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The DDD study recruited more than 13,500 families with probands with severe, probably monogenic disorders in the United Kingdom and Ireland and obtained a genetic diagnosis in approximately 41% of probands.

Purpose For neurodevelopmental disorders (NDDs), etiological evaluation can be a diagnostic odyssey involving numerous genetic tests, underscoring the need to develop a streamlined algorithm maximizing molecular diagnostic yield for this clinical indication. Our objective was to compare the yield of exome sequencing (ES) with that of chromosomal microarray (CMA), the current first-tier test for NDDs. Methods We performed a PubMed scoping review and meta-analysis investigating the diagnostic yield of ES for NDDs as the basis of a consensus development conference. We defined NDD as global developmental delay, intellectual disability, and/or autism spectrum disorder. The consensus development conference included input from genetics professionals, pediatric neurologists, and developmental behavioral pediatricians. Results After applying strict inclusion/exclusion criteria, we identified 30 articles with data on molecular diagnostic yield in individuals with isolated NDD, or NDD plus associated conditions (such as Rett-like features). Yield of ES was 36% overall, 31% for isolated NDD, and 53% for the NDD plus associated conditions. ES yield for NDDs is markedly greater than previous studies of CMA (15–20%). Conclusion Our review demonstrates that ES consistently outperforms CMA for evaluation of unexplained NDDs. We propose a diagnostic algorithm placing ES at the beginning of the evaluation of unexplained NDDs.

AbstractObjectivesTo describe neurodevelopment at age 5 among children born preterm.DesignPopulation based cohort study, EPIPAGE-2.SettingFrance, 2011.Participants4441 children aged 5½ born at 24-26, 27-31, and 32-34 weeksMain outcome measuresSevere/moderate neurodevelopmental disabilities, defined as severe/moderate cerebral palsy (Gross Motor Function Classification System (GMFCS) ≥2), or unilateral or bilateral blindness or deafness, or full scale intelligence quotient less than minus two standard deviations (Wechsler Preschool and Primary Scale of Intelligence, 4th edition). Mild neurodevelopmental disabilities, defined as mild cerebral palsy (GMFCS-1), or visual disability ≥3.2/10 and <5/10, or hearing loss <40 dB, or full scale intelligence quotient (minus two to minus one standard deviation) or developmental coordination disorders (Movement Assessment Battery for Children, 2nd edition, total score less than or equal to the fifth centile), or behavioural difficulties (strengths and difficulties questionnaire, total score greater than or equal to the 90th centile), school assistance (mainstream class with support or special school), complex developmental interventions, and parents’ concerns about development. The distributions of the scores in contemporary term born children were used as reference. Results are given after multiple imputation as percentages of outcome measures with exact binomial 95% confidence intervals.ResultsAmong 4441 participants, 3083 (69.4%) children were assessed. Rates of severe/moderate neurodevelopmental disabilities were 28% (95% confidence interval 23.4% to 32.2%), 19% (16.8% to 20.7%), and 12% (9.2% to 14.0%) and of mild disabilities were 38.5% (33.7% to 43.4%), 36% (33.4% to 38.1%), and 34% (30.2% to 37.4%) at 24-26, 27-31, and 32-34 weeks, respectively. Assistance at school was used by 27% (22.9% to 31.7%), 14% (12.1% to 15.9%), and 7% (4.4% to 9.0%) of children at 24-26, 27-31, and 32-34 weeks, respectively. About half of the children born at 24-26 weeks (52% (46.4% to 57.3%)) received at least one developmental intervention which decreased to 26% (21.8% to 29.4%) for those born at 32-34 weeks. Behaviour was the concern most commonly reported by parents. Rates of neurodevelopment disabilities increased as gestational age decreased and were higher in families with low socioeconomic status.ConclusionsIn this large cohort of children born preterm, rates of severe/moderate neurodevelopmental disabilities remained high in each gestational age group. Proportions of children receiving school assistance or complex developmental interventions might have a significant impact on educational and health organisations. Parental concerns about behaviour warrant attention.

Neurodevelopmental disorders have a heritable component and are associated with region specific alterations in brain anatomy. However, it is unclear how genetic risks for neurodevelopmental disorders are translated into spatially patterned brain vulnerabilities. Here, we integrated cortical neuroimaging data from patients with neurodevelopmental disorders caused by genomic copy number variations (CNVs) and gene expression data from healthy subjects. For each of the six investigated disorders, we show that spatial patterns of cortical anatomy changes in youth are correlated with cortical spatial expression of CNV genes in neurotypical adults. By transforming normative bulk-tissue cortical expression data into cell-type expression maps, we link anatomical change maps in each analysed disorder to specific cell classes as well as the CNV-region genes they express. Our findings reveal organizing principles that regulate the mapping of genetic risks onto regional brain changes in neurogenetic disorders. Our findings will enable screening for candidate molecular mechanisms from readily available neuroimaging data. How neurodevelopmental disorder-associated risk genes are translated into spatially patterned brain vulnerabilities is unclear. Here, the authors show that disorder-specific patterns of neuroanatomical changes are aligned to brain expression maps of disease risk genes in healthy subjects.

Health-related conditions often differ qualitatively or quantitatively between individuals of different birth-assigned sexes and gender identities, and/or with different gendered experiences, requiring tailored care. Studying the moderating and mediating effects of sex-related and gender-related factors on impairment, disability, wellbeing and health is of paramount importance especially for neurodivergent individuals, who are diagnosed with neurodevelopmental conditions with uneven sex/gender distributions. Researchers have become aware of the myriad influences that sex-related and gender-related variables have on the manifestations of neurodevelopmental conditions, and contemporary work has begun to investigate the mechanisms through which these effects are mediated. Here we describe topical concepts of sex and gender science, summarize current knowledge, and discuss research and clinical challenges related to autism, attention-deficit/hyperactivity disorder and other neurodevelopmental conditions. We consider sex and gender in the context of epidemiology, behavioural phenotypes, neurobiology, genetics, endocrinology and neighbouring disciplines. The available evidence supports the view that sex and gender are important contributors to the biological and behavioural variability in neurodevelopmental conditions. Methodological caveats such as frequent conflation of sex and gender constructs, inappropriate measurement of these constructs and under-representation of specific demographic groups (for example, female and gender minority individuals and people with intellectual disabilities) limit the translational potential of research so far. Future research and clinical implementation should integrate sex and gender into next-generation diagnostics, mechanistic investigations and support practices.Here, Sven Bölte and colleagues consider the effects of sex and gender on neurodevelopmental conditions. They discuss the available epidemiological, behavioural, neurobiological and endocrinological evidence and highlight the importance of further research in this area.

Because a genetic diagnosis can guide clinical management and improve prognosis in critically ill patients, much effort has gone into developing methods that result in rapid, reliable results. The authors describe extremely rapid sequencing and analysis of the genomes of 12 patients, 5 of whom received a diagnosis.

The authors analyzed the whole-exome sequences of over 16,000 individuals and found that very rare variants predicted to disrupt the SETD1A gene confer substantial risk for schizophrenia. Damaging variants in SETD1A were also associated with diverse, severe developmental disorders, providing an important genetic link between schizophrenia and other neurodevelopmental disorders. By analyzing the whole-exome sequences of 4,264 schizophrenia cases, 9,343 controls and 1,077 trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants in SETD1A and risk for schizophrenia ( P = 3.3 × 10 −9 ). We found only two heterozygous LoF variants in 45,376 exomes from individuals without a neuropsychiatric diagnosis, indicating that SETD1A is substantially depleted of LoF variants in the general population. Seven of the ten individuals with schizophrenia carrying SETD1A LoF variants also had learning difficulties. We further identified four SETD1A LoF carriers among 4,281 children with severe developmental disorders and two more carriers in an independent sample of 5,720 Finnish exomes, both with notable neuropsychiatric phenotypes. Together, our observations indicate that LoF variants in SETD1A cause a range of neurodevelopmental disorders, including schizophrenia. Combining these data with previous common variant evidence, we suggest that epigenetic dysregulation, specifically in the histone H3K4 methylation pathway, is an important mechanism in the pathogenesis of schizophrenia.

Genome sequencing (GS) can identify novel diagnoses for patients who remain undiagnosed after routine diagnostic procedures. We tested whether GS is a better first-tier genetic diagnostic test than current standard of care (SOC) by assessing the technical and clinical validity of GS for patients with neurodevelopmental disorders (NDD). We performed both GS and exome sequencing in 150 consecutive NDD patient-parent trios. The primary outcome was diagnostic yield, calculated from disease-causing variants affecting exonic sequence of known NDD genes. GS (30%, n = 45) and SOC (28.7%, n = 43) had similar diagnostic yield. All 43 conclusive diagnoses obtained with SOC testing were also identified by GS. SOC, however, required integration of multiple test results to obtain these diagnoses. GS yielded two more conclusive diagnoses, and four more possible diagnoses than ES-based SOC (35 vs. 31). Interestingly, these six variants detected only by GS were copy number variants (CNVs). Our data demonstrate the technical and clinical validity of GS to serve as routine first-tier genetic test for patients with NDD. Although the additional diagnostic yield from GS is limited, GS comprehensively identified all variants in a single experiment, suggesting that GS constitutes a more efficient genetic diagnostic workflow.

In March 2020, many schools were closed to prevent the spread of COVID-19 in Japan, and it is predicted that many children, especially those with neurodevelopmental disorders (NDDs), will be affected emotionally and behaviorally. Here, we examined the impact of school closures due to COVID-19 on school-aged children with NDDs using the Child Behavior Checklist. Totally, data on 121 children diagnosed with autism spectrum disorder, attention-deficit hyperactivity disorder, and/or intellectual disorder were analyzed and it was found that externalizing and aggressive behavior increased in all NDDs, regardless of the type of diagnosis. A clear prospect is important for children with NDDs children to lead a stable life, and more generous supports for children with NDDs and their families are needed.

Sleep problems are prevalent in children with neurodevelopmental disabilities and are associated with the expression of restricted and repetitive behaviors (RRBs). Children (n = 57) with autism spectrum disorder (ASD, n = 38) or developmental delay (DD, n = 19) participated in multiple assessments of intellectual ability, ASD symptoms, and RRBs (3 timepoints for ASD, 2 for DD). Sleep problems assessed at age 4 via parent report were associated with trajectories of higher-order RRBs (sameness/ritualistic/compulsive behaviors) from age 2–6 in the ASD group, and from age 2–4 in the DD group, even after controlling for intellectual ability, social-affective symptoms, and anxiety. Trajectories of stereotyped/restricted behaviors were unrelated to sleep problems. Sleep problems were associated with trajectories of higher-order (but not lower-order) RRBs in a transdiagnostic sample.