Genes to therapy: a comprehensive literature review of whole-exome sequencing in neurology and neurosurgery

Abstract

Whole-exome sequencing (WES), a ground-breaking technology, has emerged as a linchpin in neurology and neurosurgery, offering a comprehensive elucidation of the genetic landscape of various neurological disorders. This transformative methodology concentrates on the exonic portions of DNA, which constitute approximately 1% of the human genome, thus facilitating an expedited and efficient sequencing process. WES has been instrumental in advancing our understanding of neurodegenerative diseases, neuro-oncology, cerebrovascular disorders, and epilepsy by revealing rare variants and novel mutations and providing intricate insights into their genetic complexities. This has been achieved while maintaining a substantial diagnostic yield, thereby offering novel perspectives on the pathophysiology and personalized management of these conditions. The utilization of WES boasts several advantages over alternative genetic sequencing methodologies, including cost-effectiveness, reduced incidental findings, simplified analysis and interpretation process, and reduced computational demands. However, despite its benefits, there are challenges, such as the interpretation of variants of unknown significance, cost considerations, and limited accessibility in resource-constrained settings. Additionally, ethical, legal, and social concerns are raised, particularly in the context of incidental findings and patient consent. As we look to the future, the integration of WES with other omics-based approaches could help revolutionize the field of personalized medicine through its implications in predictive models and the development of targeted therapeutic strategies, marking a significant stride toward more effective and clinically oriented solutions.

Keywords: Clinical genomics; Neurogenetics; Neurological disorders; Neurosurgery; Whole-Exome sequencing.

Fig. 1

Role of whole-exome sequencing in neurodegenerative diseases. AD, Alzheimer’s Disease; ALS2, Alsin Rho Guanine Nucleotide Exchange Factor ALS2; APP, Amyloid Precursor Protein; C9orf72, Chromosome 9 Open Reading Frame 72; CHMP2B, Charged Multivesicular Body Protein 2B; CSMD1, CUB and Sushi Multiple Domains 1; DCTN, Dynactin; NEFH, Neurofilament, Heavy Polypeptide; OPTN, Optineurin; PARK7, Parkinsonism-Associated Deglycase (also known as DJ-1); PD, Parkinson’s Disease; PFN1, Profilin 1; PINK1, PTEN-Induced Putative Kinase 1; PRKN, Parkin RBR E3 Ubiquitin Protein Ligase (also known as PARK2); PRPH, Peripherin; PSEN1, Presenilin 1; PSEN2, Presenilin 2; RAD51B, RAD51 Paralog B; SIGMAR1, Sigma Non-Opioid Intracellular Receptor 1; SOD1, Superoxide Dismutase 1; SPG11, Spastic Paraplegia 11 (autosomal recessive); SQSTM1, Sequestosome 1; TBK1, TANK-Binding Kinase 1; TUBA4A, Tubulin Alpha 4a; UBQLN2, Ubiquilin 2; VAPB, Vesicle-Associated Membrane Protein, Associated Protein B and C; VCP, Valosin-Containing Protein; WES, Whole-Exome Sequencing

Fig. 2

Role of whole-exome sequencing in cerebrovascular diseases. ACOT4, Acyl-CoA Thioesterase 4; CHST14, Carbohydrate Sulfotransferase 14; CVDs, Cardiovascular Diseases; EDIL3, EGF-Like Repeats and Discoidin I-Like Domains 3; LRP2, Low-Density Lipoprotein Receptor-Related Protein 2; MUC5B, Mucin 5B, Oligomeric Mucus/Gel-Forming; NECD, Notch Endocrine Complex Delta (Typically referred to as NOTCH1 or Notch Receptor 1); NFX1, Nuclear Transcription Factor, X-Box Binding 1; NICD, Notch Intracellular Domain (part of the Notch signaling pathway); NNTM, Nicotinamide Nucleotide Transhydrogenase (Typically referred to as NNT); PALD1, Phosphatase Domain Containing, Paladin 1; PDE4DIP, Phosphodiesterase 4D Interacting Protein; PLOD3, Procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase 3; SNPs, Single-Nucleotide Polymorphisms; TMEM132B, Transmembrane Protein 132B; TPO, Thyroid Peroxidase; TRPV3, Transient Receptor Potential Cation Channel Subfamily V Member 3

Fig. 3

Role of whole-exome sequencing in neuro-oncological conditions. AHNAK2, AHNAK Nucleoprotein 2; ATRX, Alpha Thalassemia/Mental Retardation Syndrome X-Linked; BBB, Blood–Brain Barrier; BRAF, B-Raf Proto-Oncogene, Serine/Threonine Kinase; C19MC, Chromosome 19 MicroRNA Cluster; CNS, Central Nervous System; EGFR, Epidermal Growth Factor Receptor; gcGBM, Giant Cell Glioblastoma; GKRS, Gamma Knife Radiosurgery; IDH1, Isocitrate Dehydrogenase 1; KMT2C, Lysine Methyltransferase 2C; NTRK, Neurotrophic Receptor Tyrosine Kinase; PDX, Patient-Derived Xenograft; PIK3R1, Phosphoinositide-3-Kinase Regulatory Subunit 1; PTEN, Phosphatase and Tensin Homolog; RB1, Retinoblastoma 1; SCN2A, Sodium Voltage-Gated Channel Alpha Subunit 2; SCN5A, Sodium Voltage-Gated Channel Alpha Subunit 5; SCN7A, Sodium Voltage-Gated Channel Alpha Subunit 7; SETD2, SET Domain Containing 2; TERT, Telomerase Reverse Transcriptase; TP53, Tumor Protein p53; V600E, Valine replaced by Glutamic acid at position 600; WES, Whole-Exome Sequencing

Fig. 4

Role of whole-exome sequencing in spine diseases. ACTR8, ARP8 Actin-Related Protein 8 Homolog; AGBL5, ATP/GTP-Binding Protein Like 5; AOAH, Acyloxyacyl Hydrolase; ATG2B, Autophagy-Related 2B; BAZ1B, Bromodomain Adjacent To Zinc Finger Domain 1B; BCORL1, BCL6 Corepressor-Like 1; CTNNA3, Catenin Alpha 3; EWSR1, EWS RNA-Binding Protein 1; FREM2, FRAS1-Related Extracellular Matrix Protein 2; GPR83, G Protein-Coupled Receptor 83; HDAC4, Histone Deacetylase 4; HLA-DRB1, Human Leukocyte Antigen DR Beta 1; IGBP1, Immunoglobulin Binding Protein 1; KMT2D, Lysine Methyltransferase 2D (also known as MLL4); MAG13, Myelin-Associated Glycoprotein 13; MAML1, Mastermind-Like Transcriptional Coactivator 1; MKRN2, Makorin Ring Finger Protein 2; MOCOS, Molybdenum Cofactor Sulfurase; MTMR8, Myotubularin-Related Protein 8; NRG4, Neuregulin 4; NTRK1, Neurotrophic Receptor Tyrosine Kinase 1; NUP205, Nucleoporin 205; PARK2, Parkin RBR E3 Ubiquitin Protein Ligase; PDE2A, Phosphodiesterase 2A; PDE4DIP, Phosphodiesterase 4D Interacting Protein; PIK3R4, Phosphoinositide-3-Kinase Regulatory Subunit 4; PTCH1, Protein Patched Homolog 1; SHISA3, Shisa Family Member 3; SMO, Smoothened, Frizzled Class Receptor; SUFU, SUFU Negative Regulator of Hedgehog Signaling; TF, Transferrin; TNXB, Tenascin XB; TSPEAR, Thrombospondin-Type Laminin G Domain and EAR Repeats; TTC21A, Tetratricopeptide Repeat Domain 21A; VANGL1, VANGL Planar Cell Polarity Protein 1; ZNF790, Zinc Finger Protein 790

Fig. 5

Role of Whole-Exome Sequencing in Epilepsy and Seizure Disorders. ADNP, Activity-Dependent Neuroprotector Homeobox; ARX, Aristaless-Related Homeobox; COL3A1, Collagen Type III Alpha 1 Chain; DGUOK, Deoxyguanosine Kinase; FCGR3B, Fc Fragment of IgG Receptor IIIb; FGF12, Fibroblast Growth Factor 12; GABBR1, Gamma-Aminobutyric Acid Type B Receptor Subunit 1; GABBR2, Gamma-Aminobutyric Acid Type B Receptor Subunit 2; GALC, Galactosylceramidase; HIVEP2, Human Immunodeficiency Virus Type I Enhancer-Binding Protein 2; HLA-DQA2, Human Leukocyte Antigen DQ Alpha 2; HLA-DRB1, Human Leukocyte Antigen DR Beta 1; KAT6A, Lysine Acetyltransferase 6A; KCNQ2, Potassium Voltage-Gated Channel Subfamily Q Member 2; KMT2A, Lysine Methyltransferase 2A; MECP2, Methyl CpG-Binding Protein 2; MMUT, Methylmalonyl-CoA Mutase; MTOR, Mechanistic Target of Rapamycin Kinase; POLG2, Polymerase (DNA) Gamma 2, Accessory Subunit; PTPN23, Protein Tyrosine Phosphatase, Non-Receptor Type 23; RHOBTB2, Rho-Related BTB Domain Containing 2; SATB2, SATB Homeobox 2; SCN1A, Sodium Voltage-Gated Channel Alpha Subunit 1; SCN2A, Sodium Voltage-Gated Channel Alpha Subunit 2; SV2A, Synaptic Vesicle Glycoprotein 2A; SYNGAP1, Synaptic Ras GTPase Activating Protein 1