A genome-first study of sex chromosome aneuploidies provides evidence of Y chromosome dosage effects on autism risk.

A female protective effect has long been postulated as the primary explanation for the four-fold increase of autism spectrum disorder (ASD) diagnoses in males versus females. However, genetic and epidemiological investigations of this hypothesis have so far failed to explain the large difference in ASD prevalence between the sexes. To address this knowledge gap, we examined sex chromosome aneuploidy in a large ASD case-control cohort to evaluate the relationship between X and Y chromosome dosage and ASD risk.

MED13L-related disorder characterized by severe motor speech impairment.

Background: -related disorder is associated with intellectual disability, motor delay, and speech deficits. Previous studies have focused on broad clinical descriptions of individuals, but limited information regarding specific speech diagnoses and results of direct testing has been published to date. We conducted deep phenotyping to characterize the speech, language, motor, cognitive, and adaptive phenotypes of individuals with -related disorder.

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.

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.

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.

Prevalence and Penetrance of Rare Pathogenic Variants in Neurodevelopmental Psychiatric Genes in a Health Care System Population.

Objective: Autism, schizophrenia, and other clinically distinct neurodevelopmental psychiatric disorders (NPDs) have shared genetic etiologies, including single-gene and multigenic copy number variants (CNVs). Because rare variants are primarily investigated in clinical cohorts, population-based estimates of their prevalence and penetrance are lacking. The authors determined the prevalence, penetrance, and NPD risk of pathogenic single-gene variants in a large health care system population.

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.

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.

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

Background: A neurodevelopmental syndrome was recently reported in four patients with 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 variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients' phenotypes.

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.

Factors Associated with Self-Reported Dysphagia in Older Adults Receiving Meal Support.

Objectives: Dysphagia is common in older adults. However, there are no current estimates of dysphagia in community-dwelling older adults those receiving meal support. It is unknown whether dysphagia is associated with other measures of physical function (activities of daily living [ADL] ability or nutrition status).

IQ in Autism Spectrum Disorder: A Population-Based Birth Cohort Study.

Objectives: We aimed to describe the intellectual ability and ratio of boys to girls with average or higher IQ within autism spectrum disorder (ASD) cases identified in a population-based birth cohort. We hypothesized that research-identified individuals with ASD would be more likely to have average or higher IQ, compared to clinically diagnosed ASD. We also hypothesized the male to female ratio would decrease as the definition of ASD broadened.

Association Between Exposure of Children to General Anesthesia and Autism Spectrum Disorder.

This study tested the hypothesis that exposure of children prior to their third birthday to procedures requiring general anesthesia is associated with an increased incidence of autism spectrum disorder (ASD) in later life. This study employed a nested, 1:2 matched-case control study design using ASD cases identified in a population-based birth cohort of children born in Olmsted County, MN from 1976 to 2000. Matching variables included sex, date of birth, and mother's age in conditional logistic regression including 499 ASD cases and 998 controls.

Genetic Testing in Neurodevelopmental Disorders.

Neurodevelopmental disorders are the most prevalent chronic medical conditions encountered in pediatric primary care. In addition to identifying appropriate descriptive diagnoses and guiding families to evidence-based treatments and supports, comprehensive care for individuals with neurodevelopmental disorders includes a search for an underlying etiologic diagnosis, primarily through a genetic evaluation. Identification of an underlying genetic etiology can inform prognosis, clarify recurrence risk, shape clinical management, and direct patients and families to condition-specific resources and supports.

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.