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In the line-up: deleted genes associated with DiGeorge/22q11.2 deletion syndrome: are they all suspects?
Journal of Neurodevelopmental Disorders ( IF 4.9 ) Pub Date : 2019-06-07 , DOI: 10.1186/s11689-019-9267-z
Zahra Motahari 1 , Sally Ann Moody 1 , Thomas Michael Maynard 1 , Anthony-Samuel LaMantia 1
Affiliation  

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.

中文翻译:

在阵容中:与DiGeorge / 22q11.2缺失综合征相关的缺失基因:它们都是可疑的吗?

背景技术22q11.2缺失综合征(22q11DS)是一种拷贝数变异(CNV)疾病,由于人类22号染色体(hChr22)q臂11.2位(近端)的杂合微缺失而在大约1:4000活产中发生( McDonald-McGinn and Sullivan,Medicine 90:1-18,2011)。根据诊断性心血管,咽和颅面畸形,这种疾病被称为DiGeorge综合征,Velo-心血管面部综合征(VCFS)或锥鼻异常脸综合征(CTAF)(McDonald-McGinn和Sullivan,Medicine 90:1-18,2011 ; Burn等人,J Med Genet 30:822-4,1993)之前,该表型谱与22q11.2 CNV相关。随后,是22q11。2缺失是与一些神经发育障碍常见的几种临床定义的行为缺陷相关的,与脆弱性相关的主要基因组病变(Fernandez等人,Principles of Developmental Genetics,2015; Robin and Shprintzen,J Pediatr 147:90-6,2005 ; Schneider等人,Am J Psychiatry 171:627-39,2014)。结果杂合缺失的22q11.2基因与22q11DS表型之间的机制关系仍然未知。我们在hChr22q11.2的1.5 Mb最小关键缺失区域中组装了36个蛋白质编码基因座的全面“阵容”,并在远端1.5 Mb中定义了3 Mb典型的22q11DS缺失的20个蛋白质编码基因座。我们根据明显的原代细胞生物学功能对候选者进行了分类。我们分析了编码已知蛋白质的这些基因中的41个,以确定是否有22q11.2基因的单倍不足-一个基因与一个表型对应,这是由于杂合性缺失所致,该杂合缺失仅限于基因座与复杂的多基因相互作用,可以解释单个或多个22q11DS表型。结论我们的22q11.2功能基因组学评估不支持当前针对一种或所有22q11DS表型的单基因单倍体功能不足的理论。共同的分子功能,基本细胞生物学过程的趋同性以及各个22q11.2基因的相关后果,归因于22q11.2基因剂量的减少,导致了多基因相互作用的矩阵。这些相互作用的目标是22q11DS表型位点的子集对发育,成熟或体内稳态必不可少的基本细胞机制。
更新日期:2020-04-22
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