Genotype-phenotype correlation in 22q11.2 deletion syndrome

Abstract

BackgroundThe 22q11.2 deletion syndrome (22q11.2DS) is caused by hemizygous microdeletions on chromosome 22q11.2 with highly variable physical and neuropsychiatric manifestations. We explored the genotype-phenotype relationship in a relatively large 22q11.2DS cohort treated and monitored in our clinic using comprehensive clinical evaluation and detailed molecular characterization of the deletion.MethodsMolecular analyses in 142 subjects with 22q11.2DS features were performed by FISH and MLPA methods. Participants underwent clinical assessment of physical symptoms and structured psychiatric and cognitive evaluation.ResultsDeletions were found in 110 individuals including one with an atypical nested distal deletion which was missed by the FISH test. Most subjects (88.2%) carried the 3Mb typically deleted region and 11.8% carried 4 types of deletions differing in size and location. No statistically significant genotype-phenotype correlations were found between deletion type and clinical data although some differences in hypocalcemia and cardiovascular anomalies were noted.Analysis of the patient with the distal nested deletion suggested a redundancy of genes causing the physical and neuropsychiatric phenotype in 22q11.2DS and indicating that the psychiatric and cognitive trajectories may be governed by different genes.ConclusionsMLPA is a useful and affordable molecular method combining accurate diagnosis and detailed deletion characterization. Variations in deletion type and clinical manifestations impede the detection of significant differences in samples of moderate size, but analysis of individuals with unique deletions may provide insight into the underlying biological mechanisms.Future genotype-phenotype studies should involve large multicenter collaborations employing uniform clinical standards and high-resolution molecular methods.

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.…”

“…[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. 17 The TDR contains over 40 genes that primarily code for transcription factors (TBX1, TUPLE1, etc), cell cycle components (UFD1L and PNUTL1), cell adhesion molecules (DGCR2, DGCR6, etc) and metabolic and enzymatic factors (COMT and PRODH).…”

predicted v. real prevalence of the 22q11.2 deletion syndrome in children with congenital heart disease presenting to Red Cross War Memorial Children’s Hospital, South Africa: A prospective study

“…[7] Alternatives to FISH testing are now available, including multiplex ligationdependent probe amplification (MLPA), array comparative genomic hybridisation (CGH) and single nucleotide polymorphism (SNP) arrays. [12,13] Although these methods are more expensive, they have advantages in terms of turnaround time and detection rates. [12][13][14][15] Owing to the broad spectrum of disease presentation in individuals with 22qDS, and because many clinical characteristics are treatable, it is imperative that clinicians maintain a high index of suspicion.…”