Phenotypic variability of atypical 22q11.2 deletions not includingTBX1

Abstract

Interstitial deletions of the chromosome 22q11.2 region are the most common microdeletions in humans. The TBX1 gene is considered to be the major candidate gene for the main features in 22q11.2 deletion syndrome, including congenital heart malformations, (para)thyroid hypoplasia, and craniofacial abnormalities. We report on eight patients with atypical deletions of chromosome 22q11.2. These deletions comprise the distal part of the common 22q11.2 deleted region but do not encompass the TBX1 gene. Ten similar patients with overlapping distal 22q11.2 deletions have been reported previously. The clinical features of these patients are described and compared to those found in the classic 22q11.2 deletion syndrome. We discuss the possible roles of a position effect or haploinsufficiency of distally located genes (e.g., CRKL) in the molecular pathogenesis of the 22q11.2 deletion syndrome.

Implications of COMT long-range interactions on the phenotypic variability of 22q11.2 deletion syndrome

“…For instance, several cases of psychiatric disorders and congenital heart disease, including tetralogy of Fallot, are observed in patients with atypical deletions not encompassing COMT or TBX1. 17,32 Features overlapping with 22q11DS have also been observed with 22q11 distal deletions. 10 One gene implicated in the craniofacial, neurodevelopmental and congenital heart malformations associated with 22q11 distal deletions is mitogen-Activated Protein Kinase 1 (MAPK1).…”

“…[13][14][15] Moreover, patients with non-overlapping deletions may share many of the same features. 16,17 Varying Implications of COMT long-range interactions on the phenotypic variability of 22q11.2 deletion syndrome 22q11.2 deletion syndrome (22q11Ds) results from a hemizygous microdeletion on chromosome 22 and is characterized by extensive phenotypic variability. Penetrance of signs, including congenital heart, craniofacial, and neurobehavioral abnormalities, varies widely and is not well correlated with genotype.…”

“…In agreement with a position effect, phenotypes commonly attributed to TBX1 and COMT haploinsufficiency have been reported in shorter atypical and distal deletions not encompassing either gene. 17,21 It is becoming clear that nuclear architecture, including global structure and local chromosome conformation, plays an important role in gene regulation. 22 For example, point mutations in the Shh enhancer located 1 Mb away from Shh interfere with its developmental regulation, resulting in preaxial polydactyly.…”

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.…”

“…[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. 11 Since 1999, o60 cases with recurrent 22q11.2 distal deletions (between LCR22-D to LCR22-H) of variable size and position have been described.…”