DGCR6 at the proximal part of the DiGeorge critical region is involved in conotruncal heart defects

Gao, Wenbin; Hatori, Takashi; Eguchi‐Ishimae, Minenori; Iwabuki, Hidehiko; Wu, Zhanwen; Yamamoto, Eiichi; Takata, Hitoshi; Ohta, Masakatsu; Imoto, Issei; Ishii, Eiichi; Eguchi, Mariko

doi:10.1038/hgv.2015.4

Cited by 22 publications

(16 citation statements)

References 48 publications

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“…Such dramatic expression variations in DGCR6 and DGCR6L are epigenetically determined as there is no evidence of maternal or paternal imprinting (Chakraborty et al, 2012). Noteworthy, either deletions or duplications of DGCR6, in combination with an adjacent gene, PRODH, are linked to CHD (Gao et al, 2015b). These findings suggest that fluctuations in DGCR6 will affect TBX1 levels, and as a consequence, patterning of the pharyngeal region.…”

Section: The Genetic and Epigenetic Regulation Coupled To Tbx1 Functionsmentioning

confidence: 98%

The Genetics and Epigenetics of 22q11.2 Deletion Syndrome

Morena

Oers

2020

Front. Genet.

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Chromosome 22q11.2 deletion syndrome (22q11.2del) is a complex, multi-organ disorder noted for its varying severity and penetrance among those affected. The clinical problems comprise congenital malformations; cardiac problems including outflow tract defects, hypoplasia of the thymus, hypoparathyroidism, and/or dysmorphic facial features. Additional clinical issues that can appear over time are autoimmunity, renal insufficiency, developmental delay, malignancy and neurological manifestations such as schizophrenia. The majority of individuals with 22q11.2del have a 3 Mb deletion of DNA on chromosome 22, leading to a haploinsufficiency of~106 genes, which comprise coding RNAs, noncoding RNAs, and pseudogenes. The consequent haploinsufficiency of many of the coding genes are well described, including the key roles of T-box Transcription Factor 1 (TBX1) and DiGeorge Critical Region 8 (DGCR8) in the clinical phenotypes. However, the haploinsufficiency of these genes alone cannot account for the tremendous variation in the severity and penetrance of the clinical complications among those affected. Recent RNA and DNA sequencing approaches are uncovering novel genetic and epigenetic differences among 22q11.2del patients that can influence disease severity. In this review, the role of coding and noncoding genes, including microRNAs (miRNA) and long noncoding RNAs (lncRNAs), will be discussed in relation to their bearing on 22q11.2del with an emphasis on TBX1.

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Section: The Genetic and Epigenetic Regulation Coupled To Tbx1 Functionsmentioning

confidence: 98%

The Genetics and Epigenetics of 22q11.2 Deletion Syndrome

Morena

Oers

2020

Front. Genet.

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“…In these embryos, attenuation of DGCR6 stimulates TBX1 and UFD1L but decreases heart and pharyngeal arch HIRA expression (all A to B genes), suggesting it is a modifier of critical region phenotypes [384]. DGCR6 also has been implicated in 22q11DS conotruncal heart defects, either directly or through TBX1 activity [386]. Dysregulation of DGCR6 and DGCR6L is suggested to be associated with neuropsychological findings in 22q11DS children [387].…”

Section: Main Textmentioning

confidence: 99%

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

Motahari

Moody

Maynard

et al. 2019

J Neurodevelop Disord

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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.

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“…CNA validation and detailed mapping of altered regions were performed using an Affymetrix CytoScan HD chromosome microarray platform (Affymetrix, Santa Clara, CA), which provides 906 600 polymorphic (SNP) and 946 000 non-polymorphic (CNA) markers, according to the manufacturer’s recommendations. The raw data were processed using Chromosome Analysis Suite software (ChAS, Affymetrix), and the output data were interpreted with the UCSC Genome Browser ( http://genome.ucsc.edu ; GRCh37/hg19 assembly) [ 16 ].…”

Section: Methodsmentioning

confidence: 99%

Simultaneous Detection of Both Single Nucleotide Variations and Copy Number Alterations by Next-Generation Sequencing in Gorlin Syndrome

et al. 2015

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Gorlin syndrome (GS) is an autosomal dominant disorder that predisposes affected individuals to developmental defects and tumorigenesis, and caused mainly by heterozygous germline PTCH1 mutations. Despite exhaustive analysis, PTCH1 mutations are often unidentifiable in some patients; the failure to detect mutations is presumably because of mutations occurred in other causative genes or outside of analyzed regions of PTCH1, or copy number alterations (CNAs). In this study, we subjected a cohort of GS-affected individuals from six unrelated families to next-generation sequencing (NGS) analysis for the combined screening of causative alterations in Hedgehog signaling pathway-related genes. Specific single nucleotide variations (SNVs) of PTCH1 causing inferred amino acid changes were identified in four families (seven affected individuals), whereas CNAs within or around PTCH1 were found in two families in whom possible causative SNVs were not detected. Through a targeted resequencing of all coding exons, as well as simultaneous evaluation of copy number status using the alignment map files obtained via NGS, we found that GS phenotypes could be explained by PTCH1 mutations or deletions in all affected patients. Because it is advisable to evaluate CNAs of candidate causative genes in point mutation-negative cases, NGS methodology appears to be useful for improving molecular diagnosis through the simultaneous detection of both SNVs and CNAs in the targeted genes/regions.

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DGCR6 at the proximal part of the DiGeorge critical region is involved in conotruncal heart defects

Cited by 22 publications

References 48 publications

The Genetics and Epigenetics of 22q11.2 Deletion Syndrome

The Genetics and Epigenetics of 22q11.2 Deletion Syndrome

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

Simultaneous Detection of Both Single Nucleotide Variations and Copy Number Alterations by Next-Generation Sequencing in Gorlin Syndrome

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