Background on whole exome technology. To explain the various ways of obtaining genetic information, I often refer to an encyclopedia set as a representation of our genome. All of the information which makes us who we are is written in a 4 letter code (A, T, G, C) in our genome or ‘encyclopedia set’ and is contained within our chromosomes or ‘volumes’. We have two sets of each volume, one from mom and one from dad. Targeted panels read a select number of genes or ‘chapters’ regarding only those which are known to be associated with white matter changes. Whole exome sequencing (WES) reads all of the coding sections, approximately 20,000 genes in total, but none of the extra information. This noncoding information would represent the appendices, figure legends, and foot notes. Whole genome sequencing (WGS) reads everything cover to cover.Benign and pathogenic variants. As one could anticipate, clinicians can have difficulty fully interpreting the extensive information gathered and are limited by existing clinical registries and scientific knowledge. WES and WGS ultimately result in many variants of unknown significance (VUS), which may or may not cause disease. To better interpret the overwhelming amount of information, it is ideal to obtain WES in the context of a trio: the proband (affected patient) along with both genetic parents. This helps to distinguish a benign genetic variant from a pathogenic variant. Please refer to: NIH’s Genetics Home Reference and for a nice explanation of variants of unknown significance for more information.
The development of whole exome sequencing (WES) has resulted an exponential increase in diagnostic information available. Whole exome sequencing and its more comprehensive analog, whole genome sequencing (WGS), are both forms of massively parallel sequencing technology, also referred to as next-generation sequencing (Lapin et al. Hum Genet. 2016).
Whole exome technology in the diagnosis of white matter diseases. A recent paper described the use of whole exome sequencing in a group of 71 patients (Vanderver et al. Ann Neurol. 2016). The patients included in this study had persistently unresolved white matter abnormalities with a suspected diagnosis of leukodystrophy or genetic leukoencephalopathy. Collectively, they ranged in age from 3-26 years at the time of sequencing, with symptom onset ranging from birth to 19 years old. In this cohort, they identified a genetic cause in an additional 25 cases. In 9 patients, established leukodystrophy gene mutations were identified in TUBB4A, DARS, POLR3B, EIF2B5, POLR1C, and EIF2B2. Of interest, there were several patients found to have mutations genes more commonly associated with other non-leukodystrophy diseases, including GRIN1, KCNT1, and TERT. Overall in this study, WES technology identified a genetic cause for an additional 20% of families with persistently unresolved white matter abnormalities. As such the addition of WES to the diagnostic odyssey increased the overall rate of diagnosis to almost 75%.
Conclusions on WES and white matter. A diagnosis rate of 75% is remarkable for any neurogenetic condition, far exceeding the diagnostic rate for other conditions such as epilepsy, intellectual disability, or autism. This paper also broads our understanding of the clinical spectrum attributable to individual genes and suggests that if a ‘classic’ MRI and history are not found, much could be added by less targeted testing.
Vanderver A, Simons C, Helman G, Crawford J, Wolf NI, Bernard G, Pizzino A, Schmidt JL, Takanohashi A, Miller D, Khouzam A, Rajan V, Ramos E, Chowdhury S, Hambuch T, Ru K, Baillie GJ, Grimmond SM, Caldovic L, Devaney J, Bloom M, Evans SH, Murphy JL, McNeill N, Fogel BL; Leukodystrophy Study Group, Schiffmann R, van der Knaap MS, Taft RJ. Whole exome sequencing in patients with white matter abnormalities. Ann Neurol. 2016 Jun;79(6):1031-7. doi: 10.1002/ana.24650. Epub 2016 May 9.
Lapin V, Mighion LC, da Silva CP, Cuperus Y, Bean LJ, Hegde MR. Regulating whole exome sequencing as a diagnostic test. Hum Genet. 2016 Jun;135(6):655-73.