Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders.

Purpose: To identify genetic etiologies and genotype/phenotype associations for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs). Methods: We coupled phenotyping with exome or genome sequencing of 467 pedigrees with genetically unsolved oCCDDs, integrating analyses of pedigrees, human and animal model phenotypes, and de novo variants to identify rare candidate single nucleotide variants, insertion/deletions, and structural variants disrupting protein-coding regions. Prioritized variants were classified for pathogenicity and evaluated for genotype/phenotype correlations. Results: Analyses elucidated phenotypic subgroups, identified pathogenic/likely pathogenic variant(s) in 43/467 probands (9.2%), and prioritized variants of uncertain significance in 70/467 additional probands (15.0%). These included known and novel variants in established oCCDD genes, genes associated with syndromes that sometimes include oCCDDs (e.g., MYH10, KIF21B, TGFBR2, TUBB6), genes that fit the syndromic component of the phenotype but had no prior oCCDD association (e.g., CDK13, TGFB2), genes with no reported association with oCCDDs or the syndromic phenotypes (e.g., TUBA4A, KIF5C, CTNNA1, KLB, FGF21), and genes associated with oCCDD phenocopies that had resulted in misdiagnoses. Conclusion: This study suggests that unsolved oCCDDs are clinically and genetically heterogeneous disorders often overlapping other Mendelian conditions and nominates many candidates for future replication and functional studies.

Exome copy number variant detection, analysis, and classification in a large cohort of families with undiagnosed rare genetic disease.

Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and, with new innovative methods, can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the Genomics Research to Elucidate the Genetics of Rare Diseases consortium and analyzed using the seqr platform. The addition of CNV detection to exome analysis identified causal CNVs for 171 families (2.6%). The estimated sizes of CNVs ranged from 293 bp to 80 Mb. The causal CNVs consisted of 140 deletions, 15 duplications, 3 suspected complex structural variants (SVs), 3 insertions, and 10 complex SVs, the latter two groups being identified by orthogonal confirmation methods. To classify CNV variant pathogenicity, we used the 2020 American College of Medical Genetics and Genomics/ClinGen CNV interpretation standards and developed additional criteria to evaluate allelic and functional data as well as variants on the X chromosome to further advance the framework. We interpreted 151 CNVs as likely pathogenic/pathogenic and 20 CNVs as high-interest variants of uncertain significance. Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher-resolution alternative to arrays at a fraction of the cost of genome sequencing. Our improvements to the classification approach advances the systematic framework to assess the pathogenicity of CNVs.

Predictors of a Preference for Telemedicine Virtual Visits in Patients Undergoing Cancer Rehabilitation.

ABSTRACT: The purpose of this retrospective study was to examine the use of virtual visits (telemedicine) at our cancer rehabilitation outpatient clinics from March 2020 to August 2021, when virtual visits became more widely available, and to identify any demographic and clinical variables making patients more likely to favor virtual over in-person visits. There were 3971 outpatient encounters (2020 virtual and 1951 in-person visits from a total of 1638 patients) in our cancer rehabilitation outpatient clinics during this time frame. Significant findings in both the univariate and multivariate analyses were race (P < .001 and P = .006, respectively), cancer type (P < .001 for both), and distance to the clinic (P < .001 for both). Our research showed that virtual visits were accepted by patients with cancer, and that younger age (62 compared to 65), non-White race/ethnicity, solid tumor, and shorter distance to the clinic were associated with a preference for virtual over in-person visits.

Inpatient Rehabilitation of Hematopoietic Stem Cell Transplant Patients: Managing Challenging Impairments and Medical Fragility.

ABSTRACT: Hematopoietic stem cell transplants play an important role in the treatment of cancer, particularly hematologic malignancies. These patients can encounter functional impairments unique to hematopoietic stem cell transplant, including deconditioning, cancer-related fatigue, steroid myopathy, graft versus host disease, and capillary leak syndrome. Medical fragility and increased risk of infection may make rehabilitation challenging on the acute care and postacute care settings. Patients admitted to acute inpatient rehabilitation experience a high rate of transfer to the primary acute service and high rate of mortality after transfer back. Physical medicine and rehabilitation physicians can use a number of strategies to mitigate these patients' risk of medical complications including evidence-based predictive models to assist with postacute rehabilitation triage, physiatry-led consult-based rehabilitation, and oncology hospitalist comanagement on inpatient rehabilitation.

The Role of Outpatient Physical Medicine and Rehabilitation in a Multidisciplinary Prehabilitation Program for Older Adults before Allogeneic Hematopoietic Stem Cell Transplant.

INTRODUCTION: Physical rehabilitation is increasingly incorporated throughout the allogeneic hematopoietic stem cell transplant (allo-HSCT) journey for older adults. OBJECTIVE: This study aimed to describe physical medicine and rehabilitation (PM&R)-related diagnoses, exercise barriers, and management recommendations for older adults before allo-HSCT. DESIGN: Fifty PM&R consults as part of the Enhanced Recovery-Stem Cell Transplant (ER-SCT) multidisciplinary prehabilitation program at a comprehensive cancer center were retrospectively reviewed. RESULTS: Many PM&R-related diagnoses (173), exercise barriers (55), and management recommendations (112) were found. Common diagnoses were musculoskeletal dysfunction (more commonly back, shoulder, then knee) (n = 39, 23%) and fatigue (n = 36, 21%). Common exercise barriers were also musculoskeletal dysfunction (more commonly back, knee, then shoulder) (total n = 20, 36%) and fatigue (n = 20, 36%). Most patients (n = 32, 64%) had 1 or more exercise barriers. Common PM&R management recommendations were personalized exercise counseling (n = 37, 33%), personalized nutrition management (n = 19, 17%), body composition recommendations (n = 17, 15%), medications (n = 15, 13%), and orthotics and durable medical equipment (n = 8, 7%). CONCLUSION: Routine PM&R referral of older allo-HSCT patients for prehabilitation resulted in the identification of many rehabilitative needs and substantial additional management recommendations. Increased early, collaborative prehabilitation efforts between PM&R and allo-HSCT teams to optimize care for these patients is recommended.

Changes in Patterns of Referral for Inpatient Rehabilitation Cancer Patients Due to COVID-19: A Retrospective Study.

ABSTRACT: There is a paucity of literature on the effect of COVID-19 on hospital processes. We hypothesized that COVID-19 was associated with decreased cancer physiatry referrals in 2020. This is a retrospective cohort study of consecutive patients from April to July 2019 and 2020 admitted at an academic quaternary cancer center. The main outcomes were number of hospital admissions, rate, and characteristics of inpatient rehabilitation admissions and change in percentage of physiatry referrals as the primary endpoint. Results showed that in 2019, there were 387 referrals from 10,274 inpatient admissions (3.8%; 95% confidence interval, 2.4-4.2), compared with 337 referrals from 7051 admissions in 2020 (4.8%; 95% confidence interval, 4.3-5.3, P = 0.001). Hematology services referred more patients than neurosurgery in 2020 (20.4% vs. 31.4%; 48.2% vs. 26.5%, P = 0.01). Discharge disposition reflected an increased frequency of return to acute care service in 2020 (10.2% vs. 21.8%, P = 0.03). In conclusion, there was an increase in the rate of physiatry referrals despite a decrease in hospital admissions. There was an increase in referrals by hematology, likely due to emphasis on safe discharge and the populations hospitalized.

Exome copy number variant detection, analysis and classification in a large cohort of families with undiagnosed rare genetic disease.

Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and with new innovative methods can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the GREGoR consortium. Each family's CNV data was analyzed using the seqr platform and candidate CNVs classified using the 2020 ACMG/ClinGen CNV interpretation standards. We developed additional evidence criteria to address situations not covered by the current standards. The addition of CNV calling to exome analysis identified causal CNVs for 173 families (2.6%). The estimated sizes of CNVs ranged from 293 bp to 80 Mb with estimates that 44% would not have been detected by standard chromosomal microarrays. The causal CNVs consisted of 141 deletions, 15 duplications, 4 suspected complex structural variants (SVs), 3 insertions and 10 complex SVs, the latter two groups being identified by orthogonal validation methods. We interpreted 153 CNVs as likely pathogenic/pathogenic and 20 CNVs as high interest variants of uncertain significance. Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher resolution alternative to arrays at a fraction of the cost of genome sequencing. Our improvements to the classification approach advances the systematic framework to assess the pathogenicity of CNVs.

GATK-gCNV enables the discovery of rare copy number variants from exome sequencing data.

Copy number variants (CNVs) are major contributors to genetic diversity and disease. While standardized methods, such as the genome analysis toolkit (GATK), exist for detecting short variants, technical challenges have confounded uniform large-scale CNV analyses from whole-exome sequencing (WES) data. Given the profound impact of rare and de novo coding CNVs on genome organization and human disease, we developed GATK-gCNV, a flexible algorithm to discover rare CNVs from sequencing read-depth information, complete with open-source distribution via GATK. We benchmarked GATK-gCNV in 7,962 exomes from individuals in quartet families with matched genome sequencing and microarray data, finding up to 95% recall of rare coding CNVs at a resolution of more than two exons. We used GATK-gCNV to generate a reference catalog of rare coding CNVs in WES data from 197,306 individuals in the UK Biobank, and observed strong correlations between per-gene CNV rates and measures of mutational constraint, as well as rare CNV associations with multiple traits. In summary, GATK-gCNV is a tunable approach for sensitive and specific CNV discovery in WES data, with broad applications.

Systematic evaluation of genome sequencing for the diagnostic assessment of autism spectrum disorder and fetal structural anomalies.

Short-read genome sequencing (GS) holds the promise of becoming the primary diagnostic approach for the assessment of autism spectrum disorder (ASD) and fetal structural anomalies (FSAs). However, few studies have comprehensively evaluated its performance against current standard-of-care diagnostic tests: karyotype, chromosomal microarray (CMA), and exome sequencing (ES). To assess the clinical utility of GS, we compared its diagnostic yield against these three tests in 1,612 quartet families including an individual with ASD and in 295 prenatal families. Our GS analytic framework identified a diagnostic variant in 7.8% of ASD probands, almost 2-fold more than CMA (4.3%) and 3-fold more than ES (2.7%). However, when we systematically captured copy-number variants (CNVs) from the exome data, the diagnostic yield of ES (7.4%) was brought much closer to, but did not surpass, GS. Similarly, we estimated that GS could achieve an overall diagnostic yield of 46.1% in unselected FSAs, representing a 17.2% increased yield over karyotype, 14.1% over CMA, and 4.1% over ES with CNV calling or 36.1% increase without CNV discovery. Overall, GS provided an added diagnostic yield of 0.4% and 0.8% beyond the combination of all three standard-of-care tests in ASD and FSAs, respectively. This corresponded to nine GS unique diagnostic variants, including sequence variants in exons not captured by ES, structural variants (SVs) inaccessible to existing standard-of-care tests, and SVs where the resolution of GS changed variant classification. Overall, this large-scale evaluation demonstrated that GS significantly outperforms each individual standard-of-care test while also outperforming the combination of all three tests, thus warranting consideration as the first-tier diagnostic approach for the assessment of ASD and FSAs.

Landscape of mSWI/SNF chromatin remodeling complex perturbations in neurodevelopmental disorders.

DNA sequencing-based studies of neurodevelopmental disorders (NDDs) have identified a wide range of genetic determinants. However, a comprehensive analysis of these data, in aggregate, has not to date been performed. Here, we find that genes encoding the mammalian SWI/SNF (mSWI/SNF or BAF) family of ATP-dependent chromatin remodeling protein complexes harbor the greatest number of de novo missense and protein-truncating variants among nuclear protein complexes. Non-truncating NDD-associated protein variants predominantly disrupt the cBAF subcomplex and cluster in four key structural regions associated with high disease severity, including mSWI/SNF-nucleosome interfaces, the ATPase-core ARID-armadillo repeat (ARM) module insertion site, the Arp module and DNA-binding domains. Although over 70% of the residues perturbed in NDDs overlap with those mutated in cancer, ~60% of amino acid changes are NDD-specific. These findings provide a foundation to functionally group variants and link complex aberrancies to phenotypic severity, serving as a resource for the chromatin, clinical genetics and neurodevelopment communities.

Frequency, Characteristics, and Risk Factors for Falls at an Inpatient Cancer Rehabilitation Unit.

PURPOSE: Falls in the hospital can lead to adverse events, including injuries. Studies have shown that patients with cancer and those undergoing inpatient rehabilitation (IPR) are at higher risk for falls. Therefore, we measured the frequency, degree of harm, and characteristics of patients who fell in an inpatient cancer rehabilitation unit. METHODS: A retrospective review was conducted on inpatient cancer rehabilitation patients admitted from January 2012 to February 2016. Fall frequency, degree of harm, fall circumstances, cancer type, patient's fall risk score on the basis of the MD Anderson Cancer Center Adult Inpatient Fall Risk Assessment Tool (MAIFRAT), length of stay, and risk factors were evaluated for patients. RESULTS: There were 72 out of 1,571 unique individual falls (4.6%), with a falls incidence of 3.76 falls per 1,000 patient-days. Most fallers (86%) suffered no harm. Risk factors for falls included presence of patient-controlled analgesia pump (P = .03), pump such as insulin or wound vacuum-assisted closure (P < .01), nasogastric, gastric, or chest tube (P = .05), and higher MAIFRAT score (P < .01). The fallers were younger (62 v 66; P = .04), had a longer IPR stay (13 v 9; P = .03), and had a lower Charlson comorbidity index (6 v 8; P < .01). CONCLUSION: The frequency and degree of harm for falls in the IPR unit were less than previous studies, which suggests that mobilization for these patients with cancer is safe. The presence of certain medical devices may contribute to fall risk, and more research is needed to better prevent falls in this higher-risk subgroup.

Convergent coexpression of autism-associated genes suggests some novel risk genes may not be detectable in large-scale genetic studies.

Autism spectrum disorder (ASD) is a heritable neurodevelopmental disorder characterized by deficits in social interactions and communication. Protein-altering variants in many genes have been shown to contribute to ASD; however, understanding the convergence across many genes remains a challenge. We demonstrate that coexpression patterns from 993 human postmortem brains are significantly correlated with the transcriptional consequences of CRISPR perturbations in human neurons. Across 71 ASD risk genes, there was significant tissue-specific convergence implicating synaptic pathways. Tissue-specific convergence was further demonstrated across schizophrenia and atrial fibrillation risk genes. The degree of ASD convergence was significantly correlated with ASD association from rare variation and differential expression in ASD brains. Positively convergent genes showed intolerance to functional mutations and had shorter coding lengths than known risk genes even after removing association with ASD. These results indicate that convergent coexpression can identify potentially novel genes that are unlikely to be discovered by sequencing studies.

Frequency and reasons for unplanned transfer to the primary acute care service of inpatient rehabilitation glioblastoma multiforme patients.

PURPOSE: To determine the percentage of and factors associated with unplanned transfer to the acute care service of glioblastoma multiforme acute rehabilitation inpatients. METHODS: Retrospective review of glioblastoma multiforme acute rehabilitation inpatients admitted 4/1/2016-3/31/2020 at a National Cancer Institute Comprehensive Cancer Center. RESULTS: One hundred thirty-nine consecutive admissions of unique glioblastoma multiforme acute rehabilitation inpatients were analyzed. Fifteen patients (10.7%, 95% confidence interval 6.5-17.1%) were transferred to the acute care service for unplanned reasons. The most common reasons for transfer back were neurosurgical complication 6/15(40%), neurologic decline due to mass effect 4/15(26.7%), and pulmonary embolism 2/15(13.3%). Older age (p = 0.010), infection prior to acute inpatient rehabilitation transfer (p = 0.020), and lower activity measure of post-acute care 6-click basic mobility scores (p = 0.048) were significantly associated with transfer to the acute care service. Patients who transferred to the acute care service had significantly lower overall survival than patients who did not transfer off (log-rank test p = 0.001). CONCLUSION: Acute inpatient physiatrists should closely monitor patients for neurosurgical and neurologic complications. The variables significantly associated with transfer to the acute care service may help identify patients at increased risk for medical complications who may require closer observation.

A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders.

Unsolved Mendelian cases often lack obvious pathogenic coding variants, suggesting potential non-coding etiologies. Here, we present a single cell multi-omic framework integrating embryonic mouse chromatin accessibility, histone modification, and gene expression assays to discover cranial motor neuron (cMN) cis-regulatory elements and subsequently nominate candidate non-coding variants in the congenital cranial dysinnervation disorders (CCDDs), a set of Mendelian disorders altering cMN development. We generated single cell epigenomic profiles for ~86,000 cMNs and related cell types, identifying ~250,000 accessible regulatory elements with cognate gene predictions for ~145,000 putative enhancers. Seventy-five percent of elements (44 of 59) validated in an in vivo transgenic reporter assay, demonstrating that single cell accessibility is a strong predictor of enhancer activity. Applying our cMN atlas to 899 whole genome sequences from 270 genetically unsolved CCDD pedigrees, we achieved significant reduction in our variant search space and nominated candidate variants predicted to regulate known CCDD disease genes MAFB, PHOX2A, CHN1, and EBF3 - as well as new candidates in recurrently mutated enhancers through peak- and gene-centric allelic aggregation. This work provides novel non-coding variant discoveries of relevance to CCDDs and a generalizable framework for nominating non-coding variants of potentially high functional impact in other Mendelian disorders.

Differences in the Relationships Between Muscle Strength, Muscle Mass, Balance Function, and Quality of Life for Middle-Aged and Older Breast Cancer Survivors.

PURPOSE: The purpose of this study was to investigate the differences in muscle strength, muscle mass, balance function, and quality of life (QOL) among middle-aged breast cancer survivors (BCSs) and older BCSs. METHODS: The study included 53 middle-aged (<65 years old) BCSs and 49 older (≥65 years old) BCSs. Muscle strength was evaluated via handgrip and knee extensor strength, and muscle mass was assessed using a body composition test. Balance function was assessed using the Timed Up and Go test and the body sway test. QOL was assessed using the Medical Outcome Study 36-item Short-Form Health Survey. RESULTS: The older BCSs had significantly lower right grip strength, right knee extension strength, and muscle mass (P < .05) than the middle-aged BCSs. In addition, the body sway test showed that older BCSs had a significant increase in the length of center of pressure compared to middle-aged BCSs (P < .05). Older BCSs showed significantly lower physical functioning subscales in QOL compared to middle-aged BCSs (P < .05). The associations among muscle strength, muscle mass and QOL were more significantly observed in the older BCSs (P < .05). Furthermore, a significant correlation between QOL and balance function was observed in the older BCSs, but not in the middle-aged BCSs (P < .05). CONCLUSION: There may be associations among muscle strength, muscle mass, balance and QOL in older BCSs, but not in middle-aged BCSs. We believe that the findings of this study will be relevant in the context of planning rehabilitation for older BCSs.

Statistical and functional convergence of common and rare genetic influences on autism at chromosome 16p.

The canonical paradigm for converting genetic association to mechanism involves iteratively mapping individual associations to the proximal genes through which they act. In contrast, in the present study we demonstrate the feasibility of extracting biological insights from a very large region of the genome and leverage this strategy to study the genetic influences on autism. Using a new statistical approach, we identified the 33-Mb p-arm of chromosome 16 (16p) as harboring the greatest excess of autism's common polygenic influences. The region also includes the mechanistically cryptic and autism-associated 16p11.2 copy number variant. Analysis of RNA-sequencing data revealed that both the common polygenic influences within 16p and the 16p11.2 deletion were associated with decreased average gene expression across 16p. The transcriptional effects of the rare deletion and diffuse common variation were correlated at the level of individual genes and analysis of Hi-C data revealed patterns of chromatin contact that may explain this transcriptional convergence. These results reflect a new approach for extracting biological insight from genetic association data and suggest convergence of common and rare genetic influences on autism at 16p.

Rare coding variation provides insight into the genetic architecture and phenotypic context of autism.

Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.

A cross-disorder dosage sensitivity map of the human genome.

Rare copy-number variants (rCNVs) include deletions and duplications that occur infrequently in the global human population and can confer substantial risk for disease. In this study, we aimed to quantify the properties of haploinsufficiency (i.e., deletion intolerance) and triplosensitivity (i.e., duplication intolerance) throughout the human genome. We harmonized and meta-analyzed rCNVs from nearly one million individuals to construct a genome-wide catalog of dosage sensitivity across 54 disorders, which defined 163 dosage sensitive segments associated with at least one disorder. These segments were typically gene dense and often harbored dominant dosage sensitive driver genes, which we were able to prioritize using statistical fine-mapping. Finally, we designed an ensemble machine-learning model to predict probabilities of dosage sensitivity (pHaplo & pTriplo) for all autosomal genes, which identified 2,987 haploinsufficient and 1,559 triplosensitive genes, including 648 that were uniquely triplosensitive. This dosage sensitivity resource will provide broad utility for human disease research and clinical genetics.

Developmental Variability in Autism Across 17 000 Autistic Individuals and 4000 Siblings Without an Autism Diagnosis: Comparisons by Cohort, Intellectual Disability, Genetic Etiology, and Age at Diagnosis.

Importance: Presence of developmental delays in autism is well established, yet few studies have characterized variability in developmental milestone attainment in this population. Objective: To characterize variability in the age at which autistic individuals attain key developmental milestones based on co-occurring intellectual disability (ID), presence of a rare disruptive genetic variant associated with neurodevelopmental disorders (NDD), age at autism diagnosis, and research cohort membership. Design: The study team harmonized data from 4 cross-sectional autism cohorts: the Autism Genetics Research Exchange (n = 3284; 1997-2015), The Autism Simplex Collection (n = 694; 2008-2011), the Simons Simplex Collection (n = 2753; 2008-2011), and the Simons Foundation Powering Autism Research for Knowledge (n = 10 367; 2016-present). The last sample further included 4145 siblings without an autism diagnosis or ID. Participants: Convenience sample of 21 243 autistic individuals or their siblings without an autism diagnosis aged 4 to 17 years. Main Outcomes and Measures: Parents reported ages at which participants attained key milestones including smiling, sitting upright, crawling, walking, spoon-feeding self, speaking words, speaking phrases, and acquiring bladder and bowel control. A total of 5295 autistic individuals, and their biological parents, were genetically characterized to identify de novo variants in NDD-associated genes. The study team conducted time-to-event analyses to estimate and compare percentiles in time with milestone attainment across autistic individuals, subgroups of autistic individuals, and the sibling sample. Results: Seventeen thousand ninety-eight autistic individuals (mean age, 9.15 years; 80.8% male) compared with 4145 siblings without autism or ID (mean age, 10.2 years; 50.2% female) showed delays in milestone attainment, with median (IQR) delays ranging from 0.7 (0.3-1.6) to 19.7 (11.4-32.2) months. More severe and more variable delays in autism were associated with the presence of co-occurring ID, carrying an NDD-associated rare genetic variant, and being diagnosed with autism by age 5 years. More severe and more variable delays were also associated with membership in earlier study cohorts, consistent with autism's diagnostic and ascertainment expansion over the last 30 years. Conclusions and Relevance: As the largest summary to date of developmental milestone attainment in autism, to our knowledge, this study demonstrates substantial developmental variability across different conditions and provides important context for understanding the phenotypic and etiological heterogeneity of autism.