Prevalence Of Neurodevelopmental Disorders Research Articles

A Missense Variant in HACE1 Is Associated with Intellectual Disability, Epilepsy, Spasticity, and Psychomotor Impairment in a Pakistani Kindred.

Intellectual disability (ID), which affects around 2% to 3% of the population, accounts for 0.63% of the overall prevalence of neurodevelopmental disorders (NDD). ID is characterized by limitations in a person's intellectual and adaptive functioning, and is caused by pathogenic variants in more than 1000 genes. Here, we report a rare missense variant (c.350T>C; p.(Leu117Ser)) in HACE1 segregating with NDD syndrome with clinical features including ID, epilepsy, spasticity, global developmental delay, and psychomotor impairment in two siblings of a consanguineous Pakistani kindred. HACE1 encodes a HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1), which is involved in protein ubiquitination, localization, and cell division. HACE1 is also predicted to interact with several proteins that have been previously implicated in the ID phenotype in humans. The p.(Leu117Ser) variant replaces an evolutionarily conserved residue of HACE1 and is predicted to be deleterious by various in silico algorithms. Previously, eleven protein truncating variants of HACE1 have been reported in individuals with NDD. However, to our knowledge, p.(Leu117Ser) is the second missense variant in HACE1 found in an individual with NDD.

Systematic Review and Meta-Analysis: Prevalence of Neurodevelopmental Disorders Among Indigenous Children

Systematic Review and Meta-Analysis: Prevalence of Neurodevelopmental Disorders Among Indigenous Children

Sex-Specific Behavioural Deficits in Adulthood following Acute Activation of the GABAA Receptor in the Neonatal Mouse

Introduction: Sex differences exist in the prevalence of neurodevelopmental disorders (NDDs). Part of the aetiology of NDDs has been proposed to be alterations in the balance between excitatory and inhibitory neurotransmission, leading to the question of whether males and females respond differently to altered neurotransmitter balance. We investigated whether pharmacological alteration of GABAA signalling in early development results in sex-dependent changes in adult behaviours associated with NDDs. Methods: Male and female C57BL/6J mice received intraperitoneal injections of 0.5 mg/kg muscimol or saline on postnatal days (P) 3–5 and were subjected to behavioural testing, specifically open field, light/dark box, marble-burying, sucralose preference, social interaction, and olfactory habituation/dishabituation tests between P60 and P90. Results: Early postnatal administration of muscimol resulted in reduced anxiety in the light/dark box test in both male and female adult mice. Muscimol reduced sucralose preference in males, but not females, whereas female mice showed reduced social behaviours. Regional alterations in cortical thickness were observed in the weeks following GABAA receptor activation, pointing to an evolving structural difference in the brain underlying adult behaviour. Conclusions: We conclude that activation of the GABAA receptor in the first week of life resulted in long-lasting changes in a range of behaviours in adulthood following altered neurodevelopment. Sex of the individual affected the nature and severity of these abnormalities, explaining part of the varied pathophysiology and neurodevelopmental diagnosis that derive from excitatory/inhibitory imbalance.

Novel and known minor alleles of CNTNAP2 gene variants are associated with comorbidity of intellectual disability and epilepsy phenotypes: a case-control association study reveals potential biomarkers.

Neurodevelopmental disorders are heterogeneous due to underlying multiple shared genetic pathways and risk factors. Intellectual disability, epilepsy and autism spectrum disorder phenotypes overlap which indicates the diverse effects of common genes. Recent studies suggested the probable contribution of CNTNAP2 gene polymorphisms to the comorbidity of these neurological conditions. This study was conducted to investigate the role of CNTNAP2 polymorphisms rs147815978 (G>T) and rs2710102 (A>G) as a risk factor for comorbidity of intellectual disability and epilepsy in a group of 345 individuals including 170 patients and 175 healthy controls recruited from various ethnic groups of Pakistani population. Our case-control study group was genotyped by tetra primer ARMS-PCR technique and results were analysed to know the effects of CNTNAP2 rs147815978 (G>T) and rs2710102 (A>G) polymorphisms in the group. The frequency of risk allele T (rs147815978) and risk allele G (rs2710102) for homozygous recessive genotypes (TT/GG) in our study group was 36.47% while odds ratios for risk allele T (rs147815978) was 5.45 (3.90-7.61: 95% CI, P = 0.000) and that for risk allele G (rs2710102) was 2.39 (1.76-3.24: 95% CI, P = 0.0001). Homozygous recessive genotypes (TT/GG) appeared only in cases and not in control group which indicated these as suspected risk genotypes and the significant association (p < 0.05%) of CNTNAP2 gene polymorphisms rs147815978 (G>T) and rs2710102 (A>G) with co-occurrence of intellectual disability and epilepsy phenotypes in our study group which is in HWE (χ2 = 174, P < 0.0001). Logistic regression analysis shows additive (p < 0.0001) and multiplicative (p < 0.001) models which confirms significant association of both the polymorphisms in our data, which are closely located on same haplotype (D' = -0.168). We propose that CNTNAP2 rs147815978 (G>T) and rs2710102 (A>G) polymorphisms are possible risk loci for overlapping neurodevelopmental disorders in Pakistani population. We propose the role of a previously reported common SNP rs2710102 (A>G) with a rarely reported novel SNP rs147815978 (G>T) for CNTNAP2 gene association with neurodevelopmental disorders in our data. Our study has expanded the knowledge of CNTNAP2 gene polymorphisms as probable biomarkers for susceptibility of co-occurrence of intellectual disability and epilepsy phenotypes in Pakistani population. We hope that our study will open new horizons of CNTNAP2 gene variants research to cure the neurological conditions in Pakistani population where consanguinity is a tradition and prevalence of neurodevelopmental disorders has increased from 1 to 2% during last 5 years.

Acetaminophen causes neurodevelopmental injury in susceptible babies and children: no valid rationale for controversy.

Despite the worldwide acceptance of acetaminophen (APAP) as a necessary medicine in pediatrics, evidence that early exposure to APAP causes neurodevelopmental injury in susceptible babies and children has been mounting for over a decade. The evidence is diverse and includes extensive work with laboratory animals, otherwise unexplained associations, factors associated with APAP metabolism, and limited studies in humans. Although the evidence has reached an overwhelming level and was recently reviewed in detail, controversy persists. This narrative review evaluates some of that controversy. Evidence from the pre- and postpartum periods was considered to avoid controversy raised by consideration of only limited evidence of risks during the prepartum period. Among other issues, the association between APAP use and the prevalence of neurodevelopmental disorders was considered. A systematic review revealed that the use of APAP in the pediatric population was never tracked carefully; however, historical events that affected its use were documented and are sufficient to establish apparent correlations with changes in the prevalence of neurodevelopmental disorders. Moreover, problems with the exclusive reliance on results of meta-analyses of large datasets with limited time frames of drug exposure were reviewed. Furthermore, the evidence of why some children are susceptible to APAPinduced neurodevelopmental injuries was examined. We concluded that available evidence demonstrates that early exposure to APAP causes neurodevelopmental injury in susceptible babies and small children.

The interplay of ADHD symptoms and exercise in youth

The interplay of ADHD symptoms and exercise in youth

Association between maternal influenza vaccination and neurodevelopmental disorders in childhood: a longitudinal, population-based linked cohort study

ObjectiveTo assess the association between in utero exposure to seasonal inactivated influenza vaccine (IIV) and the risk of a diagnosis of a neurodevelopmental disorder in early childhood.DesignRetrospective cohort study.SettingPopulation-based birth...

Gut Microbiome and Neurodevelopmental Disorders: A Link Yet to Be Disclosed.

Τhe importance of the gut microbiome and its functions has only recently been recognized and researched in greater depth. The establishment of the human gut microbiome begins in utero, forming its adult-like phenotype in the first 2-3 years of life. Several factors affect and alter the gut microbiome composition and its metabolic functions, such as early onset of breastfeeding, mode of delivery, antibiotic administration, or exposure to chemical substances, among others. Existing data support the important connection between health status and gut microbiome homeostasis. In cases when this balance is disturbed, several disorders may arise, such as inflammatory reactions that lead to atopy, eczema, or allergic asthma. The so-called gut-brain axis refers to the complex biochemical pathways between the central nervous system and the gastrointestinal system. One of the most fascinating areas of ongoing research is the broad spectrum of neurodevelopmental disorders (NDDs) and how gut health may be associated with such disorders. The prevalence of NDDs, such as autism spectrum disorder or attention deficit hyperactivity disorder, has increased over recent years. Whether gut microbiota homeostasis plays a role in these disorders is not yet fully understood. The aim of this narrative review is to provide an account of current knowledge on how gut health is linked with these disorders. We performed a literature review in order to identify and synthesize available data that highlights the potential association between NDDs and a balanced gut microbiome in terms of composition and proper function. The connection between the gut microbiome and NDDs offers promising new opportunities for future research.

Prevalence of neurodevelopmental disorders in children from the rural population of Oaxaca evaluated by means of the Child Development Evaluation test

During child's growth, access to health, nutrition, opportunities for stimulation, and early learning are necessary for an optimal development of the central nervous system. In rural areas there is a lack of access to them, and this has an impact on children's neurodevelopment. To identify the prevalence of lag or delay in the development of children in rural areas. A descriptive, cross-sectional and prospective study, with non-probabilistic convenience sampling, where 97 infants from 1 month of age to one day before their 5th birthday, all belonging to rural communities in the state of Oaxaca, Mexico, were applied the Child Development Evaluation, designed and validated for the Mexican population in the early detection of neurodevelopmental problems. The prevalence of developmental disorders was 43%, with predominance in the male sex. The area of development with the greatest affectation was language, with a total of 29%, and in second place gross motor skills, with 18%; however, neurological affectation as the only one occurred in 2% of the participants, the most prevalent risk factors were the urinary tract infections in 56% of mothers. There is a percentage greater than 30% of neurodevelopmental disorders in rural communities due to social risk factors that infants face, such as the difficult access to medical care, a poorly stimulating environment and bad nutrition.

Prevalence of neurodevelopmental disorders among US children and adolescents in 2019 and 2020.

Concerning the changes in the prevalence of neurodevelopmental disorders (NDDs), we estimate the prevalence of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), intellectual disorder (ID), and learning disability (LD) among US children and adolescents aged 3-17 years in 2019 and 2020. The study includes 14,983 US children and adolescents aged 3-17 years in 2019 and 2020 from the National Health Interview Survey (NHIS). Parents were interviewed about whether their children ever and/or currently had NDDs diagnosed. Prevalence estimates of NDDs were calculated with a survey-based weighting scheme. Logistic regression models were used to estimate the associations between NDDs prevalence and subgroups. The weighted prevalence of ADHD, ASD, ID, and LD was 8.5% (95% CI: 7.9-9.2%), 2.9% (95% CI: 2.6-3.4%), 1.4% (95% CI: 1.2-1.7%), and 6.4% (95% CI: 5.8-7.0%), respectively. A higher prevalence of ADHD, ASD, ID, and LD was observed in boys, those who ever had anxiety or depression symptoms, those with lower family income, those living in a rented house, ever been bullied, and ever lived with anyone mentally ill. The study found the prevalence of ADHD, ASD, ID, and LD was different by demographics, comorbidity/mental problems, household/parental characteristics, and stressful life events.

Neurodevelopmental Outcomes of Pregnancies Resulting from Assisted Reproduction: A Review of the Literature.

The term infertility is defined as the lack of conception within 1 year of unprotected intercourse. It affects more than 80 million individuals worldwide. It is estimated that 10-15% of couples of reproductive age are challenged by reproductive issues. Assisted reproduction techniques (ART) are responsible for more than 4% of live births. Our aim is to review the research on neurodevelopmental outcomes of newborns born after the implementation of assisted reproduction methods compared to those conceived naturally. We conducted a comprehensive search of the PubMed, Crossref and Google Scholar electronic databases for related articles up to June 2022 using the PRISMA guidelines. Our research revealed a large number of long term follow-up studies between 2 and 18 years of age, with comparable developmental outcomes. Many studies compared the effects of different infertility treatments against natural conception. The review of the literature revealed that ART is safe, as the majority of studies showed no effect on the neurodevelopmental outcomes of the offspring. In most cases when such an effect was observed, it could be attributed to confounding factors such as subfertility, multiple pregnancies and gestational age at delivery. Finally, the increase in the prevalence of neurodevelopmental disorders after ART, as described in studies with statistically significant results, is predominantly marginal, and given the low incidence of neurodevelopmental disorders in the general population, its clinical significance is debatable.

Balanced Sex Ratios and the Autism Continuum

SEE CORRESPONDING ARTICLE ON PAGE 654 A Data-Driven Approach in an Unbiased Sample Reveals Equivalent Sex Ratio of Autism Spectrum Disorder–Associated Impairment in Early ChildhoodBiological PsychiatryVol. 92Issue 8PreviewSex differences in the prevalence of neurodevelopmental disorders are particularly evident in autism spectrum disorder (ASD). Heterogeneous symptom presentation and the potential of measurement bias hinder early ASD detection in females and may contribute to discrepant prevalence estimates. We examined trajectories of social communication (SC) and restricted and repetitive behaviors (RRBs) in a sample of infant siblings of children with ASD, adjusting for age- and sex-based measurement bias. We hypothesized that leveraging a prospective elevated familial likelihood sample, deriving data-driven behavioral constructs, and accounting for measurement bias would reveal less discrepant sex ratios than are typically seen in ASD. Full-Text PDF

The associations between ADHD, pain, inflammation, and quality of life in children and adolescents-a clinical study protocol.

New research shows that the prevalence of neurodevelopmental disorders, such as attention-deficit/hyperactivity disorder (ADHD), is increased in children and adolescents as well as in adults with chronic pain, compared to those without chronic pain. Children and adolescents with ADHD also have an increased incidence of various physical conditions associated with pain, and they more frequently suffer from inflammatory diseases. Moreover, parents of children with ADHD can often suffer from pain conditions. These epidemiological and clinical observations form the scientific basis of our study, which aims to map the relationships between ADHD, altered pain experiences/central sensitization, and inflammation in children and adolescents. We will investigate the presence of central sensitization in children and adolescents with newly diagnosed ADHD and compare it with those who have not been diagnosed with ADHD. Participants (and their biological parents) will complete surveys about their somatic health, pain experience, and quality of life. Biological samples (saliva and stool) will be collected, aiming to utilize proteome and metabolome data to discover disease mechanisms and to predict, prevent and treat them. The results from our investigation should enable an expanded understanding of the pathophysiology behind both ADHD and pain/central sensitization. Presently, there are no established protocols for addressing psychiatric symptoms when examining patients with pain conditions in a somatic care setting, nor is there any knowledge of offering patients with ADHD or other neurodevelopmental disorders adapted treatments for pain conditions. Our results, therefore, can contribute to the development of new treatment strategies for pathological pain conditions in children and adolescents with ADHD. They may also increase awareness about and provide opportunities for the treatment of attention and impulse control problems in children and adolescents with pain syndromes.

A Data-Driven Approach in an Unbiased Sample Reveals Equivalent Sex Ratio of Autism Spectrum Disorder–Associated Impairment in Early Childhood

BackgroundSex differences in the prevalence of neurodevelopmental disorders are particularly evident in autism spectrum disorder (ASD). Heterogeneous symptom presentation and the potential of measurement bias hinder early ASD detection in females and may contribute to discrepant prevalence estimates. We examined trajectories of social communication (SC) and restricted and repetitive behaviors (RRBs) in a sample of infant siblings of children with ASD, adjusting for age- and sex-based measurement bias. We hypothesized that leveraging a prospective elevated familial likelihood sample, deriving data-driven behavioral constructs, and accounting for measurement bias would reveal less discrepant sex ratios than are typically seen in ASD. MethodsWe conducted direct assessments of ASD symptoms at 6 to 9, 12 to 15, 24, and 36 to 60 months of age (total nobservations = 1254) with infant siblings of children with ASD (n = 377) and a lower ASD-familial-likelihood comparison group (n = 168; nobservations = 527). We established measurement invariance across age and sex for separate models of SC and RRB. We then conducted latent class growth mixture modeling with the longitudinal data and evaluated for sex differences in trajectory membership. ResultsWe identified 2 latent classes in the SC and RRB models with equal sex ratios in the high-concern cluster for both SC and RRB. Sex differences were also observed in the SC high-concern cluster, indicating that girls classified as having elevated social concerns demonstrated milder symptoms than boys in this group. ConclusionsThis novel approach for characterizing ASD symptom progression highlights the utility of assessing and adjusting for sex-related measurement bias and identifying sex-specific patterns of symptom emergence.

Individual and Combined Effects of Paternal Deprivation and Developmental Exposure to Firemaster 550 on Socio-Emotional Behavior in Prairie Voles.

The prevalence of neurodevelopmental disorders (NDDs) is rapidly rising, suggesting a confluence of environmental factors that are likely contributing, including developmental exposure to environmental contaminants. Unfortunately, chemical exposures and social stressors frequently occur simultaneously in many communities, yet very few studies have sought to establish the combined effects on neurodevelopment or behavior. Social deficits are common to many NDDs, and we and others have shown that exposure to the chemical flame retardant mixture, Firemaster 550 (FM 550), or paternal deprivation impairs social behavior and neural function. Here, we used a spontaneously prosocial animal model, the prairie vole (Microtus ochrogaster), to explore the effects of perinatal chemical (FM 550) exposure alone or in combination with an early life stressor (paternal absence) on prosocial behavior. Dams were exposed to vehicle (sesame oil) or 1000 µg FM 550 orally via food treats from conception through weaning and the paternal absence groups were generated by removing the sires the day after birth. Adult offspring of both sexes were then subjected to open-field, sociability, and a partner preference test. Paternal deprivation (PD)-related effects included increased anxiety, decreased sociability, and impaired pair-bonding in both sexes. FM 550 effects include heightened anxiety and partner preference in females but reduced partner preference in males. The combination of FM 550 exposure and PD did not exacerbate any behaviors in either sex except for distance traveled by females in the partner preference test and, to a lesser extent, time spent with, and the number of visits to the non-social stimulus by males in the sociability test. FM 550 ameliorated the impacts of parental deprivation on partner preference behaviors in both sexes. This study is significant because it provides evidence that chemical and social stressors can have unique behavioral effects that differ by sex but may not produce worse outcomes in combination.

Neurodevelopmental disorders and comorbidity in young adults attending a psychiatric outpatient clinic

“Missed” cases with neurodevelopmental disorders (NDDs) within adult psychiatry services have attracted increasing attention in the last decade. Key questions have been what the prevalence of NDDs (particularly attention-deficit/hyperactivity disorder/ADHD and autism spectrum disorder/ASD) is, and what the clinical and gender characteristics of those with NDD in adult psychiatry are. All first-time attenders at an adult psychiatry clinic serving 18–25 years old were invited to take part in the study regardless of cause of concern. Participation in the study included diagnostic in-depth evaluation performed by experienced adult psychiatrists. Clinical diagnoses (DSM-IV-TR and DSM-5 criteria) were based on all available information (clinical psychiatric interview, clinical observation, and self-rating questionnaires). Almost two thirds (63%) of the study group met criteria for ADHD or ASD. Most of the patients with NDD (particularly the "NDD females") had not been diagnosed in childhood. Twelve percent of the females included had been given an ADHD diagnosis in childhood. In the current study we found that 48% of the females had ADHD. The high male:female NDD ratio reported among children, was not obvious in our NDD group. The results underscore the importance of screening for NDD in adult psychiatric services regardless of referral reason.

Effects of a Sociodrama-based Communication Enhancement Program on Mothers of Children with Neurodevelopmental Disorders: A Pilot Study

The incidence and prevalence of neurodevelopmental disorders have rapidly increased, indicating an urgent need for assistance through parenting interventions. This study aimed to evaluate the effects of a sociodrama-based communication enhancement program on mothers of children with neurodevelopmental disorders. A non-randomized controlled experimental study design was employed. The experimental and control groups had 16 and 18 participants, respectively. The once-a-week six-session intervention was conducted from September to November 2017, in South Korea. The effects of group, time, and group-by-time interactions among the groups were verified using generalized estimating equations with an autoregressive correlation structure. There was a significant decrease in the parenting burden, alongside a significant improvement in parent-child communication and parenting competence in the experimental group compared to the control group. The sociodrama-based communication enhancement program was found to positively influence the parenting burden, communication, and parenting competence of mothers of children with neurodevelopmental disorders. These findings suggest that sociodrama-based programs may be an effective intervention strategy for parents of children with neurodevelopmental disorders. The sociodrama-based communication enhancement program can be applied to decrease parenting burden and improve parent-child communication and parenting competence. Through continuous parenting interventions, an improvement in expressive language and an increase in the attachment behaviors of children with neurodevelopmental disabilities could be expected.

Prevalence of neurodevelopmental disorders and their impact on the health and social well-being among looked after children (LAC): a systematic review protocol

BackgroundLooked after children (LAC) that are placed in either a foster, kinship, residential care setting or transition to adoption continue to develop debilitating disorders that significantly impact their overall health and social well-being. The prevalence of these disorders is often depicted under broad categories such as mental, behavioural or neurodevelopmental disorders (NDDs). Limited in research is the prevalence of what specific disorders fall under these broad categories. NDDs such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) which fall under an umbrella group in the expert field of genetics and neuropsychiatry will be explored. Unsupported, these disorders can lead to suboptimal health and social outcomes for both the child and family. In the general population, the prevalence of these NDDs and impacts on health and social well-being are relatively well documented, but for minority groups such as LAC, research is extremely limited. This review aims to estimate the prevalence of NDDs among LAC and explore how they might impact the health and social well-being of these vulnerable children. If feasible, the review will compare the prevalence rates to those children who are not looked after, to illuminate any differences or similarities between populations.MethodsPubMed, ASSIA, IBSS, Web of Science, PsychINFO, Scopus, Psych articles, Social Care Online, secondary, grey literature and government publications will be searched to identify any eligible studies. No restrictions will be placed on country, design or year of publication. Studies must provide primary data on the prevalence or incidence of NDDs for individuals < 25 years of age, supported by either a diagnostic code, standardised diagnostic assessment tool or survey response. The Joanna Briggs Institute (JBI) critical appraisal tools will be utilised to assess the quality and bias and the random-effects model used to estimate a pooled prevalence of NDDs.DiscussionAttaining an estimated prevalence of these NDDs and identifying any impacts on health and social well-being might inform key stakeholders in health, educational and social sectors with important information that might aid in the early identification and intervention to safeguard and meet the unique needs of these children.Systematic review registrationPROSPERO CRD4201913103.

Sex Differences in Neurodevelopmental Disorders: A Key Role for the Immune System.

Sex differences are prominent defining features of neurodevelopmental disorders. Understanding the sex biases in these disorders can shed light on mechanisms leading to relative risk and resilience for the disorders, as well as more broadly advance our understanding of how sex differences may relate to brain development. The prevalence of neurodevelopmental disorders is increasing, and the two most common neurodevelopmental disorders, Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) exhibit male-biases in prevalence rates and sex differences in symptomology. While the causes of neurodevelopmental disorders and their sex differences remain to be fullyunderstood, increasing evidence suggests that the immune system plays a critical role in shaping development. In this chapter we discuss sex differences in prevalence and symptomology of ASD and ADHD, review sexual differentiation and immune regulation of neurodevelopment, and discuss findings from human and rodent studies of immune dysregulation and perinatal immune perturbation as they relate to potential mechanisms underlying neurodevelopmental disorders. This chapter will give an overview of how understanding sex differences in neuroimmune function in the context of neurodevelopmental disorders could lend insight into their etiologies and better treatment strategies.

High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population

Neurodevelopmental disorders (NDDs) are clinically and genetically heterogenous; many such disorders are secondary to perturbation in brain development and/or function. The prevalence of NDDs is > 3%, resulting in significant sociocultural and economic challenges to society. With recent advances in family-based genomics, rare-variant analyses, and further exploration of the Clan Genomics hypothesis, there has been a logarithmic explosion in neurogenetic "disease-associated genes" molecular etiology and biology of NDDs; however, the majority of NDDs remain molecularly undiagnosed. We applied genome-wide screening technologies, including exome sequencing (ES) and whole-genome sequencing (WGS), to identify the molecular etiology of 234 newly enrolled subjects and 20 previously unsolved Turkish NDD families. In 176 of the 234 studied families (75.2%), a plausible and genetically parsimonious molecular etiology was identified. Out of 176 solved families, deleterious variants were identified in 218 distinct genes, further documenting the enormous genetic heterogeneity and diverse perturbations in human biology underlying NDDs. We propose 86 candidate disease-trait-associated genes for an NDD phenotype. Importantly, on the basis of objective and internally established variant prioritization criteria, we identified 51 families (51/176= 28.9%) with multilocus pathogenic variation (MPV), mostly driven by runs of homozygosity (ROHs) - reflecting genomic segments/haplotypes that are identical-by-descent. Furthermore, with the use of additional bioinformatic tools and expansion of ES to additional family members, we established a molecular diagnosis in 5 out of 20 families (25%) who remained undiagnosed in our previously studied NDD cohort emanating from Turkey.