In the line-up: deleted genes associated with DiGeorge/22q11.2 deletion syndrome: are they all suspects?

Abstract

Background 22q11.2 deletion syndrome (22q11DS), a copy number variation (CNV) disorder, occurs in approximately 1:4000 live births due to a heterozygous microdeletion at position 11.2 (proximal) on the q arm of human chromosome 22 (hChr22) (McDonald-McGinn and Sullivan, Medicine 90:1-18, 2011). This disorder was known as DiGeorge syndrome, Velo-cardio-facial syndrome (VCFS) or conotruncal anomaly face syndrome (CTAF) based upon diagnostic cardiovascular, pharyngeal, and craniofacial anomalies (McDonald-McGinn and Sullivan, Medicine 90:1-18, 2011; Burn et al., J Med Genet 30:822-4, 1993) before this phenotypic spectrum was associated with 22q11.2 CNVs. Subsequently, 22q11.2 deletion emerged as a major genomic lesion associated with vulnerability for several clinically defined behavioral deficits common to a number of neurodevelopmental disorders (Fernandez et al., Principles of Developmental Genetics, 2015; Robin and Shprintzen, J Pediatr 147:90-6, 2005; Schneider et al., Am J Psychiatry 171:627-39, 2014). Results The mechanistic relationships between heterozygously deleted 22q11.2 genes and 22q11DS phenotypes are still unknown. We assembled a comprehensive “line-up” of the 36 protein coding loci in the 1.5 Mb minimal critical deleted region on hChr22q11.2, plus 20 protein coding loci in the distal 1.5 Mb that defines the 3 Mb typical 22q11DS deletion. We categorized candidates based upon apparent primary cell biological functions. We analyzed 41 of these genes that encode known proteins to determine whether haploinsufficiency of any single 22q11.2 gene—a one gene to one phenotype correspondence due to heterozygous deletion restricted to that locus—versus complex multigenic interactions can account for single or multiple 22q11DS phenotypes. Conclusions Our 22q11.2 functional genomic assessment does not support current theories of single gene haploinsufficiency for one or all 22q11DS phenotypes. Shared molecular functions, convergence on fundamental cell biological processes, and related consequences of individual 22q11.2 genes point to a matrix of multigenic interactions due to diminished 22q11.2 gene dosage. These interactions target fundamental cellular mechanisms essential for development, maturation, or homeostasis at subsets of 22q11DS phenotypic sites. Electronic supplementary material The online version of this article (10.1186/s11689-019-9267-z) contains supplementary material, which is available to authorized users.

Aberrant early growth of individual trigeminal sensory and motor axons in a series of mouse genetic models of 22q11.2 deletion syndrome

“…These phenotypes, like several others associated with heterozygous deletion of 22q11.2 genes (reviewed by 1 , 54 ), are subtle and variable. This partial penetrance may reflect stochastic variation in gene expression associated with aneuploidy ( 55 , 56 ), including in the LgDel +/− CNgV ( 7 ).…”

The Inflamed Brain in Schizophrenia: The Convergence of Genetic and Environmental Risk Factors That Lead to Uncontrolled Neuroinflammation

“…Claudin-5, expressed in brain endothelial cells, forms a major component of the BBB barrier-forming tight junctions ( Morita et al, 1999 ; Greene et al, 2019 ). Claudin-5 maps to a region on chromosome 22 where small deletions cause the 22q11 deletion syndrome, which is found in 30% of SCZ cases ( Murphy, 2002 ; Motahari et al, 2019 ). People with this syndrome are haploinsufficient for claudin-5 and have increased odds of developing SCZ ( Fiksinski et al, 2018 ; Greene et al, 2018 ).…”

Association Between Parental Anxiety and Depression Level and Psychopathological Symptoms in Offspring With 22q11.2 Deletion Syndrome

“…To date, the reasons for this clinical heterogeneity remain unclear and could encompass a complex combination of both gene x gene (GxG) and gene x environment (GxE) interactions. Some studies have recently shown evidence that GxG interactions modulate risk for schizophrenia in 22q11DS (6)(7)(8). In particular, Cleynen et al (6) observed that the presence of common genetic variants outside of the 22q11.2 locus and known to be associated with risk for schizophrenia-also known as the polygenic risk score for schizophrenia-is more frequent in individuals with 22q11DS diagnosed with a psychotic disorder compared to those without psychosis.…”

“…To date, the reasons for this clinical heterogeneity remain unclear and could encompass a complex combination of both gene x gene (GxG) and gene x environment (GxE) interactions. Some studies have recently shown evidence that GxG interactions modulate risk for schizophrenia in 22q11DS ( 6 – 8 ). In particular, Cleynen et al.…”