22q11.2 deletion syndrome

(22q11.2DS)

The first clinically identifiable molecular

cause of schizophrenia

Anne S. Bassett, MD, FRCPC

Canada Research Chair in Schizophrenia Genetics and Genomic Disorders

Dalglish Chair in 22q11.2 Deletion Syndrome

Senior Scientist, Toronto General Research Institute

Senior Scientist, Campbell Family Mental Health Research Institute

Director, Dalglish Family 22q Clinic, Toronto General Hospital

22q11.2 Deletion Syndrome (22q11.2DS)

• Known clinical condition since the 1960s

– Variety of names, now under one molecular umbrella

• Targeted clinical testing (FISH) available since 1994

• Clinical testing: now genome-wide microarray or MLPA

• Known association with schizophrenia since 1992-94(Shprintzen, 1992; Pulver et al., 1994; Chow et al., 1994)

– 1 in every 4 individuals with 22q11.2DS develops schizophrenia

• Not found in large control samples

• Unbiased prevalence studies show deletion 22q11.2 in

an estimated 1 in 100-200 patients with schizophrenia(Horowitz et al., 2005; Bassett et al., 2010)

• The first true molecular genetic subtype of schizophrenia

Am J Psychiatry 2010; 167:899–914

Structural genomic changes

Copy number variation

(CNV)

Broader context

Genome-wide CNV – discovery(Iafrate et al., 2004; Sebat et al., 2004;

Redon et al., 2006)

Associated with schizophrenia

Rare

Often recurrent (*)

Loss (deletion) or

Gain (duplication)

Some have high penetrance

Clinically pathogenic CNVs

Up to 5% of schizophrenia(Costain et al., Human Molecular

Genetics 22:4485-4501, 2013)

*

22q11.2 deletion region

Deletions~90%

~5%

Segmental duplications (LCRs)

22q11.2 deletion syndrome. Nat. Rev. Dis. Primers 2015; doi:10.1038/nrdp.2015.71

Non-allelic homologous recombination (NAHR) between misaligned low copy repeats

(LCRs) during gametogenesis underlies recurrent rearrangements

Slight excess of maternal origin

No maternal or paternal age effect (Bassett et al., 2008; Delio et al., 2013)

22q11.2 Deletion Syndrome (22q11.2DS)

• Hemizygous chromosome 22q11.2 deletion

• Most common microdeletion syndrome in humans

– Usual prevalence estimate: ~1/2000-1/4000 live births

– Prenatal studies prevalence of typical 22q11.2 deletions

In 3,822 karyotypically normal pregnancies (Wapner et al., 2012):

– 1/347 pregnancies had 22q11.2 deletions

In 9,648 pregnancies in a multicentre study (Grati et al., 2015):

– 1/992 pregnancies had 22q11.2 deletions

• The true live birth prevalence remains to be determined

• Most are de novo (spontaneous) genetic changes

• Only ~ 5-10% are found to be inherited from a parent

• Congenital and later onset features, variable expression

• Clinically recognizable though under-recognized

Neuropsychiatric expression of 22q11.2DS

• Neonatal seizures (usually hypocalcemic)

• Developmental delay and intellectual disabilities

• Autism spectrum features and disorder

• Attention deficit disorder

• Recurrent seizures / epilepsy

• Mood and anxiety disorders

• Schizophrenia and other psychotic disorders

• Neurodegenerative disorders (Parkinson disease)Butcher et al. JAMA Neurology 70:1359-1366, 2013

Bassett et al. AJMG 138A:307-313, 2005; Fung et al. Am J Psychiatry 167:998, 2010; Schneider et al. Am J

Psychiatry 171:627-639, 2014; McDonald-McGinn et al. Nature Reviews Disease Primers 1:15071, 2015

The Schizophrenia Phenotype in

22q11 Deletion Syndrome (22q11DS)American Journal of Psychiatry, 160:1580-86, 2003

Is it Schizophrenia?

Is the schizophrenia in 22q11DS similar to that of other

forms of schizophrenia?

Yes

Median age at onset ~ 21 y

Meets DSM criteria, same signs and symptoms as for

heterogeneous schizophrenia samples

Could the clinical features of schizophrenia be used to

identify 22q11.2DS patients?

No (rely on physical features/developmental history for

index of suspicion)

• Clinical practice guidelines (J Peds, 2011; GIM, 2015)

• Standard management for each individual condition– Personalized for 22q11.2DS

– Clozapine, e.g. (Butcher et al., British J Psychiatry, 206:484-491, 2015)

• Targeted investigations and monitoring

• Early diagnosis of treatable psychiatric illness

• Family/caregiver involvement (Costain et al., JIDR 56:641-651, 2012)

• Genetic counselling (Costain et al., JMG 48:819-824, 2011)

– Reproductive: 50% risk of transmitting 22q11.2 deletion

– Associated psychiatric and medical conditions, reduced longevity

Personalized care for 22q11.2DS

• 90 genes

• 46 protein-coding genes• Most are expressed in brain

• Many, but not all, have

decreased expression with

hemizygosity

− DGCR8 is one of the key

genes in the region− Conserved; haploinsufficient

− Encodes a protein (“Pasha”)

involved in miRNA biogenesis

− miRNAs act as buffers at

transcription and translation

of proteins genome-wide

Genes in the 22q11.2 deletion region

Possible mechanism of DGCR8

haploinsufficiency in 22q11.2DS

Hypothesis & Theory ARTICLEFront. Genet., 13 December 2012 | doi: 10.3389/fgene.2012.00291 miRNA-mediated risk for schizophrenia in 22q11.2 deletion syndromeLinda M. Brzustowicz1,2* and Anne S. Bassett3,4,5

22q11.2DS whole genome sequencing pilot study

of schizophrenia - Toronto

The

Centre for

Applied

Genomics

Extreme phenotype approach – within 22q11.2DS

Standard pipeline focusing on high quality rare variants +

Gene-set analysis that

Prioritized genes likely to be involved in brain function

Restricted to those affected by DGCR8 haploinsufficiency

= Promising strategy with notable effect sizes

Under way...

• International consortium – IBBC (NIMH)

– Whole genome sequencing and genome-wide

microarray to delineate sequence and structural

variation contributing to expression of schizophrenia

• Promise of prospective studies, Rx trials

• Animal and cellular models to investigate

mechanisms and help develop new treatments

• Further elucidation of natural history, long term

outcome and management

• Epidemiology - newborn screening