Application of whole exome sequencing (WES) in clinical diagnosis; An example

Introduction & Objective: Clinical heterogeneity in some neurological diseases makes a significant challenge in the correct diagnosis. The definite diagnosis of these heterogeneous diseases sometimes depends on identification of the causing-genes. On the other hand, genetic heterogeneity may also be observed in this group of diseases. Thus, identification of causative gene by direct sequencing is time consuming and expensive, and needs to a high-throughput method. Whole-exome sequencing(WES) is a powerful diagnostic tool for these cases. Considering the importance of early diagnosis and medications in treatable diseases, selection of a diagnostic test is very important. Herein, we emphasized the potentials of WES in diagnosis in a consanguineous family with Primary COQ10-deficiency.Materials & Methods: An affected individual was referred to us as a suspected-hereditary spastic paraplegia (HSP) case. DNA was extracted and sequenced on the Illumina HiSeq4000 platform. Sequences were analyzed. Non-synonymous exonic, exon-splicing and splicing variants with minor-allele-frequency (MAF)<0.01 were selected. Only homozygous variants that segregated with disease status, further considered as causes of disease.Results: Among the candidate variants observed was c.332T>C:p.(Leu111Pro) in the COQ7 gene that co-segregated with disease status. This gene is known to be causative of the very rare disorder COQ7-associated-COQ10-deficiency, while the proband was referred as a HSP case. She only presented muscle weakness and spasticity in her lower-limbs and a mild hearing impairment at the ages of 3 and 8 years, respectively. There is no metabolic/multisystem involvement that typically observed in Primary COQ10-deficiency.Conclusion: Due to the presence of some overlaps between neurological diseases, clinically mis-diagnosis can occur. Our case initially was diagnosed as HSP but, genetically confirmed as a primary COQ10-deficiency case. Thus, genetic approach may be helpful to distinguish this disease from other similar conditions at earlier ages. Particularly, given that some features of primary COQ10-deficiency may be ameliorated by exogenous COQ10.

کلیدواژه ها:

Primary COQ10-deficiency ، Hereditary spastic paraplegia (HSP) ، Whole-exome sequencing (WES) ، COQ7