ARL6IP1 was first reported in relation to autosomal recessive hereditary spastic paraplegia (HSP) in 2014 (Novarino G et al., PMID: 24482476). This disease is caused by biallelic variation in the ARL6IP1 gene. Phenotypes involve the nervous system and the skeletal system including spasticity, scissors gait, spasticity, and polyneuropathy. More variable features may include acropathy, absent achilles tendon reflex and increased patellar reflex. Around 2 unique frameshift variants have been reported in at least 4 probands in various publications (PMID: 24482476, 2847135, 30237576, 31272422). A loss-of-function frameshift variant was also found to segregate with the disorder in additional family members with a LOD score of 3.5 (PMID: 24482476). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is also supported by showing that a knockdown of the zebrafish ARL6IP1 ortholog causes defects in the body axis, motor neuron morphology, and spontaneous swimming behavior (PMID: 24482476).
In summary, there is definitive evidence to support the relationship of the ARL6IP1 gene with hereditary spastic paraplegia (HSP). This has been repeatedly demonstrated in research and clinical diagnostic settings and upheld over time. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on 10/17/2022 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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