22q11.2 DELETION SYNDROME. Anna Mª Cueto González Clinical Geneticist Programa de Medicina Molecular y Genética Hospital Vall d Hebrón (Barcelona)

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1 22q11.2 DELETION SYNDROME Anna Mª Cueto González Clinical Geneticist Programa de Medicina Molecular y Genética Hospital Vall d Hebrón (Barcelona)

2 Genomic disorders GENOMICS DISORDERS refers to those diseases that are caused by chromosomal rearrangements involving large regions of one to several megabase pairs. Although each individual disorder is rare in the population, when combined, they are responsible for a substantial proportion (0.7% of live births) of births defects. Most of the rearrangements are associated with both congenital malformations and mental retardation. Therefore, genomic disorders have a large impact on human health. Am J Hum Genet 2002, 70:

3 22q11.2 region Although the 22q11.2 syndromes have overlapping phenotypes, often with craniofacial, cardiac and cognitive involvement it is becoming increasingly clear that they are cytogenetically and clinically diverse. Clin Genet 2010; 78: Am J Hum Genet 2002; 70:

4 22q11.2 region 22q11.2 region is prone to chromosomal rearrangement because of the existence of segmental duplications or low copy repeat (LCR) sequences therefore non-allelic homologous recombination can result in unequal crossover rearrangements. Clin Genet 2010; 78:

5 22q11.2 region The eight characterised LCRs are labelled 2-8 (or A- H) from the centromeric to telomeric ends: the two largest being LCR22-2 and LCR22-4. (2) (3a) (3b) (4) (5) (6) (7) (8) Centromere Telomere Clin Genet 2010; 78: Dev Disabil Res Rev ; 14(1):

6 22q11.2 region The recent use of diagnostic microarrays has allowed the delineation of additional syndromes at this locus 22q11 deletion Clin Genet 2010; 78: Am J Hum Genet 2002; 70:

7 22q11.2 Deletion Syndrome The most common genomic disorder on 22q11 is the deletion of that region 22q11.2 deletion syndrome (OMIM#192430) is the term that include clinical syndromes such as: Velocardiofacial syndrome DiGeorge syndrome Conotruncal anomaly face syndrome 22q11 deletion Clin Genet 2010; 78:

8 Prevalence Initially the prevalence rate was calculated in patients with congenital cardiac defects estimated rate 1 in 4000 livebirths (Wilson et all 1993). Because not all patients have cardiac anomalies, this represents a minimum estimate. Lancet 2007 (October 20, 370):

9 Prevalence The largest study of birth prevalence of chromosome 22q11.2 deletion syndrome used a registry of birth defects in the Atlanta metropolitan area (USA) and patients identified through a screening programme of infants with congenital heart disease and positive FISH tests (Botto et all 2003) The overall prevalence was 1 in 5950 births This is the only study that measured the prevalence in different races: In white, black and Asian people 1 in 6000 to one in 6500 In Hispanic people is higher 1 in 3800 Lancet 2007 (October 20, 370):

10 Prevalence Usually it is the novo, but 8-28% are inherited from a parent Symptomatic parents frequently have a much milder phenotype than their offspring, with a lower frequency of congenital heart defects pseudoanticipation, bias of ascertainment. In this cases the recurrence risk is 50% and offspring are often more severely affected. Lancet 2007 (October 20, 370):

11 Prevalence All these studies probably underestimated the true incidence and prevalence of this disorder. The clinical phenotype is variable often patients without a congenital heart defect are diagnosed with a delay of several years And patients with atypical or minimal phenotype might be missed Lancet 2007 (October 20, 370):

12 22q11.2 Deletion Syndrome The reason of this confusing nomenclature is the enormous phenotypic heterogeneity of this syndrome Lancet 2007 (October 20, 370):

13 Clinical features PROXIMAL DELETION The most frequent deletion (90%) have a 3Mb spanning from LCR22-2(A) to LCR22-4(D) A minority (8%) has a 1.5Mb deletion from LCR22-2(A) to LCR22-3a(B) (2) (3a) (3b) (4) (5) (6) (7) (8) Centromere 3Mb (90%) 1 5Mb (8%) Others (2%) Telomere Clin Genet 2010; 78: Lancet 2007 (October 20, 370):

14 Clinical features PROXIMAL DELETION Have a distinctive craniofacial phenotype and other features including: cardiovascular defects (especially conotruncal anomalies) thymic hypoplasia (leading to variable degrees of T-cell deficiency) hypoparathyroidism and neonatal hypocalcaemia feeding difficulties renal defects cognitive deficits neuropsychiatric disorders Clin Genet 2010; 78: Lancet 2007 (October 20, 370):

15 Clinical features PROXIMAL DELETION Displays great inter and intrafamilial variability There is little discernible difference between individuals with the 3Mb deletion and those with the nested 1 5Mb deletion or smaller atypical deletions making phenotype-genotype correlation difficult Clin Genet 2010; 78: Lancet 2007 (October 20, 370):

16 Clinical features DISTAL DELETION Facial dysmorphism associated with distal deletion is different than in proximal deletion: long smooth philtrum and thin upper lip low birth weight and prematurity developmental delay is typically global but expressive language is more severely affected non-conotruncal cardiac defects (include bicuspid aortic valve, cardiac dextrorotation) choanal atresia and stenosis Clin Genet 2010; 78: Lancet 2007 (October 20, 370):

17 22q11.2 Deletion Syndrome Lancet 2007 (October 20, 370):

18 22q11.2 Deletion Syndrome The management is highly dependent on age and phenotype Lancet 2007 (October 20, 370):

19 22q11.2 Deletion Syndrome and research It is well know that TBX1 gene is the major candidate gene for cardiac and parathyroid phenotype Tbx1 gene (in knockout mice) is the responsible for the cardiovascular and most of the congenital defects observed in mouse models. The identification of eight rare point mutations in the TBX1 gene in families including probands presenting with a 22q11.2DS-like phenotype, but without any detectable deletion of the 22q11.2 region, reinforces this hypothesis. Int J Devl Nueroscience 2011 (29): Behav Genet 2011(3):

20 Psychiatric disorders and 22q11 deletion syndrome 22q11.2 deletion syndrome is a genetic risk factor for schizophrenia. It is the only confirmed recurrent structural mutation responsible for the introduction of sporadic cases of schizophrenia. Carriers of deletions in chromosome 22q11.2 develop schizophrenia or schizoaffective disorders at rate of 25-30% Deletions in 22q11.2 account for as many as 1-2% of cases of sporadic schizophrenia in general population Int J Devl Nueroscience 2011 (29):

21 Psychiatric disorders and 22q11 deletion syndrome The literature suggests that schizophrenia in 22q11.2 deletion carriers is indistinguishable from sporadic forms of illness. Cognitive dysfunction is common in patients with 22q11.2 deletion. Int J Devl Nueroscience 2011 (29):

22 Cognitive dysfunction and 22q11 deletion syndrome The existence of behavioural phenotype and susceptibility to develop psychiatric disorders in patients with 22q11.2 deletion offers unique opportunities to identify genes implicated in cognition, behaviour and schizophrenia. Int J Devl Nueroscience 2011 (29): Behav Genet 2011(3):

23 Cognitive dysfunction and 22q11 deletion syndrome There are 4 genes in which there is good evidence for them being involved in the pathogenic process The evidence that these genes are implicated in the increased risk of developing schizophrenia comes from a combination of human genetic studies and animal modeling work. This are: COMT PRODH ZDHHC8 DGCR8 Int J Devl Nueroscience 2011 (29):

24 Cognitive dysfunction and 22q11 deletion syndrome Recent studies have suggested that COMT deficiency may play a significant role in neuronal dysfunction in the context of a simultaneous PRODH deletion. Further support for a interaction between PRODH and COMT came from a comprehensive study of patients with 22q11.2DS (Raux et al, 2007). This study not only showed hyperprolinemia as a likely risk factor for schizophrenia spectrum disorders but also showed than when the remaining COMT copy was the low activity Met158 allele, hyperprolinemia and COMT-Met158 synergistically increased the risk for the development of schizophrenia. Int J Devl Nueroscience 2011 (29):

25 Open questions In conclusion, 22q11.2DS offers an immense opportunity to probe the genetics and biology of schizophrenia. The open questions that there are in this moment are: - The contribution of genetic variation in the remaining copy of the region - The contribution of CNVs (especially de novo CNVs) to the genetic and neural complexity of psychiatric disorders ****

26 Clinical Genetic Consult Hospital Vall d Hebrón During the last year we evaluated 1694 patients Of those 1200 were new patients We made 130 different diagnoses during that time: monogenic syndrome chromosomal anomalies

27 Clinical Genetic Consult Hospital Vall d Hebrón Since 1996 we had diagnosed 67 patients with 22q11.2 deletion syndromes - 7 foetuses - 4 from 0-2 years - 18 from 2-6 years - 32 from 6-15 years -6 > 15 years

28 Clinical Genetic Consult Hospital Vall d Hebrón We have 62 the novo cases And inhered from a parent in 5 cases

29 Clinical Genetic Consult Hospital Vall d Hebrón The diagnosis was made by: - FISH in 53 patients - MLPA in 12 patients - array-cgh in 2

30 THANK YOU