Copy Number Variations in Hereditary Spastic Paraplegia-Related Genes: Evaluation of an Iranian Hereditary Spastic Paraplegia Cohort and Literature Review.

INTRODUCTION: In human genetic disorders, copy number variations (CNVs) are considered a considerable underlying cause. CNVs are generally detected by array-based methods but can also be discovered by read-depth analysis of whole-exome sequencing (WES) data. We performed WES-based CNV identification in a cohort of 35 Iranian families with hereditary spastic paraplegia (HSP) patients.

METHODS: Thirty-five patients whose routine single-nucleotide variants (SNVs) and insertion/deletion analyses from exome data were unrevealing underwent a pipeline of CNV analysis using the read-depth detection method. Subsequently, a comprehensive search about the existence of CNVs in all 84 known HSP-causing genes was carried out in all reported HSP cases, so far.

RESULTS AND DISCUSSION: CNV analysis of exome data indicated that 1 patient harbored a heterozygous deletion in exon 17 of the SPAST gene. Multiplex ligation-dependent probe amplification analysis confirmed this deletion in the proband and his affected father. Literature review demonstrated that, to date, pathogenic CNVs have been identified in 30 out of 84 HSP-causing genes (∼36%). However, CNVs in only 17 of these genes were specifically associated with the HSP phenotype. Among them, CNVs were more common in L1CAM , PLP1 , SPAST , SPG7 , SPG11 , and REEP1 genes. The identification of the CNV in 1 of our patients suggests that WES allows the detection of both SNVs and CNVs from a single method without additional costs and execution time. However, because of intrinsic issues of WES in the detection of large rearrangements, it may not yet be exploited to replace the CNV detection methods in standard clinical practice.