ABSTRACT
The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.
ABSTRACT
PURPOSE: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. METHODS: Clinicians entered clinical data in an extensive web-based survey. RESULTS: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. CONCLUSION: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.
Subject(s)
DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Abnormalities, Multiple/genetics , Adolescent , Adult , Child , Child, Preschool , Chromosomal Proteins, Non-Histone/genetics , Exome , Face/abnormalities , Female , Genetic Association Studies/methods , Genetic Variation/genetics , Hand Deformities, Congenital/genetics , Humans , Infant , Infant, Newborn , Intellectual Disability/genetics , Male , Micrognathism/genetics , Middle Aged , Mutation , Neck/abnormalities , PenetranceABSTRACT
Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.
Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Child Development Disorders, Pervasive/genetics , Glycoproteins/genetics , Nerve Tissue Proteins/genetics , Transcription Factors/genetics , Adolescent , Adult , Case-Control Studies , Child , Child, Preschool , Chromosomes, Human, Pair 9 , DNA Copy Number Variations , Exons , Female , Gene Expression , Genetic Association Studies , Genetic Predisposition to Disease , Glycoproteins/metabolism , Humans , Infant , Infant, Newborn , Male , Nerve Tissue Proteins/metabolism , Organ Specificity , Phenotype , Polymorphism, Single Nucleotide , Protein Isoforms/genetics , Protein Isoforms/metabolism , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Risk Factors , Sequence Deletion , Transcription Factors/metabolism , Transcription Initiation Site , Tripartite Motif Proteins , Ubiquitin-Protein Ligases , Young AdultABSTRACT
AIM: This paper is a report of a study of the effects of communication-skills training for healthcare professionals on parents' perceptions of information, care and continuity. BACKGROUND: As training in communication skills has been more and more integrated into clinical practice it has been subject to an increasing number of studies. However, the majority of studies have been conducted in outpatient clinics, have only targeted physicians, and have not been evaluated from the perspective of patients. METHOD: This intervention study, conducted from 2005 to 2007, was performed to investigate the effect of a 3-day communication course offered to all healthcare professionals in a department of paediatrics. In a pre-/post-test design, the effect of the intervention was evaluated by the parents using electronic questionnaires filled in on touch-screen computers located centrally in the wards. RESULTS: A total of 895 parents answered the questionnaires before the course (80%) and 1937 answered after the course (72%). For the questions on care and continuity, the proportion of satisfied parents increased statistically significantly for 4 out of 13 questions, e.g. Did you feel that the staff understood you situation? and Did you find that the information given by the different nurses was consistent? For the information questions, no statistically significant differences were found. CONCLUSION: It is possible to incorporate key communication skills into clinical practice by targeting all healthcare professionals. Communication skills training using interactive methods such as role-play and feedback on video recordings is recommended.