Complex translocation disrupting TCF4 and altering TCF4 isoform expression segregates as mild autosomal dominant intellectual disability.

BACKGROUND: Mutations of TCF4, which encodes a basic helix-loop-helix transcription factor, cause Pitt-Hopkins syndrome (PTHS) via multiple genetic mechanisms. TCF4 is a complex locus expressing multiple transcripts by alternative splicing and use of multiple promoters. To address the relationship between mutation of these transcripts and phenotype, we report a three-generation family segregating mild intellectual disability with a chromosomal translocation disrupting TCF4. RESULTS: Using whole genome sequencing, we detected a complex unbalanced karyotype disrupting TCF4 (46,XY,del(14)(q23.3q23.3)del(18)(q21.2q21.2)del(18)(q21.2q21.2)inv(18)(q21.2q21.2)t(14;18)(q23.3;q21.2)(14pter®14q23.3::18q21.2®18q21.2::18q21.1®18qter;18pter®18q21.2::14q23.3®14qter). Subsequent transcriptome sequencing, qRT-PCR and nCounter analyses revealed that cultured skin fibroblasts and peripheral blood had normal expression of genes along chromosomes 14 or 18 and no marked changes in expression of genes other than TCF4. Affected individuals had 12-33 fold higher mRNA levels of TCF4 than did unaffected controls or individuals with PTHS. Although the derivative chromosome generated a PLEKHG3-TCF4 fusion transcript, the increased levels of TCF4 mRNA arose from transcript variants originating distal to the translocation breakpoint, not from the fusion transcript. CONCLUSIONS: Although validation in additional patients is required, our findings suggest that the dysmorphic features and severe intellectual disability characteristic of PTHS are partially rescued by overexpression of those short TCF4 transcripts encoding a nuclear localization signal, a transcription activation domain, and the basic helix-loop-helix domain.

Comparison of the ASQ and PEDS in screening for developmental delay in children presenting for primary care.

OBJECTIVES: This study investigated the sensitivity and specificity of two brief, parent-completed developmental screening measures-the Ages and Stages Questionnaire (ASQ) and the Parents' Evaluation of Developmental Status (PEDS)-in children presenting to their primary care providers. METHOD: A sample of 334 children aged 12 to 60 months was recruited. Parents completed the PEDS and the ASQ in their home or the primary care clinic of one of the investigators. The presence of ≥ 1 predictive concerns or abnormal domains was considered a positive screen. All children underwent evaluation (administered by a psychologist) with the following criterion measures: the Bayley Scales of Infant Development-Third Edition or the Wechsler Preschool and Primary Scale of Intelligence-Third Edition, the Preschool Language Scale-Fourth Edition, and the Vineland Adaptive Behavior Scales-Second Edition. RESULTS: The mean age of children was 32.3 months. Developmental delay was identified in 34 children (10%). The PEDS had moderate sensitivity (74%) but low specificity (64%); comparatively, the ASQ had significantly higher sensitivity (82%) and specificity (78%). The ASQ had moderate sensitivity and specificity across age subgroups, whereas the PEDS had either low sensitivity or specificity in each of the age subgroups, except for the ≤ 30 month group, where there was moderate sensitivity (78%) and specificity (75%). Using ≥ 2 predictive concerns on the PEDS or ≥ 2 abnormal domains on the ASQ significantly improved specificity of both tests (89% and 94%, respectively) but resulted in very low sensitivity (41% and 47%, respectively). CONCLUSIONS: These findings support the guidelines of the American Academy of Pediatrics, demonstrating that both the ASQ and, to a lesser extent, the PEDS have reasonable test characteristics for developmental screening in primary care settings. Although the ASQ seems to have higher sensitivity and specificity across a variety of age groups, the choice of which measure to use should be determined by the practice setting, population served, and preference of the physician.

Nipissing District Developmental Screen: patterns of use by physicians in Ontario.

OBJECTIVE: To determine if providing the Nipissing District Developmental Screen (NDDS) free of charge is associated with increased use of this measure and to investigate regional variations in the use of the NDDS in Ontario. DESIGN: Retrospective analysis of purchasing data from before the NDDS was available at no cost compared with analysis of the results of a brief questionnaire completed by those downloading the NDDS for free. SETTING: Ontario. PARTICIPANTS: Users of the NDDS. INTERVENTION: Provision of free on-line access to the NDDS. MAIN OUTCOME MEASURES: Patterns of purchasing or downloading of the NDDS by FPs and health care professionals (HCPs) before and after implementation of the program. RESULTS: Before the program, 91 FPs (0.9% of FPs in Ontario) purchased the NDDS, and an additional 129 FPs (1.3% of FPs in Ontario) downloaded the NDDS in the year after the start of the program. Including all other HCPs increased the estimated number of users to 504 (representing an estimated 5.0% of all FPs in Ontario). Adjusting for group practice increased the estimate to 16.5% of all FPs in Ontario who had access to the NDDS. There were no significant differences in NDDS usage by FPs between central, southwestern, and northern Ontario (P > .05). Significantly fewer FPs in eastern Ontario accessed the NDDS than FPs in other areas of the province did (P < .001). CONCLUSION: Despite measures to increase usage, only a small number of FPs access the NDDS in Ontario. However, free access to the NDDS does seem to contribute to removing barriers to screening, as indicated by a 3-fold increase in the number of FPs accessing the NDDS. Further research is required to investigate the reasons for these trends so that effective methods to increase the use of developmental screening measures in clinical practice can be implemented.

Identification of cognitive impairment and mental illness in elderly homeless men: Before and after access to primary health care.

OBJECTIVE: To describe the occurrence of mental health problems and cognitive impairment in a group of elderly homeless men and to demonstrate how clinical examination and screening tests used in a shelter setting might be helpful in identifying mental illness and cognitive impairment. DESIGN: Cross-sectional study including face-to-face interviews and review of medical records. SETTING: A community-based homeless shelter in an urban metropolitan centre (Toronto, Ont). PARTICIPANTS: A total of 49 male participants 55 years of age or older. The average duration of homelessness was 8.8 (SD 10.2) years. METHODS: Participants were admitted to a community-based shelter that offered access to regular meals, personal support and housing workers, nursing, and a primary care physician. Medical chart review was undertaken to identify mental illness or cognitive impairment diagnosed either before or after admission to the facility. The 15-item Geriatric Depression Scale (GDS-15) and the Folstein Mini-Mental State Examination (MMSE) were administered. MAIN OUTCOME MEASURE: Previous or new diagnosis of mental illness or cognitive impairment. RESULTS: Thirty-six of the participants (73.5%) had previous or new diagnoses. The most prevalent diagnosis was schizophrenia or psychotic disorders (n = 17), followed by depression (n = 11), anxiety disorders (n = 3), cognitive impairment (n = 8), and bipolar affective disorder (n = 1). A total of 37% of participants were given new mental health diagnoses during the study. The GDS-15 identified 9 people with depression and the MMSE uncovered 11 individuals with cognitive impairment who had not been previously diagnosed. CONCLUSION: This study suggests that providing access to primary care physicians and other services in a community-based shelter program can assist in identification of mental illness and cognitive impairment in elderly homeless men. Use of brief screening tools for depression and cognitive impairment (like the GDS-15 and the MMSE) could be helpful in this highrisk group.