Prevalence of rearrangements in the 22q11.2 region and population-based risk of neuropsychiatric and developmental disorders in a Danish population: a case-cohort study

Olsen, Line; Sparsø, Thomas; Weinsheimer, Shantel; Santos, Marcel Bertalan Quintanilha Dos; Mazin, Wiktor; Rosengren, Anders; Sánchez, Xabier Calle; Hoeffding, Louise K.; Schmock, Henriette; Bækvad‐Hansen, Marie; Bybjerg‐Grauholm, Jonas; Daly, Mark J.; Neale, Benjamin M.; Pedersen, Marianne G.; Agerbo, Esben; Mors, Ole; Børglum, Anders D.; Nordentoft, Merete; Hougaard, David M.; Mortensen, Preben Bo; Geschwind, Daniel H.; Pedersen, Carsten; Thompson, Wesley K.; Werge, Thomas

doi:10.1016/s2215-0366(18)30168-8

Cited by 132 publications

(144 citation statements)

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“…The prevalence of both deletions and duplications was higher among individuals with a neuropsychiatric or developmental disorder than unaffected individuals. However, the overall prevalence of neuropsychiatric disorders was higher in duplication carriers compared with deletion carriers (Olsen et al., ).…”

Section: Introductionmentioning

confidence: 99%

Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance

Woodward

Stampalia

Vanyai

et al. 2019

Molec Gen & Gen Med

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Background Chromosome 22q11.2 is susceptible to genomic rearrangements and the most frequently reported involve deletions and duplications between low copy repeats LCR 22A to LCR 22D. Atypical nested deletions and duplications are rarer and can provide a valuable opportunity to investigate the dosage effects of a smaller subset of genes within the 22q11.2 genomic disorder region. Methods We describe thirteen individuals from six families, each with atypical nested duplications within the central 22q11.2 region between LCR 22B and LCR 22D. We then compared the molecular and clinical data for patients from this study and the few reported atypical duplication cases, to the cases with larger typical duplications between LCR 22A and LCR 22D. Further, we analyzed genes with the nested region to identify candidates highly enriched in human brain tissues. Results We observed that atypical nested duplications are heterogeneous in size, often familial, and associated with incomplete penetrance and highly variable clinical expressivity. We found that the nested atypical duplications are a possible risk factor for neurodevelopmental phenotypes, particularly for autism spectrum disorder ( ASD ), speech and language delay, and behavioral abnormalities. In addition, we analyzed genes within the nested region between LCR 22B and LCR 22D to identify nine genes ( ZNF 74, KLHL 22, MED 15, PI 4 KA , SERPIND 1, CRKL , AIFM 3, SLC 7A4, and BCRP 2) with enriched expression in the nervous system, each with unique spatiotemporal patterns in fetal and adult brain tissues. Interestingly, PI 4 KA is prominently expressed in the brain, and this gene is included either partially or completely in all of our subjects. Conclusion Our findings confirm variable expressivity and incomplete penetrance for atypical nested 22q11.2 duplications and identify genes such as PI 4 KA to be directly relevant to brain development and disorder. We conclude that further work is needed to elucidate the basis of variable neurodevelopmental phenotypes and to exclude the presence of a second disorder. Our findings contribute to the genotype–phenotype data for atypical nested 22q11.2 duplications, with implications for genetic counseling.

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Section: Introductionmentioning

confidence: 99%

Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance

Woodward

Stampalia

Vanyai

et al. 2019

Molec Gen & Gen Med

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“…In the majority of cases, a de novo 3 megabase (Mb) deletion occurs between low copy repeats (LCRs) 22A‐22D, causing the loss of 46 protein‐coding genes . This deletion syndrome has a variable phenotype, with characteristic features including congenital heart disease, palatal abnormalities, hypocalcemia, mild‐moderate intellectual disability (ID), and psychiatric disorders such as schizophrenia, attention‐deficit/hyperactivity disorder (ADHD), anxiety disorder and autism spectrum disorder (ASD) …”

Section: Introductionmentioning

confidence: 99%

“…In adulthood, 17.6% of patients with 22q11.2DS exposed to psychotropic drugs have epileptic seizures, suggesting a reduced seizure threshold . Between 4.4% and 36.8% have repeated unprovoked seizures (ie, epilepsy) . Structural brain abnormalities in these individuals can include diffuse cerebral atrophy (18.8%), polymicrogyria (13.9%), hippocampal malrotation (10.9%), gray and white matter heterotopia (5.9%), and focal cortical dysplasia (2%) .…”

Section: Introductionmentioning

confidence: 99%

“…2 This deletion syndrome has a variable phenotype, with characteristic features including congenital heart disease, palatal abnormalities, hypocalcemia, mild-moderate intellectual disability (ID), and psychiatric disorders such as schizophrenia, attention-deficit/hyperactivity disorder (ADHD), anxiety disorder and autism spectrum disorder (ASD). [3][4][5][6][7][8][9][10][11] The deletion increases the risk of acute symptomatic and unprovoked epileptic seizures, although the reported rates are wide-ranging. Between 1% and 14.5% of patients have hypocalcemia-induced seizures.…”

Section: Introductionmentioning

confidence: 99%

“…13 Between 4.4% and 36.8% have repeated unprovoked seizures (ie, epilepsy). 9,[13][14][15]17,18 Structural brain abnormalities in these individuals can include diffuse cerebral atrophy (18.8%), polymicrogyria (13.9%), hippocampal malrotation (10.9%), gray and white matter heterotopia (5.9%), and focal cortical dysplasia (2%). 19 Between 1% and 6.9% of patients have genetic generalized epilepsy (GGE), [13][14][15]17 and the deletion prevalence is elevated in GGE cohorts.…”

Section: Introductionmentioning

confidence: 99%

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Epilepsy and seizures in young people with 22q11.2 deletion syndrome: Prevalence and links with other neurodevelopmental disorders

et al. 2019

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Summary Objective The true prevalence of epileptic seizures and epilepsy in 22q11.2 deletion syndrome (22q11.2DS) is unknown, because previous studies have relied on historical medical record review. Associations of epilepsy with other neurodevelopmental manifestations (eg, specific psychiatric diagnoses) remain unexplored. Methods The primary caregivers of 108 deletion carriers (mean age 13.6 years) and 60 control siblings (mean age 13.1 years) completed a validated epilepsy screening questionnaire. A subsample (n = 44) underwent a second assessment with interview, prolonged electroencephalography (EEG), and medical record and epileptologist review. Intelligence quotient (IQ), psychopathology, and other neurodevelopmental problems were examined using neurocognitive assessment and questionnaire/interview. Results Eleven percent (12/108) of deletion carriers had an epilepsy diagnosis (controls 0%, P = 0.004). Fifty‐seven of the remaining 96 deletion carriers (59.4%) had seizures or seizurelike symptoms (controls 13.3%, 8/60, P < 0.001). A febrile seizure was reported for 24.1% (26/107) of cases (controls 0%, P < 0.001). One deletion carrier with a clinical history of epilepsy was diagnosed with an additional type of unprovoked seizure during the second assessment. One deletion carrier was newly diagnosed with epilepsy, and two more with possible nonmotor absence seizures. A positive screen on the epilepsy questionnaire was more likely in deletion carriers with lower performance IQ (odds ratio [OR] 0.96, P = 0.018), attention‐deficit/hyperactivity disorder (ADHD) (OR 3.28, P = 0.021), autism symptoms (OR 3.86, P = 0.004), and indicative motor coordination disorder (OR 4.56, P = 0.021). Significance Even when accounting for deletion carriers diagnosed with epilepsy, reports of seizures and seizurelike symptoms are common. These may be “true” epileptic seizures in some cases, which are not recognized during routine clinical care. Febrile seizures were far more common in deletion carriers compared to known population risk. A propensity for seizures in 22q11.2DS was associated with cognitive impairment, psychopathology, and motor coordination problems. Future research is required to determine whether this reflects common neurobiologic risk pathways or is a consequence of recurrent seizures.

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Comparing Copy Number Variations in a Danish Case Cohort of Individuals With Psychiatric Disorders

et al. 2022

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IMPORTANCEAlthough the association between several recurrent genomic copy number variants (CNVs) and mental disorders has been studied for more than a decade, unbiased, population-based estimates of the prevalence, disease risks and trajectories, fertility, and mortality to contrast chromosomal abnormalities and advance precision health care are lacking.OBJECTIVE To generate unbiased, population-based estimates of prevalence, disease risks and trajectories, fertility, and mortality of CNVs implicated in neuropsychiatric disorders. DESIGN, SETTING, AND PARTICIPANTSIn a population-based case-cohort study, using the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) 2012 database, individuals born between May 1, 1981, and December 31, 2005, and followed up until December 31, 2012, were analyzed. All individuals (n = 57 377) with attention-deficit/ hyperactivity disorder (ADHD), major depressive disorder (MDD), schizophrenia (SCZ), autism spectrum disorder (ASD), or bipolar disorder (BPD) were included, as well as 30 000 individuals randomly drawn from the database. Data analysis was conducted from July 1, 2017, to September 7, 2021.

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Prevalence of rearrangements in the 22q11.2 region and population-based risk of neuropsychiatric and developmental disorders in a Danish population: a case-cohort study

Abstract: Capital Region's Research Foundation for Mental Health Research, The Lundbeck Foundation, and US National Institutes of Health.

Cited by 132 publications

References 30 publications

Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance

Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance

Epilepsy and seizures in young people with 22q11.2 deletion syndrome: Prevalence and links with other neurodevelopmental disorders

Comparing Copy Number Variations in a Danish Case Cohort of Individuals With Psychiatric Disorders

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