Objective: To reveal a genetic cause for a syndrome of combined cerebellar ataxia, neuropathy and vestibular areflexia (CANVAS).

Background: CANVAS is a clinically defined neurological syndrome characterized by the combination of cerebellar ataxia, neuropathy and vestibular areflexia. Underlying causes of CANVAS have not yet been delineated although a strong genetic background has been suspected. Several pedigrees with more than one affected relative have been reported showing either an autosomal dominant or recessive mode of inheritance.

Methods: Exome sequencing was performed in two families with two clinically affected siblings each including a monozygotic twin pair. To evaluate the significance of the identified candidate gene ADCY6, we Sanger sequenced all 21 coding exons of ADCY6 in another 10 sporadic patients with incomplete or definite CANVAS.

Results: Exome sequencing identified a heterozygous missense variant in ADCY6 (c.1904G>A, p.R635H) in both siblings of the first family, aged 75 and 84 years. Initial symptoms (gait unsteadiness) occurred in their mid-sixties. After a disease duration of 11 years, the brother is ambulatory whereas the older sister with a disease duration of >15 years is wheelchair-bound. Further family members were not affected; however the father died in his thirties and may have been too young to develop symptoms. In the second family, both 62-year-old monozygotic twins with CANVAS harbored a frameshift variant in ADCY6 (c.771delG, p.Met257fs). They initially manifested with bilateral vestibulopathy and developed an archicerebellar syndrome in their late fifties including downbeat nystagmus. Parents were not available for testing and were reported unaffected until an age of >60 years. Both variants were rare in public databases (minor allele frequency <0.001) and in-silico predicted to be damaging (CADD score of 35 and 34). No rare, protein-changing variant was found in the sporadic patients.

Conclusions: Heterozygous variants in ADCY6 may be a monogenic cause for familial CANVAS. The lack of mutations in the sporadic patients suggests genetic heterogeneity in this clinically distinct and probably underdiagnosed disorder.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/rare-adcy6-variants-in-two-families-with-cerebellar-ataxia-neuropathy-and-vestibular-areflexia-syndrome-canvas/