CWF19L1 – Autosomal Recessive Spinocerebellar Ataxia 17

Autosomal recessive spinocerebellar ataxia 17 is characterized by early-onset, progressive cerebellar ataxia and intellectual disability in affected individuals. Biallelic variants in CWF19L1 underlie this phenotype, with onset ranging from infancy to adulthood and consistent cerebellar atrophy on imaging.

Multiple unrelated families (Chinese, Arab, Turkish, Dutch) comprising six affected individuals across four pedigrees have been reported, each with biallelic CWF19L1 variants ([PMID:36357319], [PMID:33012273], [PMID:25361784], [PMID:26197978]). Segregation analysis confirmed autosomal recessive inheritance with unaffected heterozygous carriers in all kindreds.

The variant spectrum spans missense (c.1070G>T (p.Gly357Val)), nonsense (c.946A>T (p.Lys316Ter)), frameshift (c.1158dup (p.Lys387fs)), and splice-site (c.964+1G>A) alleles, with no recurrent or founder mutations identified to date.

Functional assays demonstrated that the c.964+1G>A splice donor mutation causes exon 9 skipping, reduction of CWF19L1 mRNA, and complete protein loss in patient cell lines. Morpholino-mediated knockdown of cwf19l1 in zebrafish recapitulated cerebellar hypoplasia and motor deficits, mirroring the human phenotype ([PMID:25361784]).

No conflicting reports have been published. Together, robust genetic segregation data and concordant functional studies support a strong gene–disease association for CWF19L1 in autosomal recessive spinocerebellar ataxia 17.

Key Take-home: Biallelic CWF19L1 variants cause autosomal recessive spinocerebellar ataxia 17, informing molecular diagnosis, family counseling, and inclusion in diagnostic panels.

References

• Journal of clinical laboratory analysis • 2022 • Heterozygous pathogenic variants in CWF19L1 in a Chinese family with spinocerebellar ataxia, autosomal recessive 17 PMID:36357319
• Neurological research • 2021 • A Novel Variant in CWF19L1 Gene in a Family with Late-Onset Autosomal Recessive Cerebellar Ataxia 17 PMID:33012273
• Neurology • 2014 • Homozygous splice mutation in CWF19L1 in a Turkish family with recessive ataxia syndrome PMID:25361784
• European journal of human genetics • 2016 • Pathogenic CWF19L1 variants as a novel cause of autosomal recessive cerebellar ataxia and atrophy PMID:26197978

Evidence Based Scoring (AI generated)