Correction: Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders.

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.

National down syndrome patient database: Insights from the development of a multi-center registry study.

The Down Syndrome Study Group (DSSG) was founded in 2012 as a voluntary, collaborative effort with the goal of supporting evidenced-based health care guidelines for individuals with Down syndrome (DS). Since then, 5 DS specialty clinics have collected prospective, longitudinal data on medical conditions that co-occur with DS. Data were entered by clinical staff or trained designees into the National Down Syndrome Patient Database, which we created using REDCap software. In our pilot year, we enrolled 663 participants across the U.S., ages 36 days to 70 years, from multiple racial and ethnic backgrounds. Here we report: (i) the demographic distribution of participants enrolled, (ii) a detailed account of our database infrastructure, and (iii) lessons learned during our pilot year to assist future researchers with similar goals for other patient populations.

Developmental Delay and Behavior Challenges in an Internationally Adopted Child.

CASE: Jay is a 6-year-old boy who was referred to a multidisciplinary developmental clinic for evaluation because of speech/language delays and challenging behaviors. He attends kindergarten with an Individualized Education Program (IEP) supporting developmental challenges with speech/language, motor, and academic skills.Jay was reportedly born full-term after an uneventful pregnancy and lived with his biological family for several months before transitioning to institutional care. Shortly before his first birthday, he transitioned to the first of 3 foster homes. It is suspected that Jay experienced malnourishment, neglect, lack of appropriate supervision, and inappropriate levels of responsibility (e.g., providing care to an infant when he was a toddler) as well as limited language input while in foster care. Ages at which he attained developmental milestones are unknown, but he has displayed delays across all developmental domains, including speech/language development in his primary language, which is not English.Jay's adoptive parents report that he is learning English vocabulary well but has been noted to have occasional word-finding difficulties and errors in verb conjugation, pronoun use, and syntax in English. Behavioral concerns include impulsivity, hyperactivity, and aggression exacerbated by new or loud environments and transitions. Socially, he seems to be typically engaged with peers but lacks understanding of personal space/boundaries. His adoptive parents have also noted that he is very sensitive to the emotions of others around him, more irritable in the morning, fascinated by "scary" things, and seems to fear abandonment. During the initial months in his adoptive home, he had frequent night awakenings, fear of the dark, and aggression at bedtime, but all these concerns have improved with time.Neuropsychological testing was completed as part of the multidisciplinary developmental evaluation, and Jay demonstrated low-average cognitive abilities, delayed preacademic skills in all language-based areas, and receptive and expressive language delays. He was socially engaged during the evaluation. Ultimately, he was diagnosed with mixed receptive-expressive language disorder, attention-deficit/hyperactivity disorder, combined presentation, and unspecified trauma/stress-related disorder.Given what is known about Jay's early history, what factors would you consider in addressing his parents' concerns regarding his speech/language development and behavior challenges?

Negative effect of treatment with mGluR5 negative allosteric modulator AFQ056 on blood biomarkers in young individuals with Fragile X syndrome.

Background: Fragile X syndrome, with an approximate incidence rate of 1 in 4000 males to 1 in 8000 females, is the most prevalent genetic cause of heritable intellectual disability and the most common monogenic cause of autism spectrum disorder. The full mutation of the Fragile X Messenger Ribonucleoprotein-1 gene, characterized by an expansion of CGG trinucleotide repeats (>200 CGG repeats), leads to fragile X syndrome. Currently, there are no targeted treatments available for fragile X syndrome. In a recent large multi-site trial, FXLEARN, the effects of the mGluR5 negative allosteric modulator, AFQ056 (mavoglurant), were investigated, but did not show a significant impact of AFQ056 on language development in children with fragile X syndrome aged 3-6 years. Objectives: The current analyses from biospecimens collected in the FXLEARN study aimed to determine whether AFQ056 affects the level of potential biomarkers associated with Akt/mTOR and matrix metalloproteinase 9 signaling in young individuals with fragile X syndrome. Previous research has indicated that these biomarkers play crucial roles in the pathophysiology of fragile X syndrome. Design: A double-blind placebo-controlled parallel-group flexible-dose forced titration design. Methods: Blood samples for biomarkers were collected during the FXLEARN at baseline and subsequent visits (1- and 8-month visits). Biomarker analyses included fragile X messenger ribonucleoprotein-1 genotyping by Southern blot and PCR approaches, fragile X messenger ribonucleoprotein-1 mRNA levels determined by PCR, matrix metalloproteinase 9 levels' detection using a magnetic bead panel, and targets of the Akt/mTOR signaling pathway with their phosphorylation levels detected. Results: This research revealed that administering AFQ056 does not affect the expression levels of the investigated blood biomarkers in young children with fragile X syndrome. Conclusion: Our findings of the lack of association between clinical improvement and biomarkers' levels in the treatment group are in line with the lack of benefit observed in the FXLEARN study. These findings indicate that AFQ056 does not provide benefits as assessed by primary or secondary endpoints. Registration: ClincalTrials.gov NCT02920892.

GENE TARGET: A framework for evaluating Mendelian neurodevelopmental disorders for gene therapy.

Interest in gene-based therapies for neurodevelopmental disorders is increasing exponentially, driven by the rise in recognition of underlying genetic etiology, progress in genomic technology, and recent proof of concept in several disorders. The current prioritization of one genetic disorder over another for development of therapies is driven by competing interests of pharmaceutical companies, advocacy groups, and academic scientists. Although these are all valid perspectives, a consolidated framework will facilitate more efficient and rational gene therapy development. Here we outline features of Mendelian neurodevelopmental disorders that warrant consideration when determining suitability for gene therapy. These features fit into four broad domains: genetics, preclinical validation, clinical considerations, and ethics. We propose a simple mnemonic, GENE TARGET, to remember these features and illustrate how they could be scored using a preliminary scoring rubric. In this suggested rubric, for a given disorder, scores for each feature may be added up to a composite GENE TARGET suitability (GTS) score. In addition to proposing a systematic method to evaluate and compare disorders, our framework helps identify gaps in the translational pipeline for a given disorder, which can inform prioritization of future research efforts.

Diagnostic Uncertainty in a Complex Young Man: Autism Versus Psychosis.

CASE: James is a 7½-year-old boy born in Vietnam to a mother with mental illness. Little is known about his early history; he spent the first 6 months of his life in an orphanage, followed by foster care and a disrupted adoption. He moved to the U.S. at age 1½ and joined his current adoptive family at age 4 years. Shortly thereafter, James' psychiatric nurse practitioner diagnosed him with attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Pragmatic language and syntax deficits were also noted from an early age.James is now exhibiting anxiety, perseverative beliefs, and regression in his toileting. He began "talking to himself in his room" and using neologisms. A school-based evaluation resulted in educational diagnoses of ADHD and ASD based on social disconnectedness and invading others' personal space. James' parents felt "something else was going on" and sought a second opinion with a multidisciplinary team (consisting of a pediatric psychologist and a developmental pediatrician). Considering James' history, previous assessments, and their assessment battery (Behavior Assessment System for Children, Behavior Rating Inventory of Executive Function, and Autism Diagnostic Observation Schedule, and Rorschach Inkblot Test), the team characterized his current symptoms as an emerging psychotic disorder.Several consultations occurred over the next 9 months of the school term. First, clinicians in the psychiatry department confirmed symptoms of functional decline, cognitive disorganization, and hallucinations, which were attributed to post-traumatic stress rather than a psychotic disorder. Second, adding to the diagnostic uncertainty, when James started an atypical antipsychotic medication and was under good symptom control, the school team believed that ADHD-not psychosis-best accounted for his presentation. There was significant contention between the medical team and consulting school psychologist regarding the extent to which data from the parental history and Rorschach should be considered in formulating the patient's diagnosis.Two-and-a-half years later, James was weaned off risperidone to manage a new side effect of tics. He subsequently manifested significant paranoia with reactive aggression toward peers for imagined slights and insults that he could "swear he heard." A different school-contracted psychologist's re-evaluation corroborated the diagnosis of schizophrenia based on the several years of unfolding clinical observations. Acting from the supposition that early-onset psychosis was too rare and too stigmatizing a condition to apply to a "kid who's just having trouble paying attention," the first school psychologist remained adamant that ADHD and ASD were the most appropriate diagnoses, and James would be ill-served "pumped full of neuroleptics."He returns now to the original Developmental Behavioral Pediatric consulting team. What would you do to try to bridge this impasse?

Craniofacial features as assessed by lateral cephalometric measurements in children with Down syndrome.

OBJECTIVE: The objective of the present study is to examine the craniofacial development of patients with Down syndrome (DS) and compare them with a neurotypical population. METHODS: This study is a cross-sectional analysis of lateral cephalometric radiographs of participants with DS. The study population consisted of children and young adults with DS aged 3-25 years. Cephalometric data were summarized by age and sex. Raw and normalized z-scores were computed. One-sample t tests were used to test whether mean z-scores differed from zero. The demographic characteristics between those with or without lateral cephalograms among all study participants were compared by Fisher's exact tests. RESULTS: The study sample comprised of 27 participants with DS. Study subjects demonstrated a class III skeletal pattern. This was more pronounced in the older age groups as compared to younger age groups. Subjects also had an increased proportionate lower anterior face height to total facial height compared to normative standards. Gonial angles, mandibular plane angles, and airway measurements increased with age. CONCLUSIONS: Patients with Down syndrome present typically with class III skeletal pattern and long lower anterior facial heights. In patients with Down syndrome, comprehensive phase of orthodontic treatment may be best initiated following cessation of growth.

When the adoption becomes termination.

CASE: Steven is an 11-year-old boy who was adopted from an orphanage in Eastern Europe 8 years ago, when he was 3 years old along with his biological sister who is 1 year older. You have cared for him in your practice since that time seeing them annually for well child care. His mother reports that the first 2 years after adoption were very difficult, and Steven has never really bonded with her or her husband. Currently, he is reported to steal possessions of family members and instigate arguments with his older sister and act defiantly. The parents have put locks on their bedroom door due to fears of violence, primarily by Steven's older sister. Steven's mother reports that she and her husband no longer attempt to "parent" the children and provide minimal supervision to avoid conflict. In school, Steven is reported to have symptoms of inattention and hyperactivity that improved with treatment with stimulant medication and some learning challenges, but otherwise he is described as a lovely boy who has good relationships with his teachers.They present to urgent care clinic when mom stated "We have had enough." That day both children were caught taking $10 from the mother's wallet. On further discussion, it was discovered that they had done this several times over the last month to buy ice cream for neighborhood friends to "welcome them" to the neighborhood. Steven's mother presents today stating that the family has exhausted therapy services and are experiencing financial hardship secondary to investing time and money into behavioral and psychiatric services for Steven and his sister. They want to dissolve the adoption and have the children removed from their home. They seek guidance on how to do this. What would be your initial approach with the parents?

Attention-deficit/hyperactivity disorder in young children: predictors of diagnostic stability.

OBJECTIVES: The goals of this study were (1) to provide estimates of diagnostic stability for a sample of young children diagnosed with attention-deficit/hyperactivity disorder (ADHD) after undergoing comprehensive multidisciplinary assessments and (2) to identify baseline child and family characteristics that predict diagnostic stability over time. METHODS: Children aged 3 to 6 years, 11 months consecutively diagnosed with ADHD after multidisciplinary consultations at a tertiary care clinic between 2003 and 2008 were recontacted in 2012 and 2013 (N = 120). At follow-up, the primary outcome was the proportion of children who continued to meet diagnostic criteria for ADHD. To identify predictors of diagnostic stability, logistic regression models were used. In addition, a latent class model was used to independently classify subjects into distinct clusters. RESULTS: In this cohort, 70.4% of the children contacted at follow-up continued to meet diagnostic criteria for ADHD. Predictors of diagnostic stability included externalizing and internalizing symptoms at baseline, parental history of psychopathology, and family socioeconomic status. The latent class model independently identified 3 distinct profiles: (1) children who no longer met ADHD criteria; (2) children with persistent ADHD and high parental psychopathology; and (3) children with persistent ADHD and low family socioeconomic status. CONCLUSIONS: Young children who underwent comprehensive developmental and psychological assessments before receiving an ADHD diagnosis, had higher rates of diagnostic stability than in previous studies of community samples. Child and family factors that predict diagnostic stability have the potential to guide treatment planning for children diagnosed with ADHD before 7 years of age.

Speech delay and autism spectrum behaviors are frequently associated with duplication of the 7q11.23 Williams-Beuren syndrome region.

PURPOSE: Williams-Beuren syndrome is among the most well-characterized microdeletion syndromes, caused by recurrent de novo microdeletions at 7q11.23 mediated by nonallelic homologous recombination between low copy repeats flanking this critical region. However, the clinical phenotype associated with reciprocal microduplication of this genomic region is less well described. We investigated the molecular, clinical, neurodevelopmental, and behavioral features of seven patients with dup(7)(q11.23), including two children who inherited the microduplication from one of their parents, to more fully characterize this emerging microduplication syndrome. METHODS: Patients were identified by array-based comparative genomic hybridization. Clinical examinations were performed on seven affected probands, and detailed cognitive and behavioral evaluations were carried out on four of the affected probands. RESULTS: Our findings confirm initial reports of speech delay seen in patients with dup(7)(q11.23) and further delineate and expand the phenotypic spectrum of this condition to include communication, social interactions, and repetitive interests that are often observed in individuals diagnosed with autism spectrum disorders. CONCLUSIONS: Array-based comparative genomic hybridization is a powerful means of detecting genomic imbalances and identifying molecular etiologies in the clinic setting, including genomic disorders such as Williams-Beuren syndrome and dup(7)(q11.23). We propose that dup(7)(q11.23) syndrome may be as frequent as Williams-Beuren syndrome and a previously unrecognized cause of language delay and behavioral abnormalities. Indeed, these individuals may first be referred for evaluation of autism, even if they do not ultimately meet diagnostic criteria for an autism spectrum disorder.