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Concept: Down syndrome


Approximately one third of adults with intellectual and developmental disabilities have emotion dysregulation and challenging behaviors (CBs). Although research has not yet confirmed that existing treatments adequately reduce CBs in this population, dialectical behavior therapy (DBT) holds promise, as it has been shown to effectively reduce CBs in other emotionally dysregulated populations. This longitudinal single-group pilot study examined whether individuals with impaired intellectual functioning would show reductions in CBs while receiving standard DBT individual therapy used in conjunction with the Skills System (DBT-SS), a DBT emotion regulation skills curriculum adapted for individuals with cognitive impairment. Forty adults with developmental disabilities (most of whom also had intellectual disabilities) and CBs, including histories of aggression, self-injury, sexual offending, or other CBs, participated in this study. Changes in their behaviors were monitored over 4 years while in DBT-SS. Large reductions in CBs were observed during the 4 years. These findings suggest that modified DBT holds promise for effectively treating individuals with intellectual and developmental disabilities.

Concepts: Psychology, Population, Down syndrome, Developmental disability, Disability, Emotion, Behaviorism, Emotional dysregulation


Deletion and duplication of the -3.7-Mb region in 17p11.2 result in two reciprocal syndrome, Smith-Magenis syndrome and Potocki-Lupski syndrome. Smith-Magenis syndrome is a well-known developmental disorder. Potocki-Lupski syndrome has recently been recognized as a microduplication syndrome that is a reciprocal disease of Smith-Magenis syndrome. In this paper, we report on the clinical and cytogenetic features of two Korean patients with Smith-Magenis syndrome and Potocki-Lupski syndrome. Patient 1 (Smith-Magenis syndrome) was a 2.9-yr-old boy who showed mild dysmorphic features, aggressive behavioral problems, and developmental delay. Patient 2 (Potocki-Lupski syndrome), a 17-yr-old boy, had only intellectual disabilities and language developmental delay. We used array comparative genomic hybridization (array CGH) and found a 2.6 Mb-sized deletion and a reciprocal 2.1 Mb-sized duplication involving the 17p11.2. These regions overlapped in a 2.1 Mb size containing 11 common genes, including RAI1 and SREBF.

Concepts: DNA, Genetics, Copy number variation, Genome, Syndromes, Down syndrome, Array comparative genomic hybridization, Comparative genomic hybridization


Distinct isoforms of the PI3K catalytic subunit have specialized functions in the brain, but their role in cognition is unknown. Here, we show that the catalytic subunit p110β plays an important role in prefrontal cortex (PFC)-dependent cognitive defects in mouse models of Fragile X syndrome (FXS), an inherited intellectual disability. FXS is caused by loss of function of the fragile X mental retardation protein (FMRP), which binds and translationally represses mRNAs. PFC-selective knockdown of p110β, an FMRP target that is translationally upregulated in FXS, reverses deficits in higher cognition in Fmr1 knockout mice. Genetic full-body reduction of p110β in Fmr1 knockout mice normalizes excessive PI3K activity, restores stimulus-induced protein synthesis, and corrects increased dendritic spine density and behavior. Notably, adult-onset PFC-selective Fmr1 knockdown mice show impaired cognition, which is rescued by simultaneous p110β knockdown. Our results suggest that FMRP-mediated control of p110β is crucial for neuronal protein synthesis and cognition.

Concepts: Brain, Autism, Down syndrome, Mental retardation, Disability, Fragile X syndrome, FMR1, Dendritic spine


KBG syndrome (KBGS) is an autosomal dominant multiple congenital anomaly-intellectual disability syndrome, characterized by developmental delay with neurological involvements, macrodontia of the upper central incisors, characteristic facial dysmorphism and skeletal anomalies. Variants in ANKRD11 cause KBGS. We present five individuals from four families with ANKRD11 variants identified by whole-exome sequencing. Four of the five were clinically affected, and their diagnoses were varied. One was typical KBGS, two were Coffin-Siris syndrome-like (CSS), and one was intellectual disability with infantile spasms. One individual showed extremely mild phenotype. All individuals fulfilled the proposed diagnostic criteria for KBGS. Phenotypic features overlap between KBGS and CSS to some extent, and characteristic dental and fifth finger/toe findings can indicate differential diagnosis. These findings indicate that patients with ANKRD11 variants occupy a wide spectrum of intellectual disability, including clinically normal individuals. This is the first report highlighting the clinical overlap between KBGS and CSS and supporting the recently proposed clinical concept, in which transcriptional machineries are disrupted.Journal of Human Genetics advance online publication, 2 March 2017; doi:10.1038/jhg.2017.24.

Concepts: Gene, Medical terms, Diagnosis, Greek loanwords, Down syndrome, Developmental disability, Maxillary central incisor


The Pediatric Cardiac Genomics Consortium (PCGC) designed the Congenital Heart Disease Genetic Network Study to provide phenotype and genotype data for a large congenital heart defects (CHDs) cohort. This article describes the PCGC cohort, overall and by major types of CHDs (e.g., conotruncal defects) and subtypes of conotrucal heart defects (e.g., tetralogy of Fallot) and left ventricular outflow tract obstructions (e.g., hypoplastic left heart syndrome). Cases with CHDs were recruited through ten sites, 2010-2014. Information on cases (N = 9,727) and their parents was collected through interviews and medical record abstraction. Four case characteristics, eleven parental characteristics, and thirteen parent-reported neurodevelopment outcomes were summarized using counts and frequencies and compared across CHD types and subtypes. Eleven percent of cases had a genetic diagnosis. Among cases without a genetic diagnosis, the majority had conotruncal heart defects (40%) or left ventricular outflow tract obstruction (21%). Across CHD types, there were significant differences (p<0.05) in the distribution of all four case characteristics (e.g., sex), four parental characteristics (e.g., maternal pregestational diabetes), and five neurodevelopmental outcomes (e.g., learning disabilities). Several characteristics (e.g., sex) were also significantly different across CHD subtypes. The PCGC cohort is one of the largest CHD cohorts available for the study of genetic determinants of risk and outcomes. The majority of cases do not have a genetic diagnosis. This description of the PCGC cohort, including differences across CHD types and subtypes, provides a reference work for investigators who are interested in collaborating with or using publically available resources from the PCGC.

Concepts: Gene, Heart, Hypertrophic cardiomyopathy, Down syndrome, Congenital heart defect, Congenital heart disease, Tetralogy of Fallot, Hypoplastic left heart syndrome


Despite increased awareness and concern about children with developmental disabilities wandering away from adult supervision, there is a paucity of research about elopement. This is the first study to examine and report the prevalence and correlates of elopement in a nationally representative sample of school-age children in the United States with an autism spectrum disorder (ASD) and/or cognitive impairment. Data were obtained from the CDC’s “Pathways” Survey, a follow-up telephone survey of the parents of 4,032 children with a developmental condition. 3,518 children that had ASD, intellectual disability (ID), and/or developmental delay (DD) at the time of survey administration were included for analysis. Children were divided into three condition groups: ASD-only; ID/DD-only; ASD+ID/DD. Logistic regression analyses were used to compare the prevalence of elopement and rates of preventive measure use (barriers and/or electronic devices) across condition groups, and to examine the clinical and demographic correlates of elopement. T-tests were also performed to compare scores on the Children’s Social Behavior Questionnaire (CSBQ) between wanderers and non-wanderers. Overall, 26.7% of children had reportedly eloped within the previous year, most commonly from public places. Children with ASD-only and ASD+ID/DD were more likely to have eloped than those with ID/DD-only. Across all groups, wanderers scored higher than non-wanderers on five out of six CSBQ subscales; they were more likely not to realize when there is danger, to have difficulty distinguishing between strangers and familiar people, to show sudden mood changes, to over-react to everything/everyone, to get angry quickly, to get lost easily, and to panic in new situations or if change occurs. Even after controlling for elopement history, parents of children in the ASD+ID/DD group were more likely than those in the other condition groups to report using physical or electronic measures to prevent wandering.

Concepts: Regression analysis, United States, Autism, Down syndrome, Autism spectrum, Mental retardation, Developmental disability, Disability


National medical organizations recommend that during prenatal counseling sessions, healthcare providers discuss how having a child with Down syndrome (DS) might impact the family unit. Few studies, to date, have surveyed families about their life experiences. For this investigation, we examined 41 family attitudes, which were obtained from mailed questionnaires completed by 1,961 parents/guardians, 761 brothers/sisters, and 283 people with DS who were members of six DS non-profit organizations, chosen for their size, ethnic/racial diversities, and geographic distribution throughout the United States. About 83% of families reported to all being proud of the family member with DS, and 87% reported to all feeling love for the member with DS. Younger siblings (ages 9-11) were more likely to feel embarrassed by their sibling with DS if their parents/guardians also did. If one or more parents/guardians felt that their children without DS did have a good relationship with their child with DS, siblings were more likely to report that they loved and liked their brother/sister with DS. Overall, our data demonstrate that positive themes tend to dominate within modern-day families who have members with DS, although challenges were not insignificant for some. © 2015 Wiley Periodicals, Inc.

Concepts: Family, United States, Interpersonal relationship, Down syndrome, Love, Sibling, Non-profit organization, Federal Bureau of Investigation


Immune abnormalities have been described in some individuals with autism spectrum disorders (ASDs) as well as their family members. However, few studies have directly investigated the role of prenatal cytokine and chemokine profiles on neurodevelopmental outcomes in humans. In the current study, we characterized mid-gestational serum profiles of 22 cytokines and chemokines in mothers of children with ASD (N=415), developmental delay (DD) without ASD (N=188), and general population (GP) controls (N=428) using a bead-based multiplex technology. The ASD group was further divided into those with intellectual disabilities (developmental/cognitive and adaptive composite score<70) (ASD+ID, N=184) and those without (composite score⩾70) (ASD-noID, N=201). Levels of cytokines and chemokines were compared between groups using multivariate logistic regression analyses, adjusting for maternal age, ethnicity, birth country and weight, as well as infant gender, birth year and birth month. Mothers of children with ASD+ID had significantly elevated mid-gestational levels of numerous cytokines and chemokines, such as granulocyte macrophage colony-stimulating factor, interferon-γ, interleukin-1α (IL-1α) and IL-6, compared with mothers of children with either ASD-noID, those with DD, or GP controls. Conversely, mothers of children with either ASD-noID or with DD had significantly lower levels of the chemokines IL-8 and monocyte chemotactic protein-1 compared with mothers of GP controls. This observed immunologic distinction between mothers of children with ASD+ID from mothers of children with ASD-noID or DD suggests that the intellectual disability associated with ASD might be etiologically distinct from DD without ASD. These findings contribute to the ongoing efforts toward identification of early biological markers specific to subphenotypes of ASD.Molecular Psychiatry advance online publication, 24 May 2016; doi:10.1038/mp.2016.77.

Concepts: Immune system, Regression analysis, Cytokines, Autism, Chemokine, Down syndrome, Mental retardation, Developmental disability


Since the early 1970s, the ethical norm governing counselors involved in testing and screening for genetic conditions related to reproduction has been strict neutrality. Counseling about reproductive genetics was to be patient centered but nondirective. Many advocates for people with Down syndrome believe that high abortion rates following a diagnosis of this condition show an unfounded bias against those with Down syndrome. These advocates have succeeded in enacting federal and state legislation that requires women who receive a prenatal diagnosis of Down syndrome to receive positive information about the condition, thereby ending the nominal goal of value-neutral counseling and setting the stage for further normative shifts in clinical reproductive genetics as counseling expands because of cell-free testing.

Concepts: Genetics, Reproduction, Organism, Greek loanwords, Down syndrome, Sexual reproduction, Prenatal diagnosis, Normative ethics


Motor speech characteristics of children with Down syndrome (DS) have historically been viewed as either Childhood Dysarthria (CD) or, more infrequently, as Childhood Apraxia of Speech (CAS). The objective of this study was to investigate motor speech deficits in a systematic manner, considering characteristics from both CAS and CD.

Concepts: Down syndrome, Disability, Neurological disorders, Apraxia