The missing heritability of SPG7: a part of the answer in the detection of copy number variant

Background: Spastic paraplegia 7 (SPG7) represents the most frequent autosomal recessive spastic paraplegia. The phenotype picture is either pure or complex encompassing ataxia, optic atrophy, and parkinsonian features.1 Dominant inheritance has been reported in the literature, associated with specific variants, but it remains a subject of debate.1
Materials and methods: We analysed genomic data from 74 patients from SPATAX/BIOMOV cohorts at the Paris Brain Institute (ICM) with a monoallelic variants in SPG7 and a phenotype compatible with SPG7. Copy number variant (CNV) analyses were performed on exome data using the Illumina Dragen software CNV pipeline.
Results: We identified seven patients (9.4%) carrying a deletion and the Ala510Val variant. A recessive transmission was described for two cases, the other five were sporadic. The age at onset was 43 ± 6.3 years, with unsteadiness and/or stiffness as the first signs. The pure form of SPG7 accounted for 30% and complex form for 70% associating with neuropathy, cerebellar ataxia, and oculomotor signs. No patients exhibited cognitive impairment or parkinsonism. MRI revealed cerebellar atrophy in four patients.
Conclusion: The detection of a CNV enabled the diagnosis of SPG7 in 9.4% of our cohort of heterozygous SPG7 carriers. The apparent heterozygous state of affected patients could be due to an insufficient variant coverage in SPG7 with previous techniques (e.g., NGS panel or WES), which hides a second pathogenic variant such as a CNV, an intronic variant, etc. Additionally, another explanation could be the presence of a second causative gene, specifically impacting the mitochondrial respiratory complex.