Consensus reporting guidelines to address gaps in descriptions of ultra-rare genetic conditions.

Genome-wide sequencing and genetic matchmaker services are propelling a new era of genotype-driven ascertainment of novel genetic conditions. The degree to which reported phenotype data in discovery-focused studies address informational priorities for clinicians and families is unclear. We identified reports published from 2017 to 2021 in 10 genetics journals of novel Mendelian disorders. We adjudicated the quality and detail of the phenotype data via 46 questions pertaining to six priority domains: (I) Development, cognition, and mental health; (II) Feeding and growth; (III) Medication use and treatment history; (IV) Pain, sleep, and quality of life; (V) Adulthood; and (VI) Epilepsy. For a subset of articles, all subsequent published follow-up case descriptions were identified and assessed in a similar manner. A modified Delphi approach was used to develop consensus reporting guidelines, with input from content experts across four countries. In total, 200 of 3243 screened publications met inclusion criteria. Relevant phenotypic details across each of the 6 domains were rated superficial or deficient in >87% of papers. For example, less than 10% of publications provided details regarding neuropsychiatric diagnoses and "behavioural issues", or about the type/nature of feeding problems. Follow-up reports (n = 95) rarely contributed this additional phenotype data. In summary, phenotype information relevant to clinical management, genetic counselling, and the stated priorities of patients and families is lacking for many newly described genetic diseases. The PHELIX (PHEnotype LIsting fiX) reporting guideline checklists were developed to improve phenotype reporting in the genomic era.

Selective Serotonin Reuptake Inhibitor Treatment Post Gene Therapy for an Ultrarare Neurometabolic Disorder (AADC Deficiency).

Aromatic L-amino acid decarboxylase (AADC) deficiency is an ultrarare genetic disorder affecting 1 in 500,000 individuals. It causes complete absence of monoamine neurotransmitter synthesis, profound motor impairment, and developmental delays. Treatment guidelines recommend against selective serotonin re-uptake inhibitors (SSRIs) in AADC deficiency, given reports of movement-related side effects and no benefits. Newly developed disease modifying gene therapy for this condition substantially improves motor symptoms. Herein, we describe a case of beneficial treatment response to SSRIs for anxiety in a child post AADC gene therapy. The child was diagnosed with AADC deficiency in infancy during investigations for hypotonia. Between 6 months and 5 years of age, she experienced severe irritability and sleep disturbance, severe hypotonia (no voluntary motor movements or head control, g-tube fed), and several hours of dystonic episodes weekly. At age 5 years, she received gene therapy that delivered an adeno-associated viral gene vector (AAV2-AADC) to the midbrain, resulting in marked improvements in motor function. At age 6 and 7 years, standardized developmental assessment estimated cognitive skills in the 10-month range, and she was diagnosed with autism spectrum disorder and an anxiety disorder. A cautious trial of sertraline 12.5 mg titrated to 75 mg over 4 months was well tolerated and substantially reduced anxiety and emotional lability, without adverse effects. This report is illustrative of the challenges and opportunities posed by genetic therapies, including a need to systematically revisit existing evidence and treatment guidelines in the emerging era of genomic medicine.

Personal preferences for treatment and care during and after a First Episode Psychosis: A qualitative study.

AIM: A first episode of psychosis (FEP) is a stressful, often life-changing experience. Scarce information is available about personal preferences regarding their care needs during and after a FEP. Whereas a more thorough understanding of these preferences is essential to aid shared decision-making during treatment and improve treatment satisfaction. METHODS: Face-to-face interviews with participants in remission of a FEP were set up, addressing personal preferences and needs for care during and after a FEP. The interviews were conducted by a female and a male researcher, the latter being an expert with lived experience. RESULTS: Twenty individuals in remission of a FEP were interviewed, of which 16 had been hospitalized. The distinguished themes based on personal preferences were tranquillity, peace and quietness, information, being understood, support from significant others, and practical guidance in rebuilding one's life. Our findings revealed that the need for information and the need to be heard were often not sufficiently met. For 16/20 participants, the tranquillity of inpatient treatment of the FEP was predominantly perceived as a welcome safe haven. The presence and support of family and close friends were mentioned as an important factor in the process of achieving remission. CONCLUSIONS: The current exploratory study showed that patients were able to indicate their personal needs. Important findings are the need for information and the need to be heard. Interestingly, hospitalization was mostly seen as an opportunity to achieve tranquillity. More lived experience expertise is needed to elucidate the needs of individuals in the early phase of a FEP to aid people who are recovering from their first psychosis in rebuilding their lives again.

Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS.

Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2DS cases. Many of these genes were identified as risk factors for sporadic CHD in the general population. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. The genes KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the TBX1 gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the TBX1 gene network in the etiology of CHD.

Gene copy number variation and pediatric mental health/neurodevelopment in a general population.

We assessed the relationship of gene copy number variation (CNV) in mental health/neurodevelopmental traits and diagnoses, physical health and cognition in a community sample of 7100 unrelated children and youth of European or East Asian ancestry (Spit for Science). Clinically significant or susceptibility CNVs were present in 3.9% of participants and were associated with elevated scores on a continuous measure of attention-deficit/hyperactivity disorder (ADHD) traits (P = 5.0 × 10-3), longer response inhibition (a cognitive deficit found in several mental health and neurodevelopmental disorders; P = 1.0 × 10-2) and increased prevalence of mental health diagnoses (P = 1.9 × 10-6, odds ratio: 3.09), specifically ADHD, autism spectrum disorder anxiety and learning problems/learning disorder (P's < 0.01). There was an increased burden of rare deletions in gene-sets related to brain function or expression in brain associated with more ADHD traits. With the current mental health crisis, our data established a baseline for delineating genetic contributors in pediatric-onset conditions.

Executive functioning in preschoolers with 22q11.2 deletion syndrome and the impact of congenital heart defects.

BACKGROUND: Executive functioning (EF) is an umbrella term for various cognitive functions that play a role in monitoring and planning to effectuate goal-directed behavior. The 22q11.2 deletion syndrome (22q11DS), the most common microdeletion syndrome, is associated with a multitude of both somatic and cognitive symptoms, including EF impairments in school-age and adolescence. However, results vary across different EF domains and studies with preschool children are scarce. As EF is critically associated with later psychopathology and adaptive functioning, our first aim was to study EF in preschool children with 22q11DS. Our second aim was to explore the effect of a congenital heart defects (CHD) on EF abilities, as CHD are common in 22q11DS and have been implicated in EF impairment in individuals with CHD without a syndromic origin. METHODS: All children with 22q11DS (n = 44) and typically developing (TD) children (n = 81) were 3.0 to 6.5 years old and participated in a larger prospective study. We administered tasks measuring visual selective attention, visual working memory, and a task gauging broad EF abilities. The presence of CHD was determined by a pediatric cardiologist based on medical records. RESULTS: Analyses showed that children with 22q11DS were outperformed by TD peers on the selective attention task and the working memory task. As many children were unable to complete the broad EF task, we did not run statistical analyses, but provide a qualitative description of the results. There were no differences in EF abilities between children with 22q11DS with and without CHDs. CONCLUSION: To our knowledge, this is the first study measuring EF in a relatively large sample of young children with 22q11DS. Our results show that EF impairments are already present in early childhood in children with 22q11DS. In line with previous studies with older children with 22q11DS, CHDs do not appear to have an effect on EF performance. These findings might have important implications for early intervention and support the improvement of prognostic accuracy.

Rare coding variants as risk modifiers of the 22q11.2 deletion implicate postnatal cortical development in syndromic schizophrenia.

22q11.2 deletion is one of the strongest known genetic risk factors for schizophrenia. Recent whole-genome sequencing of schizophrenia cases and controls with this deletion provided an unprecedented opportunity to identify risk modifying genetic variants and investigate their contribution to the pathogenesis of schizophrenia in 22q11.2 deletion syndrome. Here, we apply a novel analytic framework that integrates gene network and phenotype data to investigate the aggregate effects of rare coding variants and identified modifier genes in this etiologically homogenous cohort (223 schizophrenia cases and 233 controls of European descent). Our analyses revealed significant additive genetic components of rare nonsynonymous variants in 110 modifier genes (adjusted P = 9.4E-04) that overall accounted for 4.6% of the variance in schizophrenia status in this cohort, of which 4.0% was independent of the common polygenic risk for schizophrenia. The modifier genes affected by rare coding variants were enriched with genes involved in synaptic function and developmental disorders. Spatiotemporal transcriptomic analyses identified an enrichment of coexpression between modifier and 22q11.2 genes in cortical brain regions from late infancy to young adulthood. Corresponding gene coexpression modules are enriched with brain-specific protein-protein interactions of SLC25A1, COMT, and PI4KA in the 22q11.2 deletion region. Overall, our study highlights the contribution of rare coding variants to the SCZ risk. They not only complement common variants in disease genetics but also pinpoint brain regions and developmental stages critical to the etiology of syndromic schizophrenia.

A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome.

Recently, increasing numbers of rare pathogenic genetic variants have been identified that are associated with variably elevated risks of a range of neurodevelopmental outcomes, notably including Autism Spectrum Disorders (ASD), Schizophrenia Spectrum Disorders (SSD), and Intellectual Disability (ID). This review is organized along three main questions: First, how can we unify the exclusively descriptive basis of our current psychiatric diagnostic classification system with the recognition of an identifiable, highly penetrant genetic risk factor in an increasing proportion of patients with ASD or SSD? Second, what can be learned from studies of individuals with ASD or SSD who share a common genetic basis? And third, what accounts for the observed variable penetrance and pleiotropy of neuropsychiatric phenotypes in individuals with the same pathogenic variant? In this review, we focus on findings of clinical and preclinical studies of the 22q11.2 deletion syndrome (22q11DS). This particular variant is not only one of the most common among the increasing list of known rare pathogenic variants, but also one that benefits from a relatively long research history. Consequently, 22q11DS is an appealing model as it allows us to: (1) elucidate specific genotype-phenotype associations, (2) prospectively study behaviorally defined classifications, such as ASD or SSD, in the context of a known, well-characterized genetic basis, and (3) elucidate mechanisms underpinning variable penetrance and pleiotropy, phenomena with far-reaching ramifications for research and clinical practice. We discuss how findings from animal and in vitro studies relate to observations in human studies and can help elucidate factors, including genetic, environmental, and stochastic, that impact the expression of neuropsychiatric phenotypes in 22q11DS, and how this may inform mechanisms underlying neurodevelopmental expression in the general population. We conclude with research priorities for the field, which may pave the way for novel therapeutics.

From Genes to Therapy in Autism Spectrum Disorder.

In recent years, findings from genetic and other biological studies are starting to reveal the role of various molecular mechanisms that contribute to the etiology of ASD [...].

Developing Gene-Based Personalised Interventions in Autism Spectrum Disorders.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with onset in early childhood [...].

Clinical validity assessment of genes frequently tested on intellectual disability/autism sequencing panels.

PURPOSE: Neurodevelopmental disorders (NDDs), such as intellectual disability (ID) and autism spectrum disorder (ASD), exhibit genetic and phenotypic heterogeneity, making them difficult to differentiate without a molecular diagnosis. The Clinical Genome Resource Intellectual Disability/Autism Gene Curation Expert Panel (GCEP) uses systematic curation to distinguish ID/ASD genes that are appropriate for clinical testing (ie, with substantial evidence supporting their relationship to disease) from those that are not. METHODS: Using the Clinical Genome Resource gene-disease validity curation framework, the ID/Autism GCEP classified genes frequently included on clinical ID/ASD testing panels as Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Known Disease Relationship. RESULTS: As of September 2021, 156 gene-disease pairs have been evaluated. Although most (75%) were determined to have definitive roles in NDDs, 22 (14%) genes evaluated had either Limited or Disputed evidence. Such genes are currently not recommended for use in clinical testing owing to the limited ability to assess the effect of identified variants. CONCLUSION: Our understanding of gene-disease relationships evolves over time; new relationships are discovered and previously-held conclusions may be questioned. Without periodic re-examination, inaccurate gene-disease claims may be perpetuated. The ID/Autism GCEP will continue to evaluate these claims to improve diagnosis and clinical care for NDDs.

Assessment of Social Behavior Using a Passive Monitoring App in Cognitively Normal and Cognitively Impaired Older Adults: Observational Study.

BACKGROUND: In people with cognitive impairment, loss of social interactions has a major impact on well-being. Therefore, patients would benefit from early detection of symptoms of social withdrawal. Current measurement techniques such as questionnaires are subjective and rely on recall, in contradiction to smartphone apps, which measure social behavior passively and objectively. OBJECTIVE: This study uses the remote monitoring smartphone app Behapp to assess social behavior, and aims to investigate (1) the association between social behavior, demographic characteristics, and neuropsychiatric symptoms in cognitively normal (CN) older adults, and (2) if social behavior is altered in cognitively impaired (CI) participants. In addition, we explored in a subset of individuals the association between Behapp outcomes and neuropsychiatric symptoms. METHODS: CN, subjective cognitive decline (SCD), and CI older adults installed the Behapp app on their own Android smartphone for 7 to 42 days. CI participants had a clinical diagnosis of mild cognitive impairment (MCI) or Alzheimer-type dementia. The app continuously measured communication events, app use and location. Neuropsychiatric Inventory (NPI) total scores were available for 20 SCD and 22 CI participants. Linear models were used to assess group differences on Behapp outcomes and to assess the association of Behapp outcomes with the NPI. RESULTS: We included CN (n=209), SCD (n=55) and CI (n=22) participants. Older cognitively normal participants called less frequently and made less use of apps (P<.05). No sex effects were found. Compared to the CN and SCD groups, CI individuals called less unique contacts (ß=-0.7 [SE 0.29], P=.049) and contacted the same contacts relatively more often (ß=0.8 [SE 0.25], P=.004). They also made less use of apps (ß=-0.83 [SE 0.25], P=.004). Higher total NPI scores were associated with further traveling (ß=0.042 [SE 0.015], P=.03). CONCLUSIONS: CI individuals show reduced social activity, especially those activities that are related to repeated and unique behavior, as measured by the smartphone app Behapp. Neuropsychiatric symptoms seemed only marginally associated with social behavior as measured with Behapp. This research shows that the Behapp app is able to objectively and passively measure altered social behavior in a cognitively impaired population.

Untargeted metabolic analysis in dried blood spots reveals metabolic signature in 22q11.2 deletion syndrome.

The 22q11.2 deletion syndrome (22q11.2DS) is characterized by a well-defined microdeletion and is associated with increased risk of neurodevelopmental phenotypes including autism spectrum disorders (ASD) and intellectual impairment. The typically deleted region in 22q11.2DS contains multiple genes with the potential of altering metabolism. Deficits in metabolic processes during early brain development may help explain the increased prevalence of neurodevelopmental phenotypes seen in 22q11.2DS. However, relatively little is known about the metabolic impact of the 22q11.2 deletion, while such insight may lead to increased understanding of the etiology. We performed untargeted metabolic analysis in a large sample of dried blood spots derived from 49 22q11.2DS patients and 87 controls, to identify a metabolic signature for 22q11.2DS. We also examined trait-specific metabolomic patterns within 22q11.2DS patients, focusing on intelligence (intelligence quotient, IQ) and ASD. We used the Boruta algorithm to select metabolites distinguishing patients from controls, patients with ASD from patients without, and patients with an IQ score in the lowest range from patients with an IQ score in the highest range. The relevance of the selected metabolites was visualized with principal component score plots, after which random forest analysis and logistic regression were used to measure predictive performance of the selected metabolites. Analysis yielded a distinct metabolic signature for 22q11.2DS as compared to controls, and trait-specific (IQ and ASD) metabolomic patterns within 22q11.2DS patients. The metabolic characteristics of 22q11.2DS provide insights in biological mechanisms underlying the neurodevelopmental phenotype and may ultimately aid in identifying novel therapeutic targets for patients with developmental disorders.

Genes To Mental Health (G2MH): A Framework to Map the Combined Effects of Rare and Common Variants on Dimensions of Cognition and Psychopathology.

Rare genomic disorders (RGDs) confer elevated risk for neurodevelopmental psychiatric disorders. In this era of intense genomics discoveries, the landscape of RGDs is rapidly evolving. However, there has not been comparable progress to date in scalable, harmonized phenotyping methods. As a result, beyond associations with categorical diagnoses, the effects on dimensional traits remain unclear for many RGDs. The nature and specificity of RGD effects on cognitive and behavioral traits is an area of intense investigation: RGDs are frequently associated with more than one psychiatric condition, and those studied to date affect, to varying degrees, a broad range of developmental and cognitive functions. Although many RGDs have large effects, phenotypic expression is typically influenced by additional genomic and environmental factors. There is emerging evidence that using polygenic risk scores in individuals with RGDs offers opportunities to refine prediction, thus allowing for the identification of those at greatest risk of psychiatric illness. However, translation into the clinic is hindered by roadblocks, which include limited genetic testing in clinical psychiatry, and the lack of guidelines for following individuals with RGDs, who are at high risk of developing psychiatric symptoms. The Genes to Mental Health Network (G2MH) is a newly funded National Institute of Mental Health initiative that will collect, share, and analyze large-scale data sets combining genomics and dimensional measures of psychopathology spanning diverse populations and geography. The authors present here the most recent understanding of the effects of RGDs on dimensional behavioral traits and risk for psychiatric conditions and discuss strategies that will be pursued within the G2MH network, as well as how expected results can be translated into clinical practice to improve patient outcomes.

A Regional Burden of Sequence-Level Variation in the 22q11.2 Region Influences Schizophrenia Risk and Educational Attainment.

BACKGROUND: Genomic loci where recurrent pathogenic copy number variants are associated with psychiatric phenotypes in the population may also be sensitive to the collective impact of multiple functional low-frequency single nucleotide variants (SNVs). METHODS: We examined the cumulative impact of low-frequency, functional SNVs within the 22q11.2 region on schizophrenia risk in a discovery cohort and an independent replication cohort (N = 1933 and N = 11,128, respectively), as well as the impact on educational attainment (EA) in a third, independent, general population cohort (N = 2081). In the discovery and EA cohorts, SNVs were identified using genotyping arrays; in the replication cohort, whole-exome sequencing was available. For verification, we compared the regional SNV count for schizophrenia cases in the discovery cohort with a normative count distribution derived from a large population dataset (N = 26,500) using bootstrap procedures. RESULTS: In both schizophrenia cohorts, an increased regional SNV burden (≥4 low-frequency SNVs) in the 22q11.2 region was associated with schizophrenia (discovery cohort: odds ratio = 7.48, p = .039; replication cohort: odds ratio = 1.92, p = .004). In the EA cohort, an increased regional SNV burden at 22q11.2 was associated with decreased EA (odds ratio = 4.65, p = .049). Comparing the SNV count for schizophrenia cases with a normative distribution confirmed the unique nature of the distribution for schizophrenia cases (p = .002). CONCLUSIONS: In the general population, an increased burden of low-frequency, functional SNVs in the 22q11.2 region is associated with schizophrenia risk and a decrease in EA. These findings suggest that in addition to structural variation, a cumulative regional burden of low-frequency, functional SNVs in the 22q11.2 region can also have a relevant phenotypic impact.

Within-family influences on dimensional neurobehavioral traits in a high-risk genetic model.

BACKGROUND: Genotype-first and within-family studies can elucidate factors that contribute to psychiatric illness. Combining these approaches, we investigated the patterns of influence of parental scores, a high-impact variant, and schizophrenia on dimensional neurobehavioral phenotypes implicated in major psychiatric disorders. METHODS: We quantitatively assessed cognitive (FSIQ, VIQ, PIQ), social, and motor functioning in 82 adult individuals with a de novo 22q11.2 deletion (22 with schizophrenia), and 148 of their unaffected parents. We calculated within-family correlations and effect sizes of the 22q11.2 deletion and schizophrenia, and used linear regressions to assess contributions to neurobehavioral measures. RESULTS: Proband-parent intra-class correlations (ICC) were significant for cognitive measures (e.g. FSIQ ICC = 0.549, p < 0.0001), but not for social or motor measures. Compared to biparental scores, the 22q11.2 deletion conferred significant impairments for all phenotypes assessed (effect sizes -1.39 to -2.07 s.d.), strongest for PIQ. There were further decrements in those with schizophrenia. Regression models explained up to 37.7% of the variance in IQ and indicated that for proband IQ, parental IQ had larger effects than schizophrenia. CONCLUSIONS: This study, for the first time, disentangles the impact of a high-impact variant from the modifying effects of parental scores and schizophrenia on relevant neurobehavioral phenotypes. The robust proband-parent correlations for cognitive measures, independent of the impact of the 22q11.2 deletion and of schizophrenia, suggest that, for certain phenotypes, shared genetic variation plays a significant role in expression. Molecular genetic and predictor studies are needed to elucidate shared factors and their contribution to psychiatric illness in this and other high-risk groups.

Harnessing rare variants in neuropsychiatric and neurodevelopment disorders-a Keystone Symposia report.

Neurodevelopmental neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia, have strong genetic risk components, but the underlying mechanisms have proven difficult to decipher. Rare, high-risk variants may offer an opportunity to delineate the biological mechanisms responsible more clearly for more common idiopathic diseases. Indeed, different rare variants can cause the same behavioral phenotype, demonstrating genetic heterogeneity, while the same rare variant can cause different behavioral phenotypes, demonstrating variable expressivity. These observations suggest convergent underlying biological and neurological mechanisms; identification of these mechanisms may ultimately reveal new therapeutic targets. At the 2021 Keystone eSymposium "Neuropsychiatric and Neurodevelopmental Disorders: Harnessing Rare Variants" a panel of experts in the field described significant progress in genomic discovery and human phenotyping and raised several consistent issues, including the need for detailed natural history studies of rare disorders, the challenges in cohort recruitment, and the importance of viewing phenotypes as quantitative traits that are impacted by rare variants.

Neurodevelopmental Trajectories and Psychiatric Morbidity: Lessons Learned From the 22q11.2 Deletion Syndrome.

PURPOSE OF REVIEW: The 22q11.2 deletion syndrome (22q11DS) is associated with a broad spectrum of neurodevelopmental phenotypes and is the strongest known single genetic risk factor for schizophrenia. Compared to other rare structural pathogenic genetic variants, 22q11DS is relatively common and one of the most extensively studied. This review provides a state-of-the-art overview of current insights regarding associated neurodevelopmental phenotypes and potential implications for 22q11DS and beyond. RECENT FINDINGS: We will first discuss recent findings with respect to neurodevelopmental phenotypic expression associated with 22q11DS, including psychotic disorders, intellectual functioning, autism spectrum disorders, as well as their interactions. Second, we will address considerations that are important in interpreting these data and propose potential implications for both the clinical care for and the empirical study of individuals with 22q11DS. Third, we will highlight variable penetrance and pleiotropy with respect to neurodevelopmental phenotypes in 22q11DS. We will discuss how these phenomena are consistently observed in the context of virtually all rare pathogenic variants and that they pose substantial challenges from both a clinical and a research perspective. We outline how 22q11DS could be viewed as a genetic model for studying neurodevelopmental phenotypes. In addition, we propose that 22q11DS research can help elucidate mechanisms underlying variable expression and pleiotropy of neurodevelopmental phenotypes, insights that are likely relevant for 22q11DS and beyond, including for individuals with other rare pathogenic genetic variants and for individuals with idiopathic neurodevelopmental conditions.

Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion.

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10-6). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.