Systematic analysis of variants escaping nonsense-mediated decay uncovers candidate Mendelian diseases.

Protein-truncating variants (PTVs) near the 3' end of genes may escape nonsense-mediated decay (NMD). PTVs in the NMD-escape region (PTVescs) can cause Mendelian disease but are difficult to interpret given their varying impact on protein function. Previously, PTVesc burden was assessed in an epilepsy cohort, but no large-scale analysis has systematically evaluated these variants in rare disease. We performed a retrospective analysis of 29,031 neurodevelopmental disorder (NDD) parent-offspring trios referred for clinical exome sequencing to identify PTVesc de novo mutations (DNMs). We identified 1,376 PTVesc DNMs and 133 genes that were significantly enriched (binomial p < 0.001). The PTVesc-enriched genes included those with PTVescs previously described to cause dominant Mendelian disease (e.g., SEMA6B, PPM1D, and DAGLA). We annotated ClinVar variants for PTVescs and identified 948 genes with at least one high-confidence pathogenic variant. Twenty-two known Mendelian PTVesc-enriched genes had no prior evidence of PTVesc-associated disease. We found 22 additional PTVesc-enriched genes that are not well established to be associated with Mendelian disease, several of which showed phenotypic similarity between individuals harboring PTVesc variants in the same gene. Four individuals with PTVesc mutations in RAB1A had similar phenotypes including NDD and spasticity. PTVesc mutations in IRF2BP1 were found in two individuals who each had severe immunodeficiency manifesting in NDD. Three individuals with PTVesc mutations in LDB1 all had NDD and multiple congenital anomalies. Using a large-scale, systematic analysis of DNMs, we extend the mutation spectrum for known Mendelian disease-associated genes and identify potentially novel disease-associated genes.

Insufficient Evidence for "Autism-Specific" Genes.

Despite evidence that deleterious variants in the same genes are implicated across multiple neurodevelopmental and neuropsychiatric disorders, there has been considerable interest in identifying genes that, when mutated, confer risk that is largely specific for autism spectrum disorder (ASD). Here, we review the findings and limitations of recent efforts to identify relatively "autism-specific" genes, efforts which focus on rare variants of large effect size that are thought to account for the observed phenotypes. We present a divergent interpretation of published evidence; discuss practical and theoretical issues related to studying the relationships between rare, large-effect deleterious variants and neurodevelopmental phenotypes; and describe potential future directions of this research. We argue that there is currently insufficient evidence to establish meaningful ASD specificity of any genes based on large-effect rare-variant data.

Consolidation of the clinical and genetic definition of a SOX4-related neurodevelopmental syndrome.

BACKGROUND: A neurodevelopmental syndrome was recently reported in four patients with SOX4 heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate clinical and genetic knowledge of this syndrome. METHODS: We newly identified 17 patients with SOX4 variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients' phenotypes. RESULTS: All variants were novel, distinct and heterozygous. Seven HMG-domain missense and five stop-gain variants were classified as pathogenic or likely pathogenic variant (L/PV) as they precluded SOX4 transcriptional activity in vitro. Five HMG-domain and non-HMG-domain missense variants were classified as of uncertain significance (VUS) due to negative results from functional tests. When known, inheritance was de novo or from a mosaic unaffected or non-mosaic affected parent for patients with L/PV, and from a non-mosaic asymptomatic or affected parent for patients with VUS. All patients had neurodevelopmental, neurological and dysmorphic features, and at least one cardiovascular, ophthalmological, musculoskeletal or other somatic anomaly. Patients with L/PV were overall more affected than patients with VUS. They resembled patients with other neurodevelopmental diseases, including the SOX11-related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS. CONCLUSION: These findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due to SOX4 haploinsufficiency in neurogenesis and multiple other developmental processes.

Factors Affecting Interfacility Transport Intervals in Stroke Patients Transferred for Endovascular Therapy.

OBJECTIVE: To describe interfacility transfer (IFT) intervals, transfer vehicle type, and levels of care in patients with large vessel occlusion (LVO) strokes transferred for emergent endovascular therapy (EVT). METHODS: We included all patients transferred by a single IFT agency in the state of Indiana from July 1, 2018 to December 1, 2020 to a comprehensive stroke center in Indianapolis for emergent EVT. Data were collected from the transfer center electronic medical records and matched to IFT and receiving hospital data. RESULTS: Two hundred eighty-eight patients were included, of which 150 (52.0%) received EVT. The median call-to-needle interval (from call to the transfer center to EVT needle puncture) was 155.5 minutes (IQR 135.8-195.3). The median resource activation interval (call to the transfer center to IFT deployment) was 16 minutes (IQR 10-27 minutes); the median IFT response interval (call to IFT to arrival of the transferring unit) was 34 minutes (IQR 25-43 minutes); the median pre-transfer interval (call to the transfer center until departure from the sending hospital) was 60.4 minutes (IQR 47.1-72.6); and the median sending hospital interval at bedside was 25 minutes (IQR 20-30 minutes). Most patients (197, 68.4%) were sent via critical care rotor. Only 61 (21.2%) required interventions other than tissue plasminogen administration, such as titration of actively transfusing medications (e.g., nicardipine, propofol) (37 of 61, 59.7%), or intubation or ventilator management (25 of 61, 40.3%). Patients sent via critical care rotor had longer sending hospital intervals (26 minutes, IQR 22-32, vs 19 minutes, IQR 16-25; p < 0.001) but shorter transfer intervals than those sent via critical care ground. CONCLUSIONS: At longer distances, rotor transport saved significant time specifically in the total IFT interval of patients with LVO strokes. Emphasizing processes to reduce the resource activation interval and the sending hospital interval may help reduce the overall time-to-EVT.

Association of Supernumerary Sex Chromosome Aneuploidies With Venous Thromboembolism.

Importance: An increased risk of venous thromboembolism (VTE) has been reported in men with an additional sex chromosome. The association between other sex chromosome aneuploidies and VTE is not well characterized. Objective: To determine if sex chromosome aneuploidy is associated with VTE. Design, Setting, and Participants: Retrospective cohort study of sex chromosome aneuploidy and VTE, performed by analyzing X- and Y-chromosome dosage and VTE incidence in 642 544 individuals from 2 population-scale biobanks: the US Geisinger MyCode Community Health Initiative (N = 154 519) and the UK Biobank (N = 488 025); analysis was limited to participants self-identified as White because of inadequate sample sizes for other race and ethnicity groups. A total of 108 461 unrelated MyCode participants with electronic health record follow-up ranging from September 1996 to December 2020 and 418 725 unrelated British and Irish UK Biobank participants who attended the baseline assessment between March 2006 and October 2010, with follow-up extending to November 2020, were included in analyses of VTE. Exposures: Sex chromosome aneuploidies. Main Outcomes and Measures: Individuals with 1 primary inpatient VTE diagnosis, 2 primary outpatient VTE diagnoses, or a self-reported VTE diagnosis were defined as VTE cases. P values were adjusted for multiple comparisons. Results: Identification of sex chromosome aneuploidy was undertaken among 642 544 individuals aged 18 to 90 years. Identification of a diagnosis of VTE was undertaken among 108 461 unrelated MyCode participants (65 565 [60.5%] female; mean age at last visit, 58.0 [SD, 17.6] years; median follow-up, 15.3 [IQR, 9.7] years) and among 418 725 unrelated UK Biobank participants (224 695 [53.7%] female; mean age at baseline interview, 56.9 [SD, 8.0] years; median follow-up, 12.0 [IQR, 1.6] years). Among MyCode participants, during 10 years of follow-up, 17 incident VTE events per 1353 person-years were detected among those with supernumerary sex chromosome aneuploidy (1.3% per person-year) compared with 2060 per 816 682 person-years among those with 46,XX or 46,XY (0.25% per person-year) (hazard ratio, 5.4 [95% CI, 3.4-8.7]; 10-year risk difference, 8.8% [95% CI, 4.2%-14.0%]; P < .001). Among UK Biobank participants, during 10 years of follow-up, 16 incident VTE events per 3803 person-years were detected among those with supernumerary sex chromosome aneuploidy (0.42% per person-year) compared with 4491 per 3 970 467 person-years among those with 46,XX or 46,XY (0.11% per person-year) (hazard ratio, 4.1 [95% CI, 2.5-6.7]; 10-year risk difference, 3.7% [95% CI, 1.4%-5.9%]; P < .001). Conclusions and Relevance: Adults with supernumerary sex chromosome aneuploidies compared with 2 sex chromosomes had a small but statistically significant increased risk of VTE. Further research is needed to understand the clinical implications of this association.

Frequency of truncating FLCN variants and Birt-Hogg-Dubé-associated phenotypes in a health care system population.

PURPOSE: Penetrance estimates of Birt-Hogg-Dubé syndrome (BHD)-associated cutaneous, pulmonary, and kidney manifestations are based on clinically ascertained families. In a health care system population, we used a genetics-first approach to estimate the prevalence of pathogenic/likely pathogenic (P/LP) truncating variants in FLCN, which cause BHD, and the penetrance of BHD-related phenotypes. METHODS: Exomes from 135,990 patient-participants in Geisinger's MyCode cohort were assessed for P/LP truncating FLCN variants. BHD-related phenotypes were evaluated from electronic health records. Association between P/LP FLCN variants and BHD-related phenotypes was assessed using Firth's logistic regression. RESULTS: P/LP truncating FLCN variants were identified in 35 individuals (1 in 3234 unrelated individuals), 68.6% of whom had BHD-related phenotype(s), including cystic lung disease (65.7%), pneumothoraces (17.1%), cutaneous manifestations (8.6%), and kidney cancer (2.9%). A total of 4 (11.4%) individuals had prior clinical BHD diagnoses. CONCLUSION: In this health care population, the frequency of P/LP truncating FLCN variants is 60 times higher than the previously reported prevalence. Although most variant-positive individuals had BHD-related phenotypes, a minority were previously clinically diagnosed, likely because cutaneous manifestations, pneumothoraces, and kidney cancer were observed at lower frequencies than in clinical cohorts. Improved clinical recognition of cystic lung disease and education concerning its association with FLCN variants could prompt evaluation for BHD.

Medical manifestations and health care utilization among adult MyCode participants with neurodevelopmental psychiatric copy number variants.

PURPOSE: Recurrent pathogenic copy number variants (pCNVs) have large-effect impacts on brain function and represent important etiologies of neurodevelopmental psychiatric disorders (NPDs), including autism and schizophrenia. Patterns of health care utilization in adults with pCNVs have gone largely unstudied and are likely to differ in significant ways from those of children. METHODS: We compared the prevalence of NPDs and electronic health record-based medical conditions in 928 adults with 26 pCNVs to a demographically-matched cohort of pCNV-negative controls from >135,000 patient-participants in Geisinger's MyCode Community Health Initiative. We also evaluated 3 quantitative health care utilization measures (outpatient, inpatient, and emergency department visits) in both groups. RESULTS: Adults with pCNVs (24.9%) were more likely than controls (16.0%) to have a documented NPD. They had significantly higher rates of several chronic diseases, including diabetes (29.3% in participants with pCNVs vs 20.4% in participants without pCNVs) and dementia (2.2% in participants with pCNVs vs 1.0% participants without pCNVs), and twice as many annual emergency department visits. CONCLUSION: These findings highlight the potential for genetic information-specifically, pCNVs-to inform the study of health care outcomes and utilization in adults. If, as our findings suggest, adults with pCNVs have poorer health and require disproportionate health care resources, early genetic diagnosis paired with patient-centered interventions may help to anticipate problems, improve outcomes, and reduce the associated economic burden.

Molecular Diagnostic Yield of Exome Sequencing in Patients With Cerebral Palsy.

Importance: Cerebral palsy is a common neurodevelopmental disorder affecting movement and posture that often co-occurs with other neurodevelopmental disorders. Individual cases of cerebral palsy are often attributed to birth asphyxia; however, recent studies indicate that asphyxia accounts for less than 10% of cerebral palsy cases. Objective: To determine the molecular diagnostic yield of exome sequencing (prevalence of pathogenic and likely pathogenic variants) in individuals with cerebral palsy. Design, Setting, and Participants: A retrospective cohort study of patients with cerebral palsy that included a clinical laboratory referral cohort with data accrued between 2012 and 2018 and a health care-based cohort with data accrued between 2007 and 2017. Exposures: Exome sequencing with copy number variant detection. Main Outcomes and Measures: The primary outcome was the molecular diagnostic yield of exome sequencing. Results: Among 1345 patients from the clinical laboratory referral cohort, the median age was 8.8 years (interquartile range, 4.4-14.7 years; range, 0.1-66 years) and 601 (45%) were female. Among 181 patients in the health care-based cohort, the median age was 41.9 years (interquartile range, 28.0-59.6 years; range, 4.8-89 years) and 96 (53%) were female. The molecular diagnostic yield of exome sequencing was 32.7% (95% CI, 30.2%-35.2%) in the clinical laboratory referral cohort and 10.5% (95% CI, 6.0%-15.0%) in the health care-based cohort. The molecular diagnostic yield ranged from 11.2% (95% CI, 6.4%-16.2%) for patients without intellectual disability, epilepsy, or autism spectrum disorder to 32.9% (95% CI, 25.7%-40.1%) for patients with all 3 comorbidities. Pathogenic and likely pathogenic variants were identified in 229 genes (29.5% of 1526 patients); 86 genes were mutated in 2 or more patients (20.1% of 1526 patients) and 10 genes with mutations were independently identified in both cohorts (2.9% of 1526 patients). Conclusions and Relevance: Among 2 cohorts of patients with cerebral palsy who underwent exome sequencing, the prevalence of pathogenic and likely pathogenic variants was 32.7% in a cohort that predominantly consisted of pediatric patients and 10.5% in a cohort that predominantly consisted of adult patients. Further research is needed to understand the clinical implications of these findings.

Gestational Age, Perinatal Characteristics, and Autism Spectrum Disorder: A Birth Cohort Study.

OBJECTIVE: To determine how gestational age relates to research-identified autism spectrum disorder (ASD-R) in the context of perinatal risk factors. STUDY DESIGN: This is a population-based cohort study using the 1994-2000 Olmsted County Birth Cohort. Children included were born and remained in Olmsted County after age 3 years. ASD-R status was determined from signs and symptoms abstracted from medical and educational records. Cox proportional hazards models were fit to identify associations between perinatal characteristics and ASD-R. RESULTS: The incidence of preterm birth (<37 weeks' gestation) was 8.6% among 7876 children. The cumulative incidence of ASD-R was 3.8% (95% CI 3.3-4.2) at 21 years of age. Compared with children born at full term, the risk of ASD-R appeared to be increased for children born preterm with unadjusted hazard ratios (HRs) of 2.62 (95% CI 0.65-10.57), 1.68 (95% CI 0.54-5.29), and 1.60 (95% CI 1.06-2.40) for children born extremely preterm, very preterm, and moderate-to-late preterm, respectively. In a multivariable model adjusted for perinatal characteristics, the associations were attenuated with adjusted HRs of 1.75 (95% CI 0.41-7.40), 1.24 (95% CI 0.38-4.01), and 1.42 (95% CI 0.93-2.15), for children born extremely preterm, very preterm, and moderate-to-late preterm, respectively. Among children with maternal history available (N = 6851), maternal psychiatric disorder was associated with ASD-R (adjusted HR 1.73, 95% CI 1.24-2.42). CONCLUSIONS: The increased risk of ASD-R among children born preterm relative to children born full term was attenuated by infant and maternal characteristics.

The value of genomic variant ClinVar submissions from clinical providers: Beyond the addition of novel variants.

With the increasing use of clinical genomic testing across broad medical disciplines, the need for data sharing and curation efforts to improve variant interpretation is paramount. The National Center for Biotechnology Information (NCBI) ClinVar database facilitates these efforts by serving as a repository for clinical assertions about genomic variants and associations with disease. Most variant submissions are from clinical laboratories, which may lack clinical details. Laboratories may also choose not to submit all variants. Clinical providers can contribute to variant interpretation improvements by submitting variants to ClinVar with their own assertions and supporting evidence. The medical genetics team at Geisinger's Autism & Developmental Medicine Institute routinely reviews the clinical significance of all variants obtained through clinical genomic testing, using published ACMG/AMP guidelines, clinical correlation, and post-test clinical data. We describe the submission of 148 sequence and 155 copy number variants to ClinVar as "provider interpretations." Of these, 192 (63.4%) were novel to ClinVar. Detailed clinical data were provided for 298 (98.3%), and when available, segregation data and follow-up clinical correlation or testing was included. This contribution marks the first large-scale submission from a neurodevelopmental clinical setting and illustrates the importance of clinical providers in collaborative efforts to improve variant interpretation.

Dimensional assessment of schizotypal, psychotic, and other psychiatric traits in children and their parents: development and validation of the Childhood Oxford-Liverpool Inventory of Feelings and Experiences on a representative US sample.

BACKGROUND: Healthy functioning relies on a variety of perceptual, cognitive, emotional, and behavioral abilities that are distributed throughout the normal population. Variation in these traits define the wide range of neurodevelopmental (NDD) and neuropsychiatric (NPD) disorders. Here, we introduce a new measure for assessing these traits in typically developing children and children at risk for NDD and NPD from age 2 to 18 years. METHOD: The Childhood Oxford-Liverpool Inventory of Feelings and Experiences (CO-LIFE) was created as a dimensional, parent-report measure of schizotypal and psychotic traits in the general population. Parents of 2,786 children also self-reported on an adapted version of the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE-US). RESULTS: The CO-LIFE resulted in continuous distributions for the total score and for each of three factor analytically-derived subscales. Item response theory (IRT) analyses indicated strong reliability across the score range for the O-LIFE-US and the CO-LIFE. Internal consistency and test-retest reliability were high across all scales. Parent-child intraclass correlations were consistent with high heritability. The scales discriminated participants who reported a lifetime psychiatric diagnosis from those who reported no diagnosis. The O-LIFE-US and CO-LIFE scores correlated positively with the Social Responsiveness Scale 2 (SRS-2) indicating good convergent validity. CONCLUSIONS: Like the original O-LIFE, the O-LIFE-US and the CO-LIFE are valid and reliable tools that reflect the spectrum of psychiatric and schizotypal traits in the general population. Such scales are necessary for conducting family studies that aim to examine a range of psychological and behavioral traits in both children and adults and are well-suited for the Research Domain Criteria (RDoC) initiative of the NIMH.

Evaluation of QTc in Rett syndrome: Correlation with age, severity, and genotype.

Rett syndrome (RTT) is caused by MECP2 mutations, resulting in various neurological symptoms. Prolonged corrected QT interval (QTc) is also reported and is a speculated cause of sudden death in RTT. The purpose of this study was to correlate QTc in RTT patients with age, clinical severity, and genotype. 100 RTT patients (98 females, 2 males) with MECP2 mutations underwent baseline neurological evaluation (KKI-RTT Severity Scale) and QTc measurement (standard 12 lead electrocardiogram) as part of our prospective natural history study. Mean QTc of the cohort was 422.6 msec, which did not exceed the normal values for age. 7/100 patients (7%) had QTc prolongation (>450 msec). There was a trend for increasing QTc with age and clinical severity (P = 0.09). No patients with R106C, R106W, R133C, R168*, R270*, R294*, R306C, R306H, and R306P mutations demonstrated QTc prolongation. There was a relatively high proportion of QTc prolongation in patients with R255* mutations (2/8, 25%) and large deletions (1/4, 25%). The overall presence of QTc prolongation did not correlate with mutation category (P = 0.52). Our findings demonstrate that in RTT, the prevalence of QTc prolongation is lower than previously reported. Hence, all RTT patients warrant baseline ECG; if QTc is prolonged, then cardiac followup is warranted. If initial QTc is normal, then annual ECGs, particularly in younger patients, may not be necessary. However, larger sample sizes are needed to solidify the association between QTc and age and clinical severity. The biological and clinical significance of mild QTc prolongation above the normative data remains undetermined.

A Comparison of Structural Brain Imaging Findings in Autism Spectrum Disorder and Attention-Deficit Hyperactivity Disorder.

ASD and ADHD are regarded as distinct disorders in the current DSM-5. However, recent research and the RDoC initiative are recognizing considerable overlap in the clinical presentation of ASD, ADHD, and other neurodevelopmental disorders. In spite of numerous neuroimaging findings in ASD and ADHD, the extent to which either of the above views are supported remains equivocal. Here we compare structural MRI and DTI literature in ASD and ADHD. Our main findings reveal both distinct and shared neural features. Distinct expressions were in total brain volume (ASD: increased volume, ADHD: decreased volume), amygdala (ASD: overgrowth, ADHD: normal), and internal capsule (ASD: unclear, ADHD: reduced FA in DTI). Considerable overlap was noted in the corpus callosum and cerebellum (lower volume in structural MRI and decreased FA in DTI), and superior longitudinal fasciculus (reduced FA in DTI). In addition, we identify brain regions which have not been studied in depth and require more research. We discuss relationships between brain features and symptomatology. We conclude by addressing limitations of current neuroimaging research and offer approaches that account for clinical heterogeneity to better distinguish brain-behavior relationships.

Genetic testing and genetic counseling among Medicaid-enrolled children with autism spectrum disorder in 2001 and 2007.

The rise in the prevalence of autism spectrum disorder (ASD) has resulted in increased efforts to understand the causes of this complex set of disorders that emerge early in childhood. Although research in this area is underway and yielding useful, but complex information about ASD, guidelines for the use of genetic testing and counseling among children with ASD conflict. The purpose of this study was to determine the frequency of use of genetic testing and counseling before the widespread implementation of clinical chromosomal microarray (CMA) to establish a baseline for the use of both services and to investigate potential disparities in the use of both services among children with ASD. We found that about two-thirds of children with ASD received genetic testing or counseling and the use of both services is increasing with time, even in the pre-CMA era. Being female and having a comorbid intellectual disability diagnosis both increased the likelihood of receiving genetic testing and genetic counseling. Initial discrepancies in the use of both services based on race/ethnicity suggest that troubling disparities observed in other services delivered to children with ASD and other mental health disorders persist in genetic testing and counseling as well. These results should incentivize further investigation of the impact of genetic testing and counseling on children with ASD and their families, and should drive efforts to explore and confront disparities in the delivery of these services, particularly with the advancing scientific research on this topic.

Etiologic Evaluation of Children with Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is clinically and etiologically heterogeneous. A causal genetic variant can be identified in approximately 20% to 25% of affected individuals with current clinical genetic testing, and all patients with an ASD diagnosis should be offered genetic etiologic evaluation. We suggest that exome sequencing with copy number variant coverage should be the first-line etiologic evaluation for ASD. Neuroimaging, neurophysiologic, metabolic, and other biochemical evaluations can provide insight into the pathophysiology of ASD but should be recommended in the appropriate clinical circumstances.

Risk of Autoimmune Disease in Research-Identified Cases of Autism Spectrum Disorder: A Longitudinal, Population-Based Birth Cohort Study.

OBJECTIVE: Determine the risk of autoimmune disease in research-identified cases of autism spectrum disorder (ASD) compared with referents using a longitudinal, population-based birth cohort. METHODS: ASD incident cases were identified from a population-based birth cohort of 31,220 individuals. Inclusive ASD definition based on DSM-IV-TR autistic disorder, Asperger syndrome, and pervasive developmental disorder, not otherwise specified, was used to determine ASD cases. For each ASD case, 2 age- and sex-matched referents without ASD were identified. Diagnosis codes assigned between birth and December 2017 were electronically obtained. Individuals were classified as having an autoimmune disorder if they had at least 2 diagnosis codes more than 30 days apart. Cox proportional hazards models were fit to estimate the hazard ratio (HR) between ASD status and autoimmune disorder. RESULTS: Of 1014 ASD cases, 747 (73.7%) were male. Fifty ASD cases and 59 of the 1:2 matched referents were diagnosed with first autoimmune disorder at the median age of 14 and 17.1 years, respectively. ASD cases had increased risk of autoimmune disease compared with matched referents (HR 1.74; 95% confidence interval [CI], 1.21-2.52). The increased risk was statistically significant among male patients (HR 2.01; 95% CI, 1.26-3.21) but not among the smaller number of female subjects (HR 1.38; 95% CI, 0.76-2.50). CONCLUSION: This study provides evidence from a longitudinal, population-based birth cohort for co-occurrence of ASD and autoimmune disorders. Thus, children with ASD should be monitored for symptoms of autoimmune disease and appropriate workup initiated.

Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia.

Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms. We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing. We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls. We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments. In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10⁻5). These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function. In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only.