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We report six patients with array deletions encompassing 12q14. Out of a total of 2538 array investigations carried out on children with developmental delay and dysmorphism in three diagnostic testing centres, six positive cases yielded a frequency of 1 in 423 for this deletion syndrome. The deleted region in each of the six cases overlaps significantly with previously reported cases with microdeletions of this region. The chromosomal range of the deletions extends from 12q13.3q15. In the current study, we report overlapping deletions of variable extent and size but primarily comprising chromosomal bands 12q13.3q14.1. Four of the six deletions were confirmed as de novo events. Two cases had deletions that included HMGA2 , and both children had significant short stature. Neither case had osteopoikilosis despite both being deleted for LEMD3 . Four cases had deletions that ended proximal to HMGA2 and all of these had much better growth. Five cases had congenital heart defects, including two with atrial septal defects, one each with pulmonary stenosis, sub-aortic stenosis and a patent ductus. Four cases had moderate delay, two had severe developmental delay and a further two had a diagnosis of autism. All six cases had significant speech delay with subtle facial dysmorphism.

Background Microdeletions of 2q23.1 disrupting MBD5 and loss of function mutations of MBD5 cause MBD5‐Associated Neurodevelopmental disorders (MAND). Nearly all reported patients have been isolated cases of de novo origin. Methods This study investigates three families with inherited MBD5 mutations from three different Regional Genetics Centres in the UK. Results Two of the parents in the study had MBD5 deletions in a mosaic form. The parent with an MBD5 deletion in an apparently nonmosaic form has a psychiatric disorder in the absence of developmental delay or dysmorphism. Conclusions Inherited forms of MBD5 deletions are rare, but do occur, especially in a mosaic form. The phenotypic spectrum of MAND may be wider than previously thought. This report describes three families with inherited 2q23.1 microdeletions including a parent who has the deletion in an apparently nonmosaic form and has mental health issues in the absence of developmental delay or dysmorphic features. We also report two instances of parental mosaicism, which could be significant for counseling parents of an affected child with an apparent de novo deletion.

The Multiplex Ligation-dependent Probe Amplification assay (MLPA) is the method of choice for the initial mutation screen in the analysis of a large number of genes where partial or total gene deletion is part of the mutation spectrum. Although MLPA dosage probes are usually designed to bind to normal DNA sequence to identify dosage imbalance, point mutation-specific MLPA probes can also be made. Using the dystrophin gene as a model, we have designed two MLPA probe multiplexes that are specific to a number of commonly listed point mutations in the Leiden dystrophin point mutation database (http://www.dmd.nl). The point mutation probes are designed to work simultaneously with two widely used dystrophin MLPA multiplexes, allowing both full dosage analysis and partial point mutation analysis in a single test. This approach may be adapted for other syndromes with well defined common point mutations or polymorphisms.

MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% patients with KS, the genetic basis remains unknown, suggesting possible genetic heterogeneity. Here, we present the largest yet reported cohort of 116 patients with KS. We identified MLL2 variants in 74 patients, of which 47 are novel and a majority are truncating. We show that pathogenic missense mutations were commonly located in exon 48. We undertook a systematic facial KS morphology study of patients with KS at our regional dysmorphology meeting. Our data suggest that nearly all patients with typical KS facial features have pathogenic MLL2 mutations, although KS can be phenotypically variable. Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. Our work expands the mutation spectrum of MLL2 that may help in better understanding of this molecule, which is important in gene expression, epigenetic control of active chromatin states, embryonic development and cancer. Our analyses of the phenotype indicates that MLL2 mutation-positive and -negative patients differ systematically, and genetic heterogeneity of KS is not as extensive as previously suggested. Moreover, phenotypic variability of KS suggests that MLL2 testing should be considered even in atypical patients.

BackgroundMicrodeletions of 2q23.1 disrupting MBD5 and loss of function mutations of MBD5 cause MBD5‐Associated Neurodevelopmental disorders (MAND). Nearly all reported patients have been isolated cases of de novo origin.MethodsThis study investigates three families with inherited MBD5 mutations from three different Regional Genetics Centres in the UK.ResultsTwo of the parents in the study had MBD5 deletions in a mosaic form. The parent with an MBD5 deletion in an apparently nonmosaic form has a psychiatric disorder in the absence of developmental delay or dysmorphism.ConclusionsInherited forms of MBD5 deletions are rare, but do occur, especially in a mosaic form. The phenotypic spectrum of MAND may be wider than previously thought.

Dialectical Behavior Therapy (DBT) demonstrates effectiveness in the treatment of individuals diagnosed with Borderline Personality Disorder in an outpatient setting. DBT has also been adapted for inpatient settings and demonstrates effectiveness with this population. To date no published literature examines the effectiveness of the standard outpatient model implemented in an inpatient setting. Furthermore, the literature examining inpatient DBT is done on treatment units where DBT is the sole treatment modality. There is no published literature regarding the use of DBT in conjunction with another treatment program. Therefore, this study examines the effectiveness of the standard outpatient DBT model implemented in conjunction with psychosocial rehabilitation or treatment as usual in a state hospital. This study also examined the effects of neuropsychological functioning and symptomatology on DBT outcome, as all previous research excludes individuals with psychotic disorders, bipolar disorder, and cognitive impairments. Results suggest that the standard outpatient DBT model can benefit individuals in a state hospital, that individuals who receive psychosocial rehabilitation in conjunction with DBT demonstrate more benefit than individuals who receive treatment as usual in conjunction with DBT, that neuropsychological functioning has an impact on DBT outcomes, and that positive symptoms do not impact DBT outcomes.

Holoprosencephaly (HPE) is a common malformation of the developing forebrain and midface characterized by incomplete penetrance and variable expressivity. Familial HPE has been reported in many families with autosomal dominant inheritance in some and apparent autosomal recessive inheritance in others. We have examined 125 individuals from nine families with autosomal dominant HPE. Expression in gene carriers varied from alobar HPE and cyclopia through microforms such as microcephaly or single central incisor to normal phenotype. We performed linkage studies by either Southern blot or polymerase chain reaction analyses with DNA markers (D7S22, D7S550, and D7S483) that are deleted from some patients with sporadic HPE and flank a translocation breakpoint in 7q36 associated with HPE. The strongest support for linkage was with D7S22, which was linked with no recombination to autosomal dominant HPE in eight of nine families with a combined logarithm of odds score of 6.4 with an affecteds-only model-free analysis and 8.2 with a reduced-penetrance model and all phenotypes. Close linkage to this region could be excluded in one family, and there was significant evidence of genetic heterogeneity. These results show that a gene for autosomal dominant HPE is located in a chromosomal region (7q36) known to be involved in sporadic HPE with visible cytogenetic deletions. They also demonstrate genetic heterogeneity in familial HPE. We hypothesize that mutations of a gene in 7q36, designated HPE3, are responsible for both sporadic HPE and a majority of families with autosomal dominant HPE.

In this study, the clinical, IQ, and cytogenetic findings in nine Turner's syndrome patients with a ring (X) cell line are compared with those in 16 patients in whom only a 45,X cell line could be found. The ring (X) patients lacked many of the \"classic\" Turner's syndrome features and the majority were not karyotyped until after the age of 11, usually because of pubertal failure. They also showed a reduction in IQ of 11 points compared with the 45,X group. Some ring (X) patients show characteristic facial features including a broad nose with anteverted nostrils, prominent philtrum, long palpebral fissures, and a wide mouth with a thin upper lip. Neither the physical features nor the IQ are related to the parental origin of the chromosome error. In the majority of cases the ring (X) chromosome was late replicating but XIST activity is being studied further.