Aberrant interchromosomal exchanges are the predominant cause of the 22q11.2 deletion

Abstract

Chromosome 22q11.2 deletions are found in almost 90% of patients with DiGeorge/velocardiofacial syndrome (DGS/VCFS). Large, chromosome-specific low copy repeats (LCRs), flanking and within the deletion interval, are presumed to lead to misalignment and aberrant recombination in meiosis resulting in this frequent microdeletion syndrome. We traced the grandparental origin of regions flanking de novo 3 Mb deletions in 20 informative three-generation families. Haplotype reconstruction showed an unexpectedly high number of proximal interchromosomal exchanges between homologs, occurring in 19/20 families. Instead, the normal chromosome 22 in these probands showed interchromosomal exchanges in 2/15 informative meioses, a rate consistent with the genetic distance. Meiotic exchanges, visualized as MLH1 foci, localize to the distal long arm of chromosome 22 in 75% of human spermatocytes tested, also reflecting the genetic map. Additionally, we found no effect of proband gender or parental age on the crossover frequency. Parental origin studies in 65 de novo 3 Mb deletions (including these 20 patients) demonstrated no bias. Unlike Williams syndrome, we found no chromosomal inversions flanked by LCRs in 22 sets of parents of 22q11 deleted patients, or in eight non-deleted patients with a DGS/VCFS phenotype using FISH. Our data are consistent with significant aberrant interchromosomal exchange events during meiosis I in the proximal region of the affected chromosome 22 as the likely etiology for the deletion. This type of exchange occurs more often than is described for deletions of chromosomes 7q11, 15q11, 17p11 and 17q11, implying a difference in the meiotic behavior of chromosome 22.

A French multicenter study of over 700 patients with 22q11 deletions diagnosed using FISH or aCGH

“…1,2 The phenotype is highly variableover 180 associated clinical manifestations already described -and ranges from severe, with life-threatening malformations, to nearly asymptomatic cases. The major clinical features include congenital heart defects (CHDs), palate defects (velopharyngeal insufficiency, cleft palate, etc), mild-to-moderate immunodeficiency (because of thymic aplasia or hypoplasia), hypocalcemia caused by hypoparathyroidism, a distinct gestalt, developmental delay (DD), learning 1 Département de Génétique, CHU de Reims, Reims, France; 2 Service de Cytogénétique, Hôpital Poissy/Saint-Germain-en-Laye, Poissy, France; 3 Service de Cytogénétique, CHU de Lyon, Lyon, France; 4 CHU Bordeaux, Génétique Médicale, Bordeaux, France; 5 Laboratoire de Cytogénétique, CHU de Marseille, Marseille, France; 6 CHU Nantes, Service de Génétique Médicale, Inserm UMR957, Faculté de Médecine, Nantes, France; 7 Laboratoire de Cytogénétique Pasteur-Cerba, Saint-Ouen l'Aumône, France; 8 Service de Cytogénétique, CHU de Necker, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; 9 Service de Cytogénétique, CHU de Besançon, Besançon, France; 10 Service de Cytogénétique, Biolille, Lille, France; 11 Service de Cytogénétique, Hôpital Saint Vincent de Paul, Paris, France; 12 Laboratoire de Cytogénétique Postnatal, CHU Clemenceau, Caen, France; 13 Service de Cytogénétique et Biologie de la Reproduction, CHRU de Brest, Brest, France; 14 Service de Cytogénétique, CHU de Robert Debré, Paris, France; 15 Service de Cytogénétique, CHU de Strasbourg, Strasbourg, France; 16 Service de Cytogénétique, CHU de Tours, Tours, France; 17 Service de Cytogénétique, CHU de Nancy, Nancy, France; 18 Laboratoire de Cytogénétique Cylab, La Rochelle, France; 19 Service de Cytogénétique, Hôpital de Saint-Denis, Saint-Denis de la Réunion, France; disabilities, intellectual disability (ID) and behavioral disturbances. [3][4][5] Renal, ocular and skeletal anomalies have also been observed.…”

“…9 Approximately 90% of patients have a 3-Mb deletion spanning LCR22-A to LCR22-D, is referred to as the 'typically deleted region' (TDR). [11][12][13] A smaller (1.5 Mb) deletion spanning LCR22-A to LCR22-B is found in 4 to 7% of patients. [11][12][13] Atypical deletions with at least one breakpoint not mediated by an LCR have also been reported.…”

“…[11][12][13] A smaller (1.5 Mb) deletion spanning LCR22-A to LCR22-B is found in 4 to 7% of patients. [11][12][13] Atypical deletions with at least one breakpoint not mediated by an LCR have also been reported. [14][15][16] The relationship between the size of the 22q11.2 deletion and the corresponding clinical features is still subject to debate.…”

Molecular characterization of deletion breakpoints in adults with 22q11 deletion syndrome

“…However, this has only been demonstrated for a small number of 22q11.2 deletions. Although most individuals with 22q11DS have a similar "common 3 Mb deletion", a minority have other overlapping and non-overlapping 22q11.2 deletions (Amati et al 1999;Saitta et al 2004). In other microdeletion syndromes such as Williams syndrome, some aspects of the phenotype appear related to the length of the deletion (Stock et al 2003).…”

Recent advance in our understanding of the molecular nature of chromosomal abnormalities

“…17,18 The LCRs involved in CMT1A or DS22 manifest recombination frequency of average levels, suggestive of no DSB or recombination hotspot activity of the LCRs. 19,20 Thus, recurrent GCRs of this type are unlikely to result from non-random DSBs, but from non-random DSB repair through illegitimate NAHR.…”