Multiple paralogues and recombination mechanisms drive the high incidence of 22q11.2 Deletion Syndrome.

The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder. Why the incidence of 22q11.2DS is much greater than that of other genomic disorders remains unknown. Short read sequencing cannot resolve the complex segmental duplicon structure to provide direct confirmation of the hypothesis that the rearrangements are caused by non-allelic homologous recombination between the low copy repeats on chromosome 22 (LCR22s). To enable haplotype-specific assembly and rearrangement mapping in LCR22 regions, we combined fiber-FISH optical mapping with whole genome (ultra-)long read sequencing or rearrangement-specific long-range PCR on 24 duos (22q11.2DS patient and parent-of-origin) comprising several different LCR22-mediated rearrangements. Unexpectedly, we demonstrate that not only different paralogous segmental duplicon but also palindromic AT-rich repeats (PATRR) are driving 22q11.2 rearrangements. In addition, we show the existence of two different inversion polymorphisms preceding rearrangement, and somatic mosaicism. The existence of different recombination sites and mechanisms in paralogues and PATRRs which are copy number expanding in the human population are a likely explanation for the high 22q11.2DS incidence.

Young adults with a 22q11.2 microdeletion and the cost of aging with complexity in a population-based context.

PURPOSE: Information about the impact on the adult health care system is limited for complex rare pediatric diseases, despite their increasing collective prevalence that has paralleled advances in clinical care of children. Within a population-based health care context, we examined costs and multimorbidity in adults with an exemplar of contemporary genetic diagnostics. METHODS: We estimated direct health care costs over an 18-year period for adults with molecularly confirmed 22q11.2 microdeletion (cases) and matched controls (total 60,459 person-years of data) by linking the case cohort to health administrative data for the Ontario population (∼15 million people). We used linear regression to compare the relative ratio (RR) of costs and to identify baseline predictors of higher costs. RESULTS: Total adult (age ≥ 18) health care costs were significantly higher for cases compared with population-based (RR 8.5, 95% CI 6.5-11.1) controls, and involved all health care sectors. At study end, when median age was <30 years, case costs were comparable to population-based individuals aged 72 years, likelihood of being within the top 1st percentile of health care costs for the entire (any age) population was significantly greater for cases than controls (odds ratio [OR], for adults 17.90, 95% CI 7.43-43.14), and just 8 (2.19%) cases had a multimorbidity score of zero (vs 1483 (40.63%) controls). The 22q11.2 microdeletion was a significant predictor of higher overall health care costs after adjustment for baseline variables (RR 6.9, 95% CI 4.6-10.5). CONCLUSION: The findings support the possible extension of integrative models of complex care used in pediatrics to adult medicine and the potential value of genetic diagnostics in adult clinical medicine.

Polygenic risk for triglyceride levels in the presence of a high impact rare variant.

BACKGROUND: Elevated triglyceride (TG) levels are a heritable and modifiable risk factor for cardiovascular disease and have well-established associations with common genetic variation captured in a polygenic risk score (PRS). In young adulthood, the 22q11.2 microdeletion conveys a 2-fold increased risk for mild-moderate hypertriglyceridemia. This study aimed to assess the role of the TG-PRS in individuals with this elevated baseline risk for mild-moderate hypertriglyceridemia. METHODS: We studied a deeply phenotyped cohort of adults (n = 157, median age 34 years) with a 22q11.2 microdeletion and available genome sequencing, lipid level, and other clinical data. The association between a previously developed TG-PRS and TG levels was assessed using a multivariable regression model adjusting for effects of sex, BMI, and other covariates. We also constructed receiver operating characteristic (ROC) curves using logistic regression models to assess the ability of TG-PRS and significant clinical variables to predict mild-moderate hypertriglyceridemia status. RESULTS: The TG-PRS was a significant predictor of TG-levels (p = 1.52E-04), along with male sex and BMI, in a multivariable model (pmodel = 7.26E-05). The effect of TG-PRS appeared to be slightly stronger in individuals with obesity (BMI ≥ 30) (beta = 0.4617) than without (beta = 0.1778), in a model unadjusted for other covariates (p-interaction = 0.045). Among ROC curves constructed, the inclusion of TG-PRS, sex, and BMI as predictor variables produced the greatest area under the curve (0.749) for classifying those with mild-moderate hypertriglyceridemia, achieving an optimal sensitivity and specificity of 0.746 and 0.707, respectively. CONCLUSIONS: These results demonstrate that in addition to significant effects of sex and BMI, genome-wide common variation captured in a PRS also contributes to the variable expression of the 22q11.2 microdeletion with respect to elevated TG levels.

Adult-onset obstructive sleep apnea and pediatric pharyngoplasty in 22q11.2 deletion syndrome.

OBJECTIVE/BACKGROUND: We aimed to evaluate adult-onset obstructive sleep apnea (OSA) and related risk factors, including history of pediatric palatal/pharyngeal surgery to remediate velopharyngeal dysfunction, in 22q11.2 deletion syndrome (22q11.2DS). PATIENTS/METHODS: Using a retrospective cohort design and standard sleep study-based criteria, we determined presence of adult-onset OSA (age ≥16 years) and relevant variables through comprehensive chart review in a well-characterized cohort of 387 adults with typical 22q11.2 microdeletions (51.4% female, median age 32.3, interquartile range 25.0-42.5, years). We used multivariate logistic regression to identify independent risk factors for OSA. RESULTS: Of the 73 adults with sleep study data, 39 (53.4%) met criteria for OSA at median age 33.6 (interquartile range 24.0-40.7) years, indicating a minimum OSA prevalence of 10.1% in this 22q11.2DS cohort. History of pediatric pharyngoplasty (odds ratio 2.56, 95% confidence interval 1.15-5.70) was a significant independent predictor of adult-onset OSA, while accounting for other significant independent predictors (asthma, higher body mass index, older age), and for male sex. An estimated 65.5% of those prescribed continuous positive airway pressure therapy were reported as adherent. CONCLUSIONS: In addition to factors of known importance in the general population, delayed effects of pediatric pharyngoplasty may contribute to risk of adult-onset OSA in individuals with 22q11.2DS. The results support increased index of suspicion for OSA in adults with a 22q11.2 microdeletion. Future research with this and other homogeneous genetic models may help to improve outcomes and to better understand genetic and modifiable risk factors for OSA.

Elevated regional cerebral blood flow in adults with 22q11.2 deletion syndrome.

OBJECTIVES: Recurrent chromosome 22q11.2 deletions cause 22q11 deletion syndrome (22q11DS), a multisystem disorder associated with high rates of schizophrenia. Neuroanatomical changes on brain MRI have been reported in relation to 22q11DS. However, to date no 22q11DS neuroimaging studies have examined cerebral blood flow (CBF). This exploratory case-control study seeks to identify differences in regional cerebral blood flow between 22q11DS subjects and controls, and their association with psychotic symptoms. METHODS: This study of 23 adults used arterial spin labelling MRI to investigate voxel-wise CBF in 22q11DS individuals compared with age- and sex-matched healthy controls. RESULTS: Four significant clusters, involving the right and left putamen, right fusiform gyrus and left middle temporal gyrus, delineated significantly elevated CBF in individuals with 22q11DS compared to controls. Post-hoc analysis determined that this elevation in CBF trended with psychotic symptom diagnosis within the 22q11DS group. CONCLUSIONS: These findings suggest possible relevance to schizophrenia risk and support further functional neuroimaging studies of 22q11DS with larger sample sizes to improve our understanding of the underlying pathophysiology.

Reproductive Outcomes in Adults with 22q11.2 Deletion Syndrome.

The 22q11.2 microdeletion and its associated conditions could affect reproductive outcomes but there is limited information on this important area. We investigated reproductive outcomes in a sample of 368 adults with typical 22q11.2 deletions (median age 32.8, range 17.9-76.3 years; 195 females), and without moderate-severe intellectual disability, who were followed prospectively. We examined all reproductive outcomes and possible effects of diagnosis as a transmitting parent on these outcomes. We used logistic regression to investigate factors relevant to reproductive fitness (liveborn offspring). There were 63 (17.1%) individuals with 157 pregnancy outcomes, 94 (60.3%) of which involved live births. Amongst the remainder involving a form of loss, were seven (5.77%) stillbirths, significantly greater than population norms (p < 0.0001). For 35 (55.6%) individuals, diagnosis of 22q11.2 deletion syndrome (22q11.2DS) followed diagnosis of an offspring, with disproportionately fewer individuals had major congenital heart disease (CHD) in that transmitting parent subgroup. The regression model indicated that major CHD, in addition to previously identified factors, was a significant independent predictor of reduced reproductive fitness. There was evidence of persisting diagnostic delay and limited prenatal genetic testing. The findings indicate that pregnancy loss is an important health issue for adults with 22q11.2DS. CHD and/or its absence is a factor to consider in reproductive outcome research. Further studies are warranted to better appreciate factors that may contribute to reproductive outcomes, including technological advances. The results suggest the need for ongoing efforts to provide optimal education and supports to individuals with 22q11.2DS, and their clinicians, around reproductive issues and early diagnosis.

Adult Height, 22q11.2 Deletion Extent, and Short Stature in 22q11.2 Deletion Syndrome.

The 22q11.2 deletion syndrome (22q11.2DS) manifests as a wide range of medical conditions across a number of systems. Pediatric growth deficiency with some catch-up growth is reported, but there are few studies of final adult height. We aimed to investigate how final adult height in 22q11.2DS compared with general population norms, and to examine predictors of short stature in in a cohort of 397 adults with 22q11.2DS (aged 17.6-76.3 years) with confirmed typical 22q11.2 microdeletion (overlapping the LCR22A to LCR22B region). We defined short stature as <3rd percentile using population norms. For the subset (n = 314, 79.1%) with 22q11.2 deletion extent, we used a binomial logistic regression model to predict short stature in 22q11.2DS, accounting for effects of sex, age, ancestry, major congenital heart disease (CHD), moderate-to-severe intellectual disability (ID), and 22q11.2 deletion extent. Adult height in 22q11.2DS showed a normal distribution but with a shift to the left, compared with population norms. Those with short stature represented 22.7% of the 22q11.2DS sample, 7.6-fold greater than population expectations (p < 0.0001). In the regression model, moderate-to-severe ID, major CHD, and the common LCR22A-LCR22D (A-D) deletion were significant independent risk factors for short stature while accounting for other factors (model p = 0.0004). The results suggest that the 22q11.2 microdeletion has a significant effect on final adult height distribution, and on short stature with effects appearing to arise from reduced gene dosage involving both the proximal and distal sub-regions of the A-D region. Future studies involving larger sample sizes with proximal nested 22q11.2 deletions, longitudinal lifetime data, parental heights, and genotype data will be valuable.

Influence of Parent-of-Origin on Intellectual Outcomes in the Chromosome 22q11.2 Deletion Syndrome.

Learning and intellectual disabilities are hallmark features of 22q11.2 deletion syndrome. Data are limited, however, regarding influences on full-scale IQ (FSIQ). Here, we investigated possible 22q11.2 deletion parent-of-origin effects. In 535 individuals, we compared FSIQ (≥50), 481 with de novo and 54 with inherited 22q11.2 deletions. In the subsets with data available, we examined parent-of-origin effects on FSIQ. We used linear regression models to account for covariates. Median FSIQ was significantly higher in de novo vs. inherited deletions (77; range 50−116 vs. 67; range 50−96, p < 0.0001). Results remained significant using a regression model accounting for age at IQ testing, sex and cohort site. No significant parent-of-origin differences in FSIQ were observed for de novo deletions (n = 81, 63.0% maternal; p = 0.6882). However, median FSIQ was significantly lower in maternally than in paternally inherited familial deletions (65, range 50−86 vs. 71.5, range 58−96, respectively, p = 0.0350), with the regression model indicating an ~8 point decrement in FSIQ for this variable (p = 0.0061). FSIQ is higher on average in de novo than in inherited 22q11.2 deletions, regardless of parental origin. However, parent-of-origin appears relevant in inherited deletions. The results have potential clinical implications with further research needed to delineate possible actionable mechanisms.

Hypertriglyceridemia in young adults with a 22q11.2 microdeletion.

Objective: Mild to moderate hypertriglyceridemia is a condition often associated with obesity and diabetes, with as yet incomplete knowledge of underlying genetic architecture. The 22q11.2 microdeletion is associated with multimorbidity, including increased risk of obesity and diabetes. In this study, we sought to investigate whether the 22q11.2 microdeletion was associated with mild to moderate hypertriglyceridemia (1.7-10 mmol/L). Design: This was a cohort study comparing 6793 population-based adults and 267 with a 22q11.2 microdeletion aged 17-69 years, excluding those with diabetes or on statins. Methods: We used binomial logistic regression modeling to identify predictors of hypertriglyceridemia, accounting for the 22q11.2 microdeletion, male sex, BMI, ethnicity, age, and antipsychotic medications. Results: The 22q11.2 microdeletion was a significant independent predictor of mild to moderate hypertriglyceridemia (odds ratio (OR): 2.35, 95% CI: 1.70-3.26). All other factors examined were also significant predictors (OR: 1.23-2.10), except for antipsychotic medication use. Within the 22q11.2 microdeletion subgroup, only male sex (OR: 3.10, 95% CI: 1.77-5.44) and BMI (OR: 1.63, 95% CI: 1.14-1.98) were significant predictors of hypertriglyceridemia, evident at mean age 31.2 years. Conclusions: The 22q11.2 microdeletion is associated with hypertriglyceridemia even when accounting for other known risk factors for elevated triglycerides. This effect is seen in young adulthood (76.6% were <40 years), in the absence of diabetes, and irrespective of antipsychotics, suggesting that the 22q11.2 microdeletion may represent an unrecognized genetic risk factor for hypertriglyceridemia, providing novel opportunities for animal and cellular models. Early dyslipidemia screening and management strategies would appear prudent for individuals with 22q11.2 microdeletions.

Genome-wide tandem repeat expansions contribute to schizophrenia risk.

Tandem repeat expansions (TREs) can cause neurological diseases but their impact in schizophrenia is unclear. Here we analyzed genome sequences of adults with schizophrenia and found that they have a higher burden of TREs that are near exons and rare in the general population, compared with non-psychiatric controls. These TREs are disproportionately found at loci known to be associated with schizophrenia from genome-wide association studies, in individuals with clinically-relevant genetic variants at other schizophrenia loci, and in families where multiple individuals have schizophrenia. We showed that rare TREs in schizophrenia may impact synaptic functions by disrupting the splicing process of their associated genes in a loss-of-function manner. Our findings support the involvement of genome-wide rare TREs in the polygenic nature of schizophrenia.

Schizophrenia Risk Mediated by microRNA Target Genes Overlapped by Genome-Wide Rare Copy Number Variation in 22q11.2 Deletion Syndrome.

The 22q11.2 deletion is associated with >20-fold increased risk for schizophrenia. The presence of gene DGCR8 in the 22q11.2 deletion region has suggested microRNA (miRNA) dysregulation as possibly contributing to this risk. We therefore investigated the role of miRNA target genes in the context of previously identified genome-wide risk for schizophrenia conveyed by additional copy number variation (CNV) in 22q11.2 deletion syndrome (22q11.2DS). Using a cohort of individuals with 22q11.2DS and documented additional rare CNVs overlapping protein coding genes, we compared those with schizophrenia (n = 100) to those with no psychotic illness (n = 118), assessing for rare CNVs that overlapped experimentally supported miRNA target genes. We further characterized the contributing miRNA target genes using gene set enrichment analyses and identified the miRNAs most implicated. Consistent with our hypothesis, we found a significantly higher proportion of individuals in the schizophrenia than in the non-psychotic group to have an additional rare CNV that overlapped one or more miRNA target genes (odds ratio = 2.12, p = 0.0138). Gene set analyses identified an enrichment of FMRP targets and genes involved in nervous system development and postsynaptic density amongst these miRNA target genes in the schizophrenia group. The miRNAs most implicated included miR-17-5p, miR-34a-5p and miR-124-3p. These results provide initial correlational evidence in support of a possible role for miRNA perturbation involving genes affected by rare genome-wide CNVs in the elevated risk for schizophrenia in 22q11.2DS, consistent with the multi-hit and multi-layered genetic mechanisms implicated in this and other forms of schizophrenia.

Biallelic PAN2 variants in individuals with a syndromic neurodevelopmental disorder and multiple congenital anomalies.

PAN2 encodes a subunit of a deadenylation complex with important functions in mRNA stability and post-transcriptional regulation of gene expression. A homozygous frameshift deletion in PAN2 was reported in a single affected individual with developmental delay and multiple congenital anomalies. Here, we describe five additional individuals from three unrelated families with homozygous predicted loss-of-function variants in PAN2. The affected individuals presented with significant overlap in their clinical features, including mild-moderate intellectual disability, hypotonia, sensorineural hearing loss, EEG abnormalities, congenital heart defects (tetralogy of Fallot, septal defects, dilated aortic root), urinary tract malformations, ophthalmological anomalies, short stature with other skeletal anomalies, and craniofacial features including flat occiput, ptosis, long philtrum, and short neck. Our data confirm that biallelic predicted loss-of-function variants in PAN2 cause a syndrome with multiple congenital anomalies, and suggest an important role of mRNA polyA tail length for proper organ formation.

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.

Sexual knowledge and behaviour in 22q11.2 deletion syndrome, a complex care condition.

BACKGROUND: There is limited information about sexual knowledge and behaviours in adults with complex care needs, including those with 22q11.2 deletion syndrome (22q) which represents a group predisposed to intellectual disabilities. METHODS: We conducted sexual health assessments with 67 adults with 22q, examining whether those with knowledge deficits and a history of engaging in sexual activities with others would be more likely to engage in high-risk behaviours. RESULTS: The majority (65.7%) of adults with 22q were sexually active with others; most (70.1%) had sexual knowledge deficits. Those with intellectual disabilities were more likely (p = .0012) to have deficits in certain topics. In the sexually active subgroup, most (81.8%) engaged in high-risk sexual behaviours, regardless of intellectual disability or knowledge deficits. CONCLUSION: The results suggest a need for increased dialogue, repeated education, genetic counselling and preventive healthcare measures related to sexuality in 22q and potentially in other complex care conditions.

Estimate of the contemporary live-birth prevalence of recurrent 22q11.2 deletions: a cross-sectional analysis from population-based newborn screening.

BACKGROUND: Although pathogenic 22q11.2 deletions are an important cause of developmental delays and lifelong disease burden, their variable and complex clinical expression contributes to under-recognition, delayed molecular diagnosis and uncertainty about prevalence. We sought to estimate the contemporary live-birth prevalence of typical 22q11.2 deletions using a population-based newborn screening sample and to examine data available for associated clinical features. METHODS: Using DNA available from an unbiased sample of about 12% of all dried blood spots collected for newborn screening in Ontario between January 2017 and September 2018, we prospectively screened for 22q11.2 deletions using multiplex quantitative polymerase chain reaction assays and conducted independent confirmatory studies. We used cross-sectional analyses to compare available clinical and T-cell receptor excision circle (TREC, used in newborn screening for severe combined immunodeficiency) data between samples with and without 22q11.2 deletions. RESULTS: The estimated minimum prevalence of 22q11.2 deletions was 1 in 2148 (4.7 per 10 000) live births (95% confidence interval [CI] 2.5 to 7.8 per 10 000), based on a total of 30 074 samples screened, with 14 having confirmed 22q11.2 deletions. Of term singletons, samples with 22q11.2 deletions had significantly younger median maternal age (25.5 v. 32.0 yr, difference -6.5 yr, 95% CI -7 to -2 yr), a greater proportion with small birth weight for gestational age (odds ratio 7.00, 95% CI 2.36 to 23.18) and lower median TREC levels (108.9 v. 602.5 copies/3 µL, p < 0.001). INTERPRETATION: These results indicate that the 22q11.2 deletion syndrome is one of the most common of rare genetic conditions and may be associated with relatively younger maternal ages and with prenatal growth abnormalities. The findings support the public health importance of early - prenatal and neonatal - diagnosis that would enable prompt screening for and management of well-known actionable features associated with 22q11.2 deletions.

Genome sequencing broadens the range of contributing variants with clinical implications in schizophrenia.

The range of genetic variation with potential clinical implications in schizophrenia, beyond rare copy number variants (CNVs), remains uncertain. We therefore analyzed genome sequencing data for 259 unrelated adults with schizophrenia from a well-characterized community-based cohort previously examined with chromosomal microarray for CNVs (none with 22q11.2 deletions). We analyzed these genomes for rare high-impact variants considered causal for neurodevelopmental disorders, including single-nucleotide variants (SNVs) and small insertions/deletions (indels), for potential clinical relevance based on findings for neurodevelopmental disorders. Also, we investigated a novel variant type, tandem repeat expansions (TREs), in 45 loci known to be associated with monogenic neurological diseases. We found several of these variants in this schizophrenia population suggesting that these variants have a wider clinical spectrum than previously thought. In addition to known pathogenic CNVs, we identified 11 (4.3%) individuals with clinically relevant SNVs/indels in genes converging on schizophrenia-relevant pathways. Clinical yield was significantly enriched in females and in those with broadly defined learning/intellectual disabilities. Genome analyses also identified variants with potential clinical implications, including TREs (one in DMPK; two in ATXN8OS) and ultra-rare loss-of-function SNVs in ZMYM2 (a novel candidate gene for schizophrenia). Of the 233 individuals with no pathogenic CNVs, we identified rare high-impact variants (i.e., clinically relevant or with potential clinical implications) for 14 individuals (6.0%); some had multiple rare high-impact variants. Mean schizophrenia polygenic risk score was similar between individuals with and without clinically relevant rare genetic variation; common variants were not sufficient for clinical application. These findings broaden the individual and global picture of clinically relevant genetic risk in schizophrenia, and suggest the potential translational value of genome sequencing as a single genetic technology for schizophrenia.

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.

22q11.2 microdeletion and increased risk for type 2 diabetes.

BACKGROUND: The 22q11.2 microdeletion is the pathogenic copy number variation (CNV) associated with 22q11.2 deletion syndrome (22q11.2DS, formerly known as DiGeorge syndrome). Familiar endocrinological manifestations include hypoparathyroidism and hypothyroidism, with recent elucidation of elevated risk for obesity in adults. In this study, we aimed to determine whether adults with 22q11.2DS have an increased risk of developing type 2 diabetes (T2D). METHODS: We studied the effect of the 22q11.2 microdeletion on risk for T2D, defined by history and glycosylated hemoglobin (HbA1c), using weighted survey data from the adult Canadian population (based on n = 11,874) and from a clinical cohort of adults with 22q11.2DS (n = 314), aged 17-69 years. Binomial logistic regression models accounted for age, sex, non-European ethnicity, family history of T2D, obesity, and antipsychotic medication use. FINDINGS: The 22q11.2 microdeletion was a significant independent risk factor for T2D (OR 2·44, 95% CI 1·39-4·31), accounting for other factors (p < 0·0001). All factors except sex were also significant within 22q11.2DS. The median age at diagnosis of T2D was significantly younger in 22q11.2DS than in the Canadian population sample (32 vs 50 years, p < 0·0001). In adults without T2D, HbA1c was significantly higher in 22q11.2DS than the population (p = 0·042), after accounting for younger age of the 22q11.2DS group. INTERPRETATION: The results support the 22q11.2 microdeletion as a novel independent risk factor and potential model for early onset T2D. The findings complement emerging evidence that rare CNVs may contribute to risk for T2D. The results have implications for precision medicine and research into the underlying pathogenesis of T2D.

Genes and Pathways Implicated in Tetralogy of Fallot Revealed by Ultra-Rare Variant Burden Analysis in 231 Genome Sequences.

Recent genome-wide studies of rare genetic variants have begun to implicate novel mechanisms for tetralogy of Fallot (TOF), a severe congenital heart defect (CHD). To provide statistical support for case-only data without parental genomes, we re-analyzed genome sequences of 231 individuals with TOF (n = 175) or related CHD. We adapted a burden test originally developed for de novo variants to assess ultra-rare variant burden in individual genes, and in gene-sets corresponding to functional pathways and mouse phenotypes, accounting for highly correlated gene-sets and for multiple testing. For truncating variants, the gene burden test confirmed significant burden in FLT4 (Bonferroni corrected p-value < 0.01). For missense variants, burden in NOTCH1 achieved genome-wide significance only when restricted to constrained genes (i.e., under negative selection, Bonferroni corrected p-value = 0.004), and showed enrichment for variants affecting the extracellular domain, especially those disrupting cysteine residues forming disulfide bonds (OR = 39.8 vs. gnomAD). Individuals with NOTCH1 ultra-rare missense variants, all with TOF, were enriched for positive family history of CHD. Other genes not previously implicated in CHD had more modest statistical support in gene burden tests. Gene-set burden tests for truncating variants identified a cluster of pathways corresponding to VEGF signaling (FDR = 0%), and of mouse phenotypes corresponding to abnormal vasculature (FDR = 0.8%); these suggested additional candidate genes not previously identified (e.g., WNT5A and ZFAND5). Results for the most promising genes were driven by the TOF subset of the cohort. The findings support the importance of ultra-rare variants disrupting genes involved in VEGF and NOTCH signaling in the genetic architecture of TOF, accounting for 11-14% of individuals in the TOF cohort. These proof-of-principle data indicate that this statistical methodology could assist in analyzing case-only sequencing data in which ultra-rare variants, whether de novo or inherited, contribute to the genetic etiopathogenesis of a complex disorder.