Molecular genetics of 22q11.2 deletion syndrome

Abstract

The 22q11.2 deletion syndrome (22q11.2DS) is a congenital malformation and neuropsychiatric disorder caused by meiotic chromosome rearrangements. One of the goals of this review is to summarize the current state of basic research studies of 22q11.2DS. It highlights efforts to understand the mechanisms responsible for the 22q11.2 deletion that occurs in meiosis. This mechanism involves the four sets of low copy repeats (LCR22) that are dispersed in the 22q11.2 region and the deletion is mediated by non-allelic homologous recombination events. This review also highlights selected genes mapping to the 22q11.2 region that may contribute to the typical clinical findings associated with the disorder and explain that mutations in genes on the remaining allele can uncover rare recessive conditions. Another important aspect of 22q11.2DS is the existence of phenotypic heterogeneity. While some patients are mildly affected, others have severe medical, cognitive and/or psychiatric challenges. Variability may be due in part to the presence of genetic modifiers. This review discusses current genome-wide efforts to identify such modifiers that could shed light on molecular pathways required for normal human development, cognition or behavior.

The Genetics and Epigenetics of 22q11.2 Deletion Syndrome

“…Even more infrequent are deletions between LCR C-E, LCR D-E, and LCR E-F, although the reported clinical phenotypes are not characteristic of 22q11.2del (Saitta et al, 1999;Shaikh et al, 2007;Burnside, 2015;Guna et al, 2015). The role of many of the genes whose haploinsufficiency contributes to the congenital malformations, immune system complications, neurological issues and other clinical phenotypes are well-described and discussed in many reviews (Zemble et al, 2010;Bassett et al, 2011;Mcdonald-Mcginn et al, 2015;Meechan et al, 2015;Morsheimer et al, 2017;Morrow et al, 2018;Sullivan, 2019;Zinkstok et al, 2019). Among some of the more well-characterized genes are T-Box 1 Transcription Factor (TBX1), DiGeorge Syndrome Critical Region 8 (DGCR8), Crk-like Adaptor Protein L (CRKL), Proline Dehydrogenase (PRODH), Reticulon 4 Receptor (RTN4R), Zinc-finger DHHC-type Containing 8 (ZDHHC8), Catechol-O-Methyl Transferase (COMT), Guanine Nucleotide Binding Protein b-polypeptide 1-Like (GNB1L), Septin 5 (SEP5) and Glycoprotein Ib Platelet Subunit Beta (GP1BB).…”

Genetic counselling and testing in adults with congenital heart disease: A consensus document of the ESC Working Group of Grown-Up Congenital Heart Disease, the ESC Working Group on Aorta and Peripheral Vascular Disease and the European Society of Human Genetics

“…[34][35][36][37] The 22q11.2 deletion (historically also described as DiGeorge syndrome, velocardiofacial syndrome) is the most common microdeletion syndrome in humans, occurring in up to 1/5950 live births. 38,39 One of the main genes in the 22q11.2 region is TBX1, a transcription factor controlling second heart field development. 40 Cardiac defects, present in 60-75% of patients include tetralogy of Fallot, interrupted aortic arch, right aortic arch, VSD and truncus arteriosus.…”

Pax9is required for cardiovascular development and interacts withTbx1in the pharyngeal endoderm to control 4thpharyngeal arch artery morphogenesis

“…Approximately 20% of foetuses identified with conotruncal defects by ultrasound are diagnosed with 22q11 deletion syndrome (22q11 DS) (Boudjemline et al, 2001), the most common microdeletion syndrome with an incidence of 1:4000 live births (Scambler, 2000). Patients typically have a 3Mb deletion on chromosome 22 that encompasses 45 protein coding genes (Morrow et al, 2018) and ~80% of patients present with some form of congenital cardiovascular defect (Momma, 2010), of which one of the most common observed is interruption of the aortic arch (Unolt et al, 2018). Although clinically rare in the general population, approximately 50% of all cases of interrupted aortic arch occur in 22q11 DS patients (Boudjemline et al, 2001; Lewin et al, 1997; Van Mierop and Kutsche, 1986).…”