Genomic medicine and neurological disease

Abstract

"Genomic medicine" refers to the diagnosis, optimized management, and treatment of disease--as well as screening, counseling, and disease gene identification--in the context of information provided by an individual patient's personal genome. Genomic medicine, to some extent synonymous with "personalized medicine," has been made possible by recent advances in genome technologies. Genomic medicine represents a new approach to health care and disease management that attempts to optimize the care of a patient based upon information gleaned from his or her personal genome sequence. In this review, we describe recent progress in genomic medicine as it relates to neurological disease. Many neurological disorders either segregate as Mendelian phenotypes or occur sporadically in association with a new mutation in a single gene. Heritability also contributes to other neurological conditions that appear to exhibit more complex genetics. In addition to discussing current knowledge in this field, we offer suggestions for maximizing the utility of genomic information in clinical practice as the field of genomic medicine unfolds.

Fig. 1

Multiple mutation types can lead to the same phenotype. Two examples are shown in which multiple mutation types can increase gene dosage, leading to a neurological phenotype. a Increased expression of APP, owing to (i) trisomy 21, (ii) duplication of APP, or (iii) mutations in regulatory or coding regions of the gene can result in Alzheimer disease. b Increased expression of SNCA, owing to (i) duplication or triplication of SNCA or (ii) mutations in regulatory or coding regions of the gene can result in Parkinson disease. SNV simple nucleotide variation [reproduced, with permission, from Shiga et al. (2008)]

Fig. 2

The timing of de novo mutagenesis. a New mutations may occur at any time during development. The effect on the individual and his or her offspring is dependent upon mutation timing and the cell type in which the mutation occurs [adapted from (Lupski 2010)]. b Mutations occurring during very early embryogenesis may result in discordant monozygotic twins [see also (Vadlamudi et al. 2010)]. c–g A complex intragenic deletion in PMP22 illustrates that mitotic mutational processes are a mechanism of de novo mutagenesis and mosaicism [adapted from (Zhang et al. 2009)]. c Array CGH detects a deletion of exon 4 of PMP22. d, e Deletion breakpoint sequencing identifies complexity and microhomology, hallmarks of DNA replication-based (i.e. mitotic) CNV-generating mechanisms [e.g. fork stalling and template switching (FoSTeS) and microhomology-mediated break-induced replication (MMBIR)]. f, g Two siblings with the PMP22 exon 4 deletion show diminished nerve conduction velocity (NCV; meters/second (m/s)), consistent with Charcot–Marie–Tooth disease, type 1 (CMT1). Their mother is mosaic (in blood) for the deletion as detected by breakpoint PCR, but does not have symptoms of CMT1