Localizing a putative mutation as the major contributor to the development of sporadic Hirschsprung disease to the RET genomic sequence between the promoter region and exon 2

Hirschsprung disease (HSCR), a congenital disorder characterized by intestinal obstruction due to absence of enteric ganglia along variable lengths of the intestinal tract, occurs both in familial and sporadic cases. RET mutations have been found in approximately 50% of the families, but explains only a minority of sporadic cases. This study aims at investigating a possible role of RET in sporadic HSCR patients. Haplotypes of 13 DNA markers, within and flanking RET, have been determined for 117 sporadic HSCR patients and their parents. Strong association was observed for six markers in the 5' region of RET. The largest distortions in allele transmission were found at the same markers. One single haplotype composed of these six markers was present in 55.6% of patients versus 16.2% of controls. Odds ratios (ORs) revealed a highly increased risk of homozygotes for this haplotype to develop HSCR (OR>20). These results allowed us to conclude that RET plays a crucial role in HSCR even when no RET mutations are found. An unknown functional disease variant(s) with a dosage-dependent effect in HSCR is likely located between the promoter region and exon 2 of RET.     

Attachment representations and response to video-feedback intervention for professional caregivers

Interventions to improve caregiving may have different effects for persons with autonomous or nonautonomous attachment representations. The current study used the Adult Attachment Interview to investigate attachment representations of professional caregivers who participated in an intervention to improve interaction with children and adults with serious intellectual and visual disabilities. Caregivers (N = 51) completed a video-feedback interaction program. Twice during a baseline period and three times during the intervention period, each caregiver was videotaped during a standard situation with their client. Of the caregivers, 28 were classified as autonomous, 12 as dismissing, and 11 as preoccupied. Unresolved loss or trauma (n = 7) was not included in the analyses. Generally, interaction quality improved from baseline to intervention period as indicated by confirmation of signals, responsiveness to signals, and affective mutuality. Caregivers with dismissing classifications continued to show less confirmation of clients' signals. Caregivers with dismissing or preoccupied classifications improved their responsiveness to the level of caregivers with autonomous classifications. Attachment representations may modify in some ways the impact of interventions to improve caregiving.     

The atypical 16p11.2 deletion: A not so atypical microdeletion syndrome?

One of the recently recognized microdeletion syndromes is the 16p11.2 deletion syndrome (593 kb; ～29.5 Mb to ～30.1 Mb), associated with developmental delay, autism spectrum disorder, epilepsy, and obesity. Less frequently reported is a smaller 220 kb deletion, adjacent and distal to this 16p11.2 deletion, which has been referred to as the atypical 16p11.2 deletion (220 kb; ～28.74 Mb to ～28.95 Mb). We describe three patients with this deletion and update the manifestations in two sibs who have been described as possibly new entity in this Journal in 1997 [Bakker and Hennekam (1997); Am J Med Genet 70:312–314] and were recently found to have the “atypical 16p11.2 deletion” as well. Patients show a developmental delay, behavioral problems, and unusual facial morphology (prominent forehead, downslanted, and narrow palpebral fissures), and some are obese. We suggest that this “atypical” deletion may turn out to become a microdeletion syndrome that will be recognizable in the future, or at least to show a phenotype that is recognizable in retrospect. As it may no longer be so “atypical,” we suggest renaming the entity “distal 16p11.2 deletion,” to distinguish it from the common proximal 16p11.2 deletion. © 2011 Wiley‐Liss, Inc.     

Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T-cell interactions

1. Download : Download high-res image (276KB)
2. Download : Download full-size image

     

Genomic array as compared to karyotyping in myelodysplastic syndromes in a prospective clinical trial

Karyotyping is considered as the gold standard in the genetic subclassification of myelodysplastic syndrome (MDS). Oligo/SNP‐based genomic array profiling is a high‐resolution tool that also enables genome wide analysis. We compared karyotyping with oligo/SNP‐based array profiling in 104 MDS patients from the HOVON‐89 study. Oligo/SNP‐array identified all cytogenetically defined genomic lesions, except for subclones in two cases and balanced translocations in three cases. Conversely, oligo/SNP‐based genomic array profiling had a higher success rate, showing 55 abnormal cases, while an abnormal karyotype was found in only 35 patients. In nine patients whose karyotyping was unsuccessful because of insufficient metaphases or failure, oligo/SNP‐based array analysis was successful. Based on cytogenetic visible abnormalities as identified by oligo/SNP‐based genomic array prognostic scores based on IPSS/‐R were assigned. These prognostic scores were identical to the IPSS/‐R scores as obtained with karyotyping in 95%‐96% of the patients. In addition to the detection of cytogenetically defined lesions, oligo/SNP‐based genomic profiling identified focal copy number abnormalities or regions of copy neutral loss of heterozygosity that were out of the scope of karyotyping and fluorescence in situ hybridization. Of interest, in 26 patients we demonstrated such cytogenetic invisible abnormalities. These abnormalities often involved regions that are recurrently affected in hematological malignancies, and may therefore be of clinical relevance. Our findings indicate that oligo/SNP‐based genomic array can be used to identify the vast majority of recurrent cytogenetic abnormalities in MDS. Furthermore, oligo/SNP‐based array profiling yields additional genetic abnormalities that may be of clinical importance.     

Rho GTPases: functions and association with cancer

Rho GTPases are small proteins that act as binary molecular switches in a wide range of signalling pathways upon stimulation of cell surface receptors. Three different classes of regulatory proteins control their activity. In the activated state small GTPases are able to bind a variety of effector proteins and initiate downstream signalling. Rho GTPases regulate important cellular processes ranging from cytoskeletal remodelling and gene expression to cell proliferation and membrane trafficking. Therefore it is not surprising that deregulated Rho signalling can contribute to disturbed cellular phenotypes in a wide range of diseases. The main focus of this review will be the diversity of functions of Rho GTPases and the effects of aberrant Rho GTPase signalling in various aspects of cancer.