Heterozygous deletion of KLHL1/ATXN8OS at the SCA8 locus are likely not associated with cerebellar impairment in humans

Spinocerebellar ataxia type 8 is a dominantly inherited ataxia, mainly occurring in adulthood, caused by a CTG.CAG tract expansion in the ATXN8OS gene, an untranslated antisense RNA partially overlapping the KLHL1 gene, and the complementary CAG repeat in the ATXN8 gene. We report a father (59 years) and his daughter (10 years) carrying a genomic deletion (800 kb) completely overlapping ATXN8OS gene and part of KLHL1 (from 70,345,271 to 71,196,665 - NCBI Build 37/hg19 - Array-CGH 60K) and a 4 Mb duplication in 8q13.33q21.11 (72,268,801-76,311,849) segregating in an unaffected brother. The girl was evaluated for dysarthria, difficulties in sentence structuring, short attention span and mild intellectual deficit. No other neurological signs were reported. Brain MRI was normal. Neurological examination of the father revealed short attention span; coordination, sensitivity, reflexes and cranial nerves were normal; no abnormal gait or dysarthria. Brain MRI revealed several areas of gliosis in the frontal white matter. Databases mining showed a partially overlapping 357 kb deletion involving only KLHL1 and ATXN8OS (chr 13:70,486,026-70,843,210) in a patient with mild speech delay (Decipher 278559), inherited from a healthy mother. In contrast with the KLHL1/ATX8OS knockout mouse model, our data suggest that heterozygous deletion of KLHL1/ATX8OS is not associated with ataxia/cerebellar involvement in humans.