Submission Details

The DDHD1 gene belongs to the intracellular phospholipase A1 gene family and is thought to be involved in mitochondrial function. DDHD1 was first reported in relation to autosomal recessive hereditary spastic paraplegia in 2012 (Tesson et al., PMID: 23176821). This slowly progressive disorder is associated with phenotypes of lower limb spasticity and weakness, mild upper limb involvement, gait difficulties, hyperreflexia, pyramidal signs, extensor plantar responses, and distal sensory impairment in lower limbs. Some patients also show phenotypes of axonal neuropathy, saccadic eye pursuit, scoliosis, and pes cavus. Age of onset typically ranges from infancy to childhood or adolescence. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation includes genetic evidence from 4 probands that reached the maximum score of 12 points. Additional evidence is available in the literature; overall, there are at least 11 loss of function variants (e.g. frameshift and nonsense) reported in 14 individuals across 9 families in 8 publications (PMIDs: 15786464, 23176821, 24989667, 27216551, 26944165, 28818478, 29980238, and 27999540). The mechanism of disease is presumed to be loss of function. This gene-disease relationship is also supported by the Ddhd1 knockout mouse model that showed reduced foot-base angle indicative of locomotive abnormality (PMID: 33600578). In summary, there is definitive evidence supporting the relationship between DDHD1 and autosomal recessive hereditary spastic paraplegia. This has been repeatedly demonstrated in research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on December 1, 2022 (SOP Version 9).