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PubMed2023

Phenotypic presentation of Mendelian disease across the diagnostic trajectory in electronic health records.

PURPOSE: To investigate the phenotypic presentation of Mendelian disease across the diagnostic trajectory in the electronic health record (EHR). METHODS: We applied a conceptual model to delineate the diagnostic trajectory of Mendelian disease to the EHRs of patients affected by 1 of 9 Mendelian diseases. We assessed data availability and phenotype ascertainment across the diagnostic trajectory using phenotype risk scores and validated our findings via chart review of patients with hereditary connective tissue disorders. RESULTS: We identified 896 individuals with genetically confirmed diagnoses, 216 (24%) of whom had fully ascertained diagnostic trajectories. Phenotype risk scores increased following clinical suspicion and diagnosis (P < 1 × 10-4, Wilcoxon rank sum test). We found that of all International Classification of Disease-based phenotypes in the EHR, 66% were recorded after clinical suspicion, and manual chart review yielded consistent results. CONCLUSION: Using a novel conceptual model to study the diagnostic trajectory of genetic disease in the EHR, we demonstrated that phenotype ascertainment is, in large part, driven by the clinical examinations and studies prompted by clinical suspicion of a genetic disease, a process we term diagnostic convergence. Algorithms designed to detect undiagnosed genetic disease should consider censoring EHR data at the first date of clinical suspicion to avoid data leakage.

Humans↗

PubMed2026

NCBoost v2: a classifier for non-coding single-nucleotide variants in Mendelian diseases.

MOTIVATION: The current diagnostic rate of rare diseases through whole-genome sequencing has stabilized at around 30% on average, highlighting the need for improved computational scores to identify pathogenic variants. In 2019, we developed NCBoost, a supervised-learning approach that mined a comprehensive set of sequence constraint features and proved particularly well suited to identifying high-effect pathogenic non-coding variants in genetic diseases. Since its first release, the substantial increase in the number of variants available for training, as well as the enhanced capacity to detect purifying selection signals from large-scale genome sequencing projects, motivated an update of NCBoost. RESULTS: We implemented NCBoost v2, a pathogenicity score for non-coding single-nucleotide variants, trained on the largest set of curated pathogenic variants in monogenic Mendelian diseases available to date. It leverages conservation features computed from recent large-scale genomic consortia such as Zoonomia and gnomAD, and incorporates recent splice-altering predictive scores. NCBoost v2 outperformed alternative state-of-the-art methods in a variety of scenarii, providing more consistent scores across non-coding genomic regions and fine-tuning the scoring of pathogenic splice-altering variants in Mendelian disease genes. AVAILABILITY AND IMPLEMENTATION: NCBoost v2 software is implemented in Python 3.10 and is freely available under the GNU General Public License Version 3 at https://doi.org/10.5281/zenodo.16029049 and https://github.com/RausellLab/NCBoost-2, together with precomputed scores for the human genome assembly GRCh38.

Polymorphism, Single Nucleotide↗

PubMed2026

Hyperthyroidism Is Genetically Associated With Reduced Risk of Parkinson's Disease: A Mendelian Randomization Analysis.

Parkinson's disease (PD) is a progressive neurodegenerative disorder whose aetiology involves an intricate interplay of genetic, immune, metabolic and environmental factors. Endocrine dysfunction-particularly disturbances of thyroid hormone signalling-has been proposed as a contributor to neurodegeneration, but conventional observational studies have produced inconsistent results, and prior Mendelian randomization (MR) work has largely focused on continuous thyroid biomarkers rather than clinically defined hyperthyroid disease states. To clarify this relationship, we performed a two-sample bidirectional and multivariable MR (MVMR) analysis using large-scale genome-wide association study (GWAS) summary statistics from the FinnGen and IEU Open GWAS databases (European ancestry). Single-nucleotide polymorphisms (SNPs) reaching genome-wide significance (p < 5 × 10-8) for Graves' disease and thyrotoxicosis with diffuse goitre served as instrumental variables. The inverse-variance weighted (IVW) method was the primary analysis, complemented by MR-Egger, weighted median, weighted mode and simple mode estimators, and MVMR adjusted for smoking, alcohol consumption, and body mass index (BMI). In forward analyses, genetically proxied Graves' disease (OR = 0.942, 95% CI 0.901-0.985, p = 0.008) and thyrotoxicosis with diffuse goitre (OR = 0.929, 95% CI 0.879-0.982, p = 0.009) were associated with a lower risk of PD, whereas reverse analyses showed no significant effect of genetic liability to PD on either thyroid trait. The inverse associations remained stable across MVMR models, and sensitivity analyses (Cochran's Q, MR-Egger intercept, MR-PRESSO, leave-one-out) showed no evidence of heterogeneity or horizontal pleiotropy. Collectively, these findings provide genetic evidence consistent with a protective relationship between hyperthyroid disease states and PD, independent of major lifestyle confounders. By focusing on clinically defined hyperthyroid entities rather than continuous thyroid indices, our study complements prior MR work and highlights the thyroid-brain axis-encompassing thyroid hormone signalling and autoimmune-mediated immune modulation-as a biologically plausible and potentially modifiable contributor to PD risk that warrants further mechanistic and translational investigation.

Humans↗

PubMed2024

Shared etiology of Mendelian and complex disease supports drug discovery.

BACKGROUND: Drugs targeting disease causal genes are more likely to succeed for that disease. However, complex disease causal genes are not always clear. In contrast, Mendelian disease causal genes are well-known and druggable. Here, we seek an approach to exploit the well characterized biology of Mendelian diseases for complex disease drug discovery, by exploiting evidence of pathogenic processes shared between monogenic and complex disease. One way to find shared disease etiology is clinical association: some Mendelian diseases are known to predispose patients to specific complex diseases (comorbidity). Previous studies link this comorbidity to pleiotropic effects of the Mendelian disease causal genes on the complex disease. METHODS: In previous work studying incidence of 90 Mendelian and 65 complex diseases, we found 2,908 pairs of clinically associated (comorbid) diseases. Using this clinical signal, we can match each complex disease to a set of Mendelian disease causal genes. We hypothesize that the drugs targeting these genes are potential candidate drugs for the complex disease. We evaluate our candidate drugs using information of current drug indications or investigations. RESULTS: Our analysis shows that the candidate drugs are enriched among currently investigated or indicated drugs for the relevant complex diseases (odds ratio = 1.84, p = 5.98e-22). Additionally, the candidate drugs are more likely to be in advanced stages of the drug development pipeline. We also present an approach to prioritize Mendelian diseases with particular promise for drug repurposing. Finally, we find that the combination of comorbidity and genetic similarity for a Mendelian disease and cancer pair leads to recommendation of candidate drugs that are enriched for those investigated or indicated. CONCLUSIONS: Our findings suggest a novel way to take advantage of the rich knowledge about Mendelian disease biology to improve treatment of complex diseases.

Humans↗

PubMed2026

Causality between noise pollution and Alzheimer disease: A Mendelian randomization analysis.

The role of noise pollution as a risk factor for Alzheimer disease (AD) is unclear, with observational studies yielding conflicting results susceptible to confounding and reverse causality. To clarify this relationship, we performed a 2-sample Mendelian randomization (MR) study using summary statistics from large-scale genome-wide association studies of European populations. Genetically predicted daytime and evening noise exposure was used as an instrumental variable to assess a causal effect on AD risk. The primary analysis was conducted using the inverse-variance weighted method, with weighted median and MR-Egger methods as key sensitivity analyses. We assessed instrument validity and pleiotropy using the Cochran Q test, the MR-Egger intercept, and leave-one-out analysis. Our MR analysis found no evidence of a causal association between genetically predicted daytime noise (odds ratio [95% confidence interval] = 0.999 [0.993-1.006], P = .819) or evening noise (odds ratio [95% confidence interval] = 0.999 [0.993-1.005], P = .643) and the risk of AD. Sensitivity analyses were consistent, with no evidence of heterogeneity or directional pleiotropy. In conclusion, this study does not support a direct causal link between noise and AD. While our findings mitigate common observational biases, they do not preclude indirect mechanisms whereby noise may influence AD pathogenesis via established risk pathways, such as chronic sleep disruption and cardiovascular stress. Studies are needed to focus on disentangling these potential indirect effects.

Alzheimer Disease↗

PubMed2026

Shared genetic basis and structure of syndromic and normal facial variation.

The question of how gene mutations of large effect and common variants of small effect relate to phenotypic variation dates from the origins of genetics. Mendelian diseases result from rare germline variants with major effects, while complex traits are associated with multiple, mostly common variants of small effect. High-dimensional phenotypes, such as facial shape, can shed new light on this age-old dichotomy, as their variation can be characterized in terms of directions in multivariate morphospace. Within such spaces, do Mendelian disease mutations move phenotypes along the same directions as common variants, or do they forge new directions that diverge from the common structure of background variation? Here, we analyze facial shape variation for 66 syndromes, quantify multivariate axes of facial shape variation for each syndrome, and test whether common genetic variants in cohorts of non-syndromic subjects are associated with phenotypic position along these same axes. We find that syndromic facial shape generally follows the background variance-covariance structure of facial shape in the general population. Furthermore, syndromic probands' unaffected relatives have subtle facial morphology resembling the syndromes of their affected relatives. These results suggest that Mendelian disease variants act on facial shape in ways similar to common variants. Syndromic probands with higher "severity" likely occur on genetic backgrounds with higher cumulative severity of common variants for each syndromic axis. These findings position Mendelian diseases at extremes along phenotypic continua that exist in the background population rather than as qualitatively different phenotypes distinct from the overall structure of normal human phenotypic variation.

Humans↗

PubMed2024

Uric Acid Levels and Cardiovascular and Cerebrovascular Diseases: A Mendelian Randomization Study.

INTRODUCTION: The relationship between uric acid (UA) levels and cardiovascular and cerebrovascular diseases (CCVD) is controversial. A two-sample Mendelian randomization (MR) study was conducted to explore the causal effects of UA levels on CCVD. METHODS: Genetic variants strongly associated with UA levels were selected as instrumental variables from the Genome-Wide Association Study (GWAS) dataset. The GWAS data, sourced from the Global Urate Genetics Consortium (GUGC), comprised a sample size of 110,347 individuals. The selected CCVD outcomes included stroke, coronary artery disease (CAD), as well as atrial fibrillation and flutter. The primary analytical approach employed the inverse-variance weighted (IVW) method, supplemented by MR-Egger and weighted median as complementary methods. Sensitivity analysis was performed to test heterogeneity and pleiotropy. RESULTS: The MR analysis results indicated a causal association between UA levels and stroke (odds ratio [OR]: 1.002; 95% confidence interval [CI]: 1.000-1.003; p = 0.036), CAD (OR: 1.118; 95% CI: 1.044-1.197; p = 0.001), as well as atrial fibrillation and flutter (OR: 1.141; 95% CI: 1.037-1.256; p = 0.007). The results of MR-Egger and weighted median methods confirmed the direction of the IVW results, enhancing the robustness of the findings. No significant anomalies were detected in the sensitivity analysis. CONCLUSION: The MR study suggests that UA levels exert causal effects on stroke, CAD, as well as atrial fibrillation and flutter.

Humans↗

PubMed2026

MAJIQ-CLIN: A novel tool to help identify Mendelian disease-causing variants from RNA-seq data.

PURPOSE: The current diagnostic rate for patients with suspected Mendelian genetic disorders is low, despite exome/genome sequencing being the standard of care. One reason for this low diagnostic rate is that traditional exome/genome sequencing analysis methods struggle to detect RNA splicing aberrations. Causative variants often involve splicing changes, with numerous splice-altering variants being responsible for known Mendelian disorders. Therefore, it is crucial to develop reliable tools to detect, quantify, prioritize, and visualize RNA splicing aberrations from patient RNA sequencing data. METHODS: We developed Modeling Alternative Junction Inclusion Quantification for Clinical Applications (MAJIQ-CLIN), a method to identify RNA splicing aberrations in patients' RNA sequencing data compared with a cohort of control samples. MAJIQ-CLIN can efficiently process large datasets, avoiding reprocessing when new data are added, while effectively detecting local splicing variations with deviations in a given patient, termed outlier local splicing variation, or unique to the patient, termed private local splicing variation. RESULTS: We performed a systematic evaluation of the accuracy of tools for detecting patients' RNA splicing aberrations from RNA sequence using synthetic data across several aberration types and transcript inclusion levels. Then, we used several real datasets to assess MAJIQ-CLINs ability to identify solved test cases and control for the effect of confounders such as batches. We showed that MAJIQ-CLIN compares favorably to existing tools in both accuracy and efficiency. We also used MAJIQ-CLIN to investigate several unsolved patient cases from the Undiagnosed Diseases Network. CONCLUSION: MAJIQ-CLIN offers an efficient, accurate, and user-friendly tool to aid in diagnosing Mendelian disease-causing variants from RNA sequence data.

Bioinformatics↗

PubMed2025

Association of genetically proxied cancer-targeted drugs with cardiovascular diseases through Mendelian randomization analysis.

BACKGROUND: Cancer-targeted therapies are progressively pivotal in oncological care. Observational studies underscore the emergence of cancer therapy-related cardiovascular toxicity (CTR-CVT), impacting patient outcomes. We aimed to investigate the causal relationship between different types of cancer-targeted therapies and cardiovascular disease (CVD) outcomes through a two-sample Mendelian randomization (MR) study. METHODS: This genome-wide association study was conducted using a two-sample Mendelian randomization framework. Genetic instruments for drug target gene expression were extracted from the eQTLGen consortium (31684 individuals, 37 cohorts). Genome-wide association study (GWAS) summary statistics for 19 cardiovascular diseases were derived from the FinnGen database. Primary analysis was carried out using the summary-data-based MR (SMR) method, with sensitivity analysis for validation. Colocalization analysis identifies shared causal variants between exposure eQTLs and CVD-associated single-nucleotide polymorphisms (SNPs). RESULTS: Among the 39 drug target genes, 8 were identified with detectable cis-eQTLs and were subsequently validated through positive control analysis for further investigation. In the SMR and sensitivity analyses, genetically proxied VEGFA inhibition showed significantly strong association with stroke (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.09-1.26, p = 1.33 × 10- 5). Additionally, the inhibition of FGFR1, FLT1, and MAP2K2 exhibited suggestive association with corresponding cardiovascular disease outcomes. Nevertheless, only VEGFA expression and stroke shared a causal variant (93.6%), whereas FGFR1, MAP2K2, and FLT1 did not share causal variants with corresponding cardiovascular diseases in the colocalization analysis. CONCLUSIONS: This genetic association study revealed evidence supporting the genetic association between the use of VEGFA inhibitors and increased stroke risk, highlighting the need for enhanced pharmacovigilance. These findings underscore the delicate balance between cardiovascular toxicity risk and the benefits of cancer-targeted therapy.

Humans↗

PubMed2024

Leveraging clinical intuition to improve accuracy of phenotype-driven prioritization.

PURPOSE: Clinical intuition is commonly incorporated into the differential diagnosis as an assessment of the likelihood of candidate diagnoses based either on the patient population being seen in a specific clinic or on the signs and symptoms of the initial presentation. Algorithms to support diagnostic sequencing in individuals with a suspected rare genetic disease do not yet incorporate intuition and instead assume that each Mendelian disease has an equal pretest probability. METHODS: The LIkelihood Ratio Interpretation of Clinical AbnormaLities (LIRICAL) algorithm calculates the likelihood ratio of clinical manifestations represented by Human Phenotype Ontology terms to rank candidate diagnoses. The initial version of LIRICAL assumed an equal pretest probability for each disease in its calculation of the posttest probability (where the test is diagnostic exome or genome sequencing). We introduce Clinical Intuition for Likelihood Ratios (ClintLR), an extension of the LIRICAL algorithm that boosts the pretest probability of groups of related diseases deemed to be more likely. RESULTS: The average rank of the correct diagnosis in simulations using ClintLR showed a statistically significant improvement over a range of adjustment factors. CONCLUSION: ClintLR successfully encodes clinical intuition to improve ranking of rare diseases in diagnostic sequencing. ClintLR is freely available at https://github.com/TheJacksonLaboratory/ClintLR.

Humans↗

PubMed2026

Myeloid Dendritic Cell Counts and Coronary Heart Disease: a Bidirectional Mendelian Randomization Study.

BACKGROUND: Coronary heart disease (CHD) remains a leading cause of morbidity and mortality worldwide, with immune and inflammatory mechanisms playing important roles in its pathogenesis. Dendritic cells (DCs) are key regulators of immune responses; however, the relationship between specific DC subsets and CHD risk remains incompletely understood. METHODS: This study conducted a bidirectional two-sample Mendelian randomization (MR) analysis using publicly available genome-wide association study (GWAS) summary statistics to investigate the potential associations between circulating dendritic cell traits and CHD. Genetic instruments for myeloid dendritic cells (Myeloid DCs) and plasmacytoid dendritic cells (Plasmacytoid DCs), including both absolute counts and relative proportions, were obtained from immune cell GWAS datasets. Summary statistics for CHD were derived from a large European-ancestry population. Multiple MR methods were applied, and sensitivity analyses were performed to assess the robustness of the findings and potential pleiotropic effects. RESULTS: Nominal associations between genetically predicted Myeloid DC counts and CHD risk were observed in the MR-Egger and weighted median analyses, whereas the inverse variance weighted analysis demonstrated no significant association. These nominal associations did not remain statistically significant after correction for multiple testing. No significant associations were observed for Plasmacytoid DC counts or for the relative proportions of either DC subset. Reverse MR analyses were inconclusive due to wide confidence intervals, precluding meaningful inference regarding a causal effect of CHD on DC-related traits. Sensitivity analyses revealed no substantial heterogeneity or horizontal pleiotropy. CONCLUSIONS: This bidirectional MR study explored the potential relationships between circulating dendritic cell traits and CHD risk. Although nominal associations involving Myeloid DC counts were observed in secondary MR analyses, no robust evidence supporting an association remained after correction for multiple testing. Further studies using larger datasets and functional approaches are warranted to clarify the role of dendritic cells in CHD.

Humans↗

PubMed1977

The George M. Kober lecture: a genetical view of modern medicine.

A genetic approach to medicine provides a powerful concept for understanding of the etiology of many diseases. Significant investigative and therapeutic advances have already been made in the chromosomal and Mendelian diseases using genetic concepts which initially were discovered completely unrelated to medicine. The combination of unfettered basic biomedical research together with family and population studies is likely to bring new insights to understanding, prevention and treatment of the yet poorly understood multifactorial diseases which represent the greatest public health problems in the Western world. Identification of specific genes involved in susceptibility and resistance to these diseases and their interaction with various environmental factors will allow a more rational preventive medicine in the future.

Chromosome Aberrations↗

PubMed2026

The impact for causal associations between common diseases and inflammatory bowel disease: a disease-wide bidirectional Mendelian randomization study.

OBJECTIVES: Observational studies on associations between various diseases and inflammatory bowel disease (IBD) are often limited by confounding and reverse causation. We aimed to assess potential causal relationships between a wide range of diseases and IBD, including Crohn's disease (CD) and ulcerative colitis (UC). METHODS: We performed a comprehensive bidirectional Mendelian randomization (MR) analysis of 104 common diseases and IBD traits using the generalized summary-data-based MR (GSMR) approach. Genome-wide association study (GWAS) summary statistics for diseases were obtained from the MRC Integrative Epidemiology Unit, and IBD data from the International IBD Genetics Consortium. Summary-data-based MR (SMR) integrating GWAS and expression quantitative trait locus data was applied to identify pleiotropic genes associated with IBD. RESULTS: MR analyses identified 38, 34, and 52 exposures significantly associated with IBD, UC, and CD, respectively. Childhood- and adult-onset asthma showed distinct causal effects on UC and CD. Reverse MR indicated associations between IBD traits and 15 diseases, including multiple sclerosis. SMR identified RGS14 and CARD9 as pleiotropic genes linked to IBD, suggesting shared genetic mechanisms with asthma and multiple sclerosis. CONCLUSIONS: These findings provide evidence for causal links and shared immune-related genetic mechanisms underlying IBD, highlighting potential targets for future research.

Humans↗

PubMed2025

Blood Pressure Genetics in Han Taiwanese With Cross-Trait Analysis in East Asians: Insights Into Comorbidities, All-Cause Mortality, and Cardiovascular Mortality.

BACKGROUND: Hypertension is a major health burden in East Asia. However, the genetic architecture and clinical implications of blood pressure (BP) traits remain underexplored beyond European-focused studies. This large-scale study aimed to investigate hypertension, systolic BP, and diastolic BP, to uncover genetic links to comorbidities and mortality in Han Taiwanese individuals. METHODS: This large-scale study used China Medical University Hospital biobank data and conducted genome-wide association studies on 25 523 hypertension cases and 47 522 controls, plus 66 236 individuals for systolic BP and 66 152 for diastolic BP. Cross-trait genetic correlations were assessed across 5 East Asian biobanks. Mendelian randomization and polygenic risk scores were applied to assess causality and predict clinical outcomes. RESULTS: We identified 8 loci and 36 genes for hypertension, 7 loci and 17 genes for systolic BP, and 9 loci and 26 genes for diastolic BP. ATP2B1 and FGF5 were common to all BP traits, implicating calcium signaling and vascular remodeling pathways. Cross-trait analyses showed shared genetic liability between BP traits and cardiovascular and metabolic comorbidities. Phenome-wide association studies confirmed strong associations with circulatory diseases. Mendelian randomization analyses demonstrated that elevated BP causally increases the risk of unstable angina pectoris. Polygenic risk scores predicted significantly higher risks and earlier onset of unstable angina pectoris, all-cause mortality, and cardiovascular mortality among individuals in the top polygenic risk score quintiles. CONCLUSIONS: Our findings highlight the genetic basis of BP and comorbidities in East Asians, suggesting that BP genetic risk may inform future approaches to early risk assessment and prevention.

Aged↗

PubMed1977

[Medico-genetic study of the population of Uzbekistan. I. Incidence and variety of hereditary pathology].

In district of the Samarkand province the screening for families burdened with multiple cases of non-infectious diseases was performed. The principles of the applied screening procedure are described in the present paper. In the course of clinical examination 98 families were detected, 55 of which included more than one person suffering presumably with Mendelian diseases and 43--with multifactorial disorders. Over 30 nosological forms were found, among which orthopaedic and neurological forms were the most frequent. As a rule, identical cases were detected in one or two families. The role of certain genetic processes in the distribution of hereditary diseases in the Uzbek population is discussed.

Genetic Diseases, Inborn↗

PubMed2025

Genome sequencing reveals the impact of pseudoexons in rare genetic disease.

PURPOSE: Advancements in sequencing technologies have significantly improved clinical genetic testing; yet, the diagnostic yield remains around 30% to 40%. Emerging technologies are now being deployed to address the remaining diagnostic gap. METHODS: We tested whether short-read genome sequencing could increase the diagnostic yield in individuals enrolled into the UCI-GREGoR research study, who had suspected Mendelian conditions and prior inconclusive testing. Two other collaborative research cohorts, focused on aortopathy and dilated cardiomyopathy, consisted of individuals who were undiagnosed but had not undergone harmonized prior testing. RESULTS: We sequenced 353 families (754 participants) and found a molecular diagnosis in 54 (15.3%) of them. Of these diagnoses, 55.5% were previously missed because the causative variants were in regions not originally interrogated. In 5 cases, they were deep intronic variants, all of which led to abnormal splicing and pseudoexons, as directly shown by RNA sequencing. All 5 of these variants had inconclusive spliceAI scores. In 26% of newly diagnosed cases, the causal variant could have been detected by exome sequencing reanalysis. CONCLUSION: Genome sequencing can overcome limitations of clinical genetic testing, such as the inability to call intronic variants. Our findings highlight pseudoexons as a common mechanism via which deep intronic variants cause Mendelian disease.

Humans↗

PubMed1978

[Medico-genetic study of the population of Uzbekistan. IV. Medico-genetic description of the population of 4 villages of the Urgut district of the Samarkand region].

The data about the incidence of hereditary diseases and those with genetic predispositions which received after subtotal medico-genetical examination of the inhabitants of 4 villages in the Urgut district of the Samarkand province are presented. 848 inhabitants (348 adults and 464 children aged 7--16 years) are examined. The nosological profile of the morbidity and spectrum of the Mendelian diseases in the population is evaluated. The integrative estimate of load of the detrimental (non-lethal) genes is about 0.166 per individual.

Adult↗

PubMed2026

Variants leading to ELAVL2 haploinsufficiency cause a neurodevelopmental disorder with prominent cognitive, behavioral, and neurological features.

RNA-binding proteins (RBPs) regulate gene expression, and a number of RBPs have been implicated in brain function and behavior. Here, we report 16 individuals with a neurodevelopmental disorder and de novo heterozygous variants in ELAVL2, encoding an RBP not previously linked to Mendelian disease. Thirteen individuals were identified through GeneMatcher. Their ELAVL2 variants include two structural, five nonsense, and six missense variants, supporting haploinsufficiency as the primary disease mechanism. The cohort presented with developmental delay, intellectual disability, autism spectrum disorder, seizures, sleep problems, sensory processing issues, emotional instability, and difficulty with socialization. Three additional variants (two missense and one terminal exon truncation), each previously reported in a different large cohort study, were also included for follow-up investigations. We provide multiple lines of evidence linking variants in ELAVL2 to the observed neurodevelopmental and behavioral phenotypes. First, we show that common genetic variants in ELAVL2 are significantly associated with intelligence, motor development, sleep-related traits, and sociability in the general population. Drosophila loss-of-function models provide further independent evidence for a conserved role in the regulation of seizure-like behavior, sensory processing, and sleep. Molecular studies confirm that some of the missense variants are deleterious, leading to decreased protein levels. Together, our integrative study combining Mendelian genetics, clinical and association studies, and animal and molecular modeling supports variants in ELAVL2 as a cause of a neurodevelopmental disorder, with haploinsufficiency as the disease mechanism, and identifies crucial roles of ELAVL2 in neuronal function, cognition, and behavior.

Humans↗