Genetic architecture of reciprocal CNVs

Abstract

Copy number variants (CNVs) represent a frequent type of lesion in human genetic disorders that typically affects numerous genes simultaneously. This has raised the challenge of understanding which genes within a CNV drive clinical phenotypes. Although CNVs can arise by multiple mechanisms, a subset is driven by local genomic architecture permissive to recombination events that can lead to both deletions and duplications. Phenotypic analyses of patients with such reciprocal CNVs have revealed instances in which the phenotype is either identical or mirrored; strikingly, molecular studies have revealed that such phenotypes are often driven by reciprocal dosage defects of the same transcript. Here we explore how these observations can help the dissection of CNVs and inform the genetic architecture of CNV-induced disorders.

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

“…However, as shown for other CNVs, it is unlikely that a single transcript is sufficient to drive the CNV-driven pathology. 18,24,37 Therefore, we asked whether other genes within the CNV might contribute through additive or multiplicative interactions with LAT. We thus re-injected LAT with each of the other eight transcripts and we determined the number of proliferating cells in the brain at 2 dpf.…”

“…18 The zebrafish embryo has emerged as a powerful in vivo model to test dosage sensitivity in neurodevelopmental traits, likely due to the high evolutionary conservation of key genes and pathways between humans and this organism. 19 Macrocephaly during infancy is a recurrent observation in ASD, while HC defects in general are common features of neurodevelopmental disorders.…”

“…20,21 For these phenotypes, the measurement of the head size of zebrafish embryos has served as a relevant and useful proxy to identify genes whose dosage imbalance contributes to the neuropathology. We used this approach to demonstrate that the major driver of the 16p11.2 600 kb BP4-BP5 CNV head phenotype was KCTD13 (MIM: 608947), in epistasis with MVP (MIM: 605088) and MAPK3 (MIM: 601795), 18,22 while similar studies helped understand the genetic architecture of other CNVs. 23,24 Here, we have applied in vivo modeling tools to dissect genes that drive neuroanatomical defects associated with the 16p11.2 220 kb BP2-BP3 CNV.…”

Clinical and Molecular Characterization of Two Patients with CNTN6 Copy Number Variations

“…Reciprocal microdeletions and microduplications of CNTN6 are characterized by very similar phenotypes. Even if our patients seem to fall into the so-called 'single-gene CNV model', in which the phenotypes of patients with microdeletions or microduplications are the product of dosage imbalance of a single gene, as suggested by Golzio and Katsanis [2013], probably in our cases the duplication/deletion of CNTN6 represented simply a risk factor for a variety of neurodevelopmental disorders.…”

Investigação da variação no número de cópias gênicas em crianças com defeito cardíaco conotruncal

“…Introdução Embora alguns CNVs são descobertos em alta frequência na população humana e são portanto uma fonte potencial de diversidade genética, grandes CNVs, especialmente de novo, são associadas a várias doenças humanas complexas, em adição ao documentado envolvimento de CNVs em defeitos congênitos (ex. craniofacial, cardíaco, respiratório, renal), CNVs são também conhecidas por estarem envolvidas na gênese de patologias do neurodesenvolvimento e neurocognitivo, como deficiência intelectual, esquizofrenia e espectro autístico 32,33 .…”