European Human Genetics Conference in Berlin, Germany, June 6–9, 2020.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/recessive-cwf19l1-mutations-in-a-family-with-dystonia-ataxia-syndrome/