While it is well-established that deletions at the 22q11.2 locus may lead to clinically well-known syndromic conditions previously known as DiGeorge or velocardiofacial syndrome, accurate estimates of risk of disease have been missing, and very little is known about the clinical consequences in individuals with the corresponding duplication. Our study aimed to provide un-biased incidence rate ratios and absolute risk estimates of the full spectrum of psychiatric disorders based on all registered carriers of the 22q11.2 microdeletion or duplication in Denmark compared to the entire Danish population. In addition, the study informed about predictors for carrying a microdeletion or duplication at the 22q11.2 locus.

2017.06.01 | Annette Bang Rasmussen

Postdoc Louise K. E. Høffding, PhD, Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen

About the study

Microdeletions and microduplications on the chromosome 22q11.2 locus are associated with increased risk of developing a wide range of cognitive and psychiatric disorders. Previous reports of the prevalence of psychiatric disorder among these carriers are based on systematic examination of children, adolescents, and adults seen in outpatient academic setting. Thus, little is known of the clinical and epidemiological consequences at the population level, including the clinical manifestations and disease trajectories.

The aim of our study was to estimate the incidence rate ratios (IRRs) and absolute risks for psychiatric disorder in clinically identified carriers of the 22q11.2 deletion or duplication as well as informing about predictors for carrying a deletion or a duplication at the 22q11.2 locus.  

In this Danish nation-wide register study, we extracted all individuals recorded in the Danish Cytogenetic Central Register with a 22q11.2 deletion or duplication. A population based cohort containing 3,768,948 individuals born in Denmark from 1955-2012 was established by linking the Danish nation-wide clinical health registers. Predictors of 22q11.2 deletion or duplication and absolute risks were estimated using a nested case-control design that included individuals from the population based cohort. Survival analysis was used to compare risk of psychiatric disorders among individuals with and without the 22q11.2 deletion or duplication.

Among the 3,768,948 individuals from the population-based cohort, 244 and 58 individuals were clinically identified with a 22q11.2 deletion or duplication, respectively. A parental diagnosis of schizophrenia – but not of other psychiatric diagnoses – predicted a 22q11.2 deletion while parental psychiatric diagnoses other than schizophrenia predicted duplication carrier status. Both the 22q11.2 deletion and duplication increased the risk of any psychiatric disorders (F00-F99) (IRR=4.24, 95%CI, 3.07-5.67 and IRR=4.99, 95%CI, 1.79-10.72, respectively) and a highly increased risk of intellectual disability was found (IRR_deletion, 34.08; 95%CI, 22.39-49.27 and IRR_duplication, 33.86; 95%CI, 8.42-87.87). Furthermore, individuals with the 22q11.2 deletion had increased risk of a number of the psychiatric disorders under study.

The study provides estimates of disease risk that are important in genetic counselling and clinical monitoring and intervention and points to individuals with the 22q11.2 duplication as being in need of the same careful and persistent clinical attention given to carriers of the 22q11.2 deletion.

The article “Risk of psychiatric disorders among individuals with the 22q11.2 deletion or duplication - A Danish nationwide, register-based study” was published in JAMA Psychiatry, 2017;74(3):282-290.

Facts about the study

• A prospective population-based study combining information from the Danish Civil Registration System and the Danish Cytogenetic Central Registry, which records all 22q11.2 deletion and duplication karyotypes identified from clinical referrals nationwide.
• Risk estimates for psychiatric disorders were similar for clinically identified individuals with the 22q11.2 deletion as well as the 22q11.2 duplication. The risk of intellectual disability was particularly high.
• A parental diagnosis of schizophrenia—but not of other psychiatric diagnoses—was associated with a 22q11.2 deletion, and parental psychiatric diagnoses other than schizophrenia were associated with duplication carrier status.
• Due to the nature of our study, the results are of direct clinical relevance useful to assist clinical ascertainment, genetic counselling, guidance of symptomatic monitoring, and early clinical intervention.

Further information

Louise K. E. Høffding, PhD, postdoc, Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. Email: Louise.K.Enggaard.Hoeffding@regionh.dk