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1.  Genetic contributions to visuospatial cognition in Williams syndrome: insights from two contrasting partial deletion patients 
Background
Williams syndrome (WS) is a rare neurodevelopmental disorder arising from a hemizygotic deletion of approximately 27 genes on chromosome 7, at locus 7q11.23. WS is characterised by an uneven cognitive profile, with serious deficits in visuospatial tasks in comparison to relatively proficient performance in some other cognitive domains such as language and face processing. Individuals with partial genetic deletions within the WS critical region (WSCR) have provided insights into the contribution of specific genes to this complex phenotype. However, the combinatorial effects of different genes remain elusive.
Methods
We report on visuospatial cognition in two individuals with contrasting partial deletions in the WSCR: one female (HR), aged 11 years 9 months, with haploinsufficiency for 24 of the WS genes (up to GTF2IRD1), and one male (JB), aged 14 years 2 months, with the three most telomeric genes within the WSCR deleted, or partially deleted.
Results
Our in-depth phenotyping of the visuospatial domain from table-top psychometric, and small- and large-scale experimental tasks reveal a profile in HR in line with typically developing controls, albeit with some atypical features. These data are contrasted with patient JB’s atypical profile of strengths and weaknesses across the visuospatial domain, as well as with more substantial visuospatial deficits in individuals with the full WS deletion.
Conclusions
Our findings point to the contribution of specific genes to spatial processing difficulties associated with WS, highlighting the multifaceted nature of spatial cognition and the divergent effects of genetic deletions within the WSCR on different components of visuospatial ability. The importance of general transcription factors at the telomeric end of the WSCR, and their combinatorial effects on the WS visuospatial phenotype are also discussed.
doi:10.1186/1866-1955-6-18
PMCID: PMC4107613  PMID: 25057328
Williams syndrome; Visuospatial cognition; Navigation; GTF2I; GTF2IRD1; LIMK1
2.  Highly penetrant alterations of a critical region including BDNF contribute to human psychopathology 
Archives of general psychiatry  2012;69(12):1238-1246.
CONTEXT
Brain-derived neurotrophic factor (BDNF) is suspected of being a causative factor in psychiatric disorders based on case reports or studies involving large structural anomalies.
OBJECTIVE
To determine the involvement of BDNF in human psychopathology
DESIGN
Case- Control study
SETTING
Microarray-based comparative genomic hybridization (aCGH) data from seven molecular diagnostic centers including 38, 550 affected subjects and 28, 705 unaffected subjects.
PATIENTS
Subjects referred to diagnostic screening centers for aCGH for physical or cognitive impairment.
MAIN OUTCOME MEASURE
Genomic copy number gains and losses
RESULTS
We report five individuals with psychopathology and genomic deletion of a critical region including BDNF. The defined critical region was never disrupted in control subjects or diagnostic cases without developmental abnormalities.
CONCLUSION
Hemizygosity of the BDNF region contributes to variable psychiatric phenotypes including anxiety, behavioral, and mood disorders.
doi:10.1001/archgenpsychiatry.2012.660
PMCID: PMC3590016  PMID: 23044507
3.  How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum 
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.
doi:10.1038/ejhg.2011.220
PMCID: PMC3306863  PMID: 22126750
Kabuki syndrome; MLL2; genetic heterogeneity; mutation spectrum; facial dysmorphism
4.  Social Cognition in Williams Syndrome: Genotype/Phenotype Insights from Partial Deletion Patients 
Identifying genotype/phenotype relations in human social cognition has been enhanced by the study of Williams syndrome (WS). Indeed, individuals with WS present with a particularly strong social drive, and researchers have sought to link deleted genes in the WS critical region (WSCR) of chromosome 7q11.23 to this unusual social profile. In this paper, we provide details of two case studies of children with partial genetic deletions in the WSCR: an 11-year-old female with a deletion of 24 of the 28 WS genes, and a 14-year-old male who presents with the opposite profile, i.e., the deletion of only four genes at the telomeric end of the WSCR. We tested these two children on a large battery of standardized and experimental social perception and social cognition tasks – both implicit and explicit – as well as standardized social questionnaires and general psychometric measures. Our findings reveal a partial WS socio-cognitive profile in the female, contrasted with a more autistic-like profile in the male. We discuss the implications of these findings for genotype/phenotype relations, as well as the advantages and limitations of animal models and of case study approaches.
doi:10.3389/fpsyg.2012.00168
PMCID: PMC3362742  PMID: 22661963
social cognition; Williams syndrome; partial deletion patients; genetic disorders; autism spectrum disorders; genotype/phenotype relations
5.  Bohring–Opitz (Oberklaid–Danks) syndrome: clinical study, review of the literature, and discussion of possible pathogenesis 
Bohring–Opitz syndrome (BOS) is a rare congenital disorder of unknown etiology diagnosed on the basis of distinctive clinical features. We suggest diagnostic criteria for this condition, describe ten previously unreported patients, and update the natural history of four previously reported patients. This is the largest series reported to date, providing a unique opportunity to document the key clinical features and course through childhood. Investigations undertaken to try and elucidate the underlying pathogenesis of BOS using array comparative genomic hybridization and tandem mass spectrometry of cholesterol precursors did not show any pathogenic changes responsible.
doi:10.1038/ejhg.2010.234
PMCID: PMC3083618  PMID: 21368916
Bohring–Opitz; Oberklaid–Danks; cholesterol biosynthesis; array CGH; trigonocephaly
6.  Autism, language and communication in children with sex chromosome trisomies 
Archives of disease in childhood  2010;96(10):954-959.
Purpose
Sex chromosome trisomies (SCTs) are found on amniocentesis in 2.3–3.7 per 1000 same-sex births, yet there is a limited database on which to base a prognosis. Autism has been described in postnatally diagnosed cases of Klinefelter syndrome (XXY karyotype), but the prevalence in non-referred samples, and in other trisomies, is unclear. The authors recruited the largest sample including all three SCTs to be reported to date, including children identified on prenatal screening, to clarify this issue.
Design
Parents of children with a SCT were recruited either via prenatal screening or via a parental support group, to give a sample of 58 XXX, 19 XXY and 58 XYY cases. Parents were interviewed using the Vineland Adaptive Behavior Scales and completed questionnaires about the communicative development of children with SCTs and their siblings (42 brothers and 26 sisters).
Results
Rates of language and communication problems were high in all three trisomies. Diagnoses of autism spectrum disorder (ASD) were found in 2/19 cases of XXY (11%) and 11/58 XYY (19%). After excluding those with an ASD diagnosis, communicative profiles indicative of mild autistic features were common, although there was wide individual variation.
Conclusions
Autistic features have not previously been remarked upon in studies of non-referred samples with SCTs, yet the rate is substantially above population levels in this sample, even when attention is restricted to early-identified cases. The authors hypothesise that X-linked and Y-linked neuroligins may play a significant role in the aetiology of communication impairments and ASD.
doi:10.1136/adc.2009.179747
PMCID: PMC3182523  PMID: 20656736
7.  Gerodermia osteodysplastica is caused by mutations in SCYL1BP1, a Rab-6 interacting golgin 
Nature Genetics  2008;40(12):1410-1412.
Gerodermia osteodysplastica (GO) is an autosomal recessive disorder characterized by wrinkly skin and osteoporosis. Here we demonstrate that GO is caused by loss-of-function mutations in SCYL1BP1, which is expressed at high levels in skin and osteoblasts. The protein localizes to the Golgi apparatus and interacts with Rab6, identifying SCYL1BP1 as a novel golgin. These results associate abnormalities of the secretory pathway with age-related changes in connective tissues.
doi:10.1038/ng.252
PMCID: PMC3122266  PMID: 18997784

Results 1-8 (8)