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Clin Genet. 2018 Mar;93(3):439-449. doi: 10.1111/cge.13146. Epub 2017 Dec 1.

Genomic disorders 20 years on-mechanisms for clinical manifestations.

Harel T1, Lupski JR2,3,4,5.

Author information

1
Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
3
Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
4
Texas Children's Hospital, Houston, Texas.
5
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.

Abstract

Genomic disorders result from copy-number variants (CNVs) or submicroscopic rearrangements of the genome rather than from single nucleotide variants (SNVs). Diverse technologies, including array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) microarrays, and more recently, whole genome sequencing and whole-exome sequencing, have enabled robust genome-wide unbiased detection of CNVs in affected individuals and in reportedly healthy controls. Sequencing of breakpoint junctions has allowed for elucidation of upstream mechanisms leading to genomic instability and resultant structural variation, whereas studies of the association between CNVs and specific diseases or susceptibility to morbid traits have enhanced our understanding of the downstream effects. In this review, we discuss the hallmarks of genomic disorders as they were defined during the first decade of the field, including genomic instability and the mechanism for rearrangement defined as nonallelic homologous recombination (NAHR); recurrent vs nonrecurrent rearrangements; and gene dosage sensitivity. Moreover, we highlight the exciting advances of the second decade of this field, including a deeper understanding of genomic instability and the mechanisms underlying complex rearrangements, mechanisms for constitutional and somatic chromosomal rearrangements, structural intra-species polymorphisms and susceptibility to NAHR, the role of CNVs in the context of genome-wide copy number and single nucleotide variation, and the contribution of noncoding CNVs to human disease.

KEYWORDS:

chromosomal microarray; copy-number variant; genomic disorders; nonallelic homologous recombination

PMID:
28950406
DOI:
10.1111/cge.13146

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