Ancestry of the AUTS2 family-A novel group of polycomb-complex proteins involved in human neurological disease.

Autism susceptibility candidate 2 (AUTS2) is a neurodevelopmental regulator associated with an autosomal dominant intellectual disability syndrome, AUTS2 syndrome, and is implicated as an important gene in human-specific evolution. AUTS2 exists as part of a tripartite gene family, the AUTS2 family, which includes two relatively undefined proteins, Fibrosin (FBRS) and Fibrosin-like protein 1 (FBRSL1). Evolutionary ancestors of AUTS2 have not been formally identified outside of the Animalia clade. A Drosophila melanogaster protein, Tay bridge, with a role in neurodevelopment, has been shown to display limited similarity to the C-terminal of AUTS2, suggesting that evolutionary ancestors of the AUTS2 family may exist within other Protostome lineages. Here we present an evolutionary analysis of the AUTS2 family, which highlights ancestral homologs of AUTS2 in multiple Protostome species, implicates AUTS2 as the closest human relative to the progenitor of the AUTS2 family, and demonstrates that Tay bridge is a divergent ortholog of the ancestral AUTS2 progenitor gene. We also define regions of high relative sequence identity, with potential functional significance, shared by the extended AUTS2 protein family. Using structural predictions coupled with sequence conservation and human variant data from 15,708 individuals, a putative domain structure for AUTS2 was produced that can be used to aid interpretation of the consequences of nucleotide variation on protein structure and function in human disease. To assess the role of AUTS2 in human-specific evolution, we recalculated allele frequencies at previously identified human derived sites using large population genome data, and show a high prevalence of ancestral alleles, suggesting that AUTS2 may not be a rapidly evolving gene, as previously thought.

Hardy-Weinberg Equilibrium in the Large Scale Genomic Sequencing Era.

Hardy-Weinberg Equilibrium (HWE) is used to estimate the number of homozygous and heterozygous variant carriers based on its allele frequency in populations that are not evolving. Deviations from HWE in large population databases have been used to detect genotyping errors, which can result in extreme heterozygote excess (HetExc). However, HetExc might also be a sign of natural selection since recessive disease causing variants should occur less frequently in a homozygous state in the population, but may reach high allele frequency in a heterozygous state, especially if they are advantageous. We developed a filtering strategy to detect these variants and applied it on genome data from 137,842 individuals. The main limitations of this approach were quality of genotype calls and insufficient population sizes, whereas population structure and inbreeding can reduce sensitivity, but not precision, in certain populations. Nevertheless, we identified 161 HetExc variants in 149 genes, most of which were specific to African/African American populations (∼79.5%). Although the majority of them were not associated with known diseases, or were classified as clinically "benign," they were enriched in genes associated with autosomal recessive diseases. The resulting dataset also contained two known recessive disease causing variants with evidence of heterozygote advantage in the sickle-cell anemia (HBB) and cystic fibrosis (CFTR). Finally, we provide supporting in silico evidence of a novel heterozygote advantageous variant in the chromodomain helicase DNA binding protein 6 gene (CHD6; involved in influenza virus replication). We anticipate that our approach will aid the detection of rare recessive disease causing variants in the future.

GeVIR is a continuous gene-level metric that uses variant distribution patterns to prioritize disease candidate genes.

With large-scale population sequencing projects gathering pace, there is a need for strategies that advance disease gene prioritization1,2. Metrics that provide information about a gene and its ability to tolerate protein-altering variation can aid in clinical interpretation of human genomes and can advance disease gene discovery1-4. Previous reported methods analyzed the total variant load in a gene1-4, but did not analyze the distribution pattern of variants within a gene. Using data from 138,632 exome and genome sequences2, we developed gene variation intolerance rank (GeVIR), a continuous gene-level metric for 19,361 genes that is able to prioritize both dominant and recessive Mendelian disease genes5, that outperforms missense constraint metrics3 and that is comparable-but complementary-to loss-of-function (LOF) constraint metrics2. GeVIR is also able to prioritize short genes, for which LOF constraint cannot be estimated with confidence2. The majority of the most intolerant genes identified here have no defined phenotype and are candidates for severe dominant disorders.

GORAB scaffolds COPI at the trans-Golgi for efficient enzyme recycling and correct protein glycosylation.

COPI is a key mediator of protein trafficking within the secretory pathway. COPI is recruited to the membrane primarily through binding to Arf GTPases, upon which it undergoes assembly to form coated transport intermediates responsible for trafficking numerous proteins, including Golgi-resident enzymes. Here, we identify GORAB, the protein mutated in the skin and bone disorder gerodermia osteodysplastica, as a component of the COPI machinery. GORAB forms stable domains at the trans-Golgi that, via interactions with the COPI-binding protein Scyl1, promote COPI recruitment to these domains. Pathogenic GORAB mutations perturb Scyl1 binding or GORAB assembly into domains, indicating the importance of these interactions. Loss of GORAB causes impairment of COPI-mediated retrieval of trans-Golgi enzymes, resulting in a deficit in glycosylation of secretory cargo proteins. Our results therefore identify GORAB as a COPI scaffolding factor, and support the view that defective protein glycosylation is a major disease mechanism in gerodermia osteodysplastica.

Functional basic reading skills in Williams syndrome.

This study investigated whether individuals with Williams syndrome (WS) can attain a functional level of basic reading skills. The Study also investigated broader cognitive factors associated with reading ability in individuals with WS. Thirty individuals with WS participated in this study (mean chronological age 21 years and mean mental age 7 years 7 months). The results supported our hypotheses that: firstly, reading abilities would be heterogeneous in WS; secondly, at least some WS individuals are capable of achieving a functional basic reading level; and thirdly, on average, WS individuals would find reading of nonwords more difficult than reading of regular and irregular words. Moreover, higher reading ability was found to be associated with increased outcomes in adaptive functioning, in particular, Written and Expressive Communication skills and Community Living skills, highlighting the potential benefits of developing reading abilities in WS. Although Intelligence Quotient (IQ) was related to overall basic reading ability generally, it was not found to be a determining factor in reading subtypes. Several cognitive skills known to be related to reading ability in typically developing individuals were found to be associated with reading performance and reading subtypes. Implications for appropriate reading instruction are discussed.

Oculo-auriculo-vertebral spectrum: clinical and molecular analysis of 51 patients.

INTRODUCTION: Oculo-auriculo-vertebral spectrum (OAVS OMIM 164210) is a craniofacial developmental disorder affecting the development of the structures derived from the 1st and the 2nd branchial arches during embryogenesis, with consequential maxillary, mandibular, and ear abnormalities. The phenotype in OAVS is variable and associated clinical features can involve the cardiac, renal, skeletal, and central nervous systems. Its aetiology is still poorly understood. METHODS: We have evaluated the clinical phenotypes of 51 previously unpublished patients with OAVS and their parents, and performed comparative genomic hybridization microarray studies to identify potential causative loci. RESULTS: Of all 51 patients, 16 (31%) had a family history of OAVS. Most had no relevant pre-natal history and only 5 (10%) cases had a history of environmental exposures that have previously been described as risk factors for OAVS. In 28 (55%) cases, the malformations were unilateral. When the involvement was bilateral, it was asymmetric. Ear abnormalities were present in 47 (92%) patients (unilateral in 24; and bilateral in 23). Hearing loss was common (85%), mostly conductive, but also sensorineural, or a combination of both. Hemifacial microsomia was present in 46 (90%) patients (17 also presented facial nerve palsy). Ocular anomalies were present in 15 (29%) patients. Vertebral anomalies were confirmed in 10 (20%) cases; 50% of those had additional heart, brain and/or other organ abnormalities. Brain abnormalities were present in 5 (10%) patients; developmental delay was more common among these patients. Limb abnormalities were found in 6 (12%) patients, and urogenital anomalies in 5 (10%). Array-CGH analysis identified 22q11 dosage anomalies in 10 out of 22 index cases screened. DISCUSSION: In this study we carried out in-depth phenotyping of OAVS in a large, multicentre cohort. Clinical characteristics are in line with those reported previously, however, we observed a higher incidence of hemifacial microsomia and lower incidence of ocular anomalies. Furthermore our data suggests that OAVS patients with vertebral anomalies or congenital heart defects have a higher frequency of additional brain, limb or other malformations. We had a higher rate of familial cases in our cohort in comparison with previous reports, possibly because these cases were referred preferentially to our genetic clinic where family members underwent examination. We propose that familial OAVS cases show phenotypic variability, hence, affected relatives might have been misclassified in previous reports. Moreover, in view of its phenotypic variability, OAVS is potentially a spectrum of conditions, which overlap with other conditions, such as mandibulofacial dysostosis. Array CGH in our cohort identified recurrent dosage anomalies on 22q11, which may contribute to, or increase the risk of OAVS. We hypothesize that although the 22q11 locus may harbour gene(s) or regulatory elements that play a role in the regulation of craniofacial symmetry and 1st and 2nd branchial arch development, OAVS is a heterogeneous condition and many cases have a multifactorial aetiology or are caused by mutations in as yet unidentified gene(s).

Oculo-auriculo-vertebral spectrum: a review of the literature and genetic update.

Oculo-auriculo-vertebral spectrum (OAVS, OMIM 164 210) is a developmental disorder primarily involving structures derived from the first and second pharyngeal arches during embryogenesis. The phenotype is clinically heterogeneous and is typically characterised by abnormal development of the ear, mandible anomalies and defects of the vertebral column. OAVS may occur as a multiple congenital abnormality, and associated findings include anomalies of the eye, brain, heart, kidneys and other organs and systems. Both genetic and environmental factors are thought to contribute to this craniofacial condition, however, the mechanisms are still poorly understood. Here, we present a review of the literature on OAVS, discussing what is known about the aetiology, candidate loci, possible mechanisms and the range of clinical features that characterise this condition. We also comment on some important aspects of recurrence risk counselling to aid clinical management.

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.

Opposite effects on facial morphology due to gene dosage sensitivity.

Sequencing technology is increasingly demonstrating the impact of genomic copy number variation (CNV) on phenotypes. Opposing variation in growth, head size, cognition and behaviour is known to result from deletions and reciprocal duplications of some genomic regions. We propose normative inversion of face shape, opposing difference from a matched norm, as a basis for investigating the effects of gene dosage on craniofacial development. We use dense surface modelling techniques to match any face (or part of a face) to a facial norm of unaffected individuals of matched age, sex and ethnicity and then we reverse the individual's face shape differences from the matched norm to produce the normative inversion. We demonstrate for five genomic regions, 4p16.3, 7q11.23, 11p15, 16p13.3 and 17p11.2, that such inversion for individuals with a duplication or (epi)-mutation produces facial forms remarkably similar to those associated with a deletion or opposite (epi-)mutation of the same region, and vice versa. The ability to visualise and quantify face shape effects of gene dosage is of major benefit for determining whether a CNV is the cause of the phenotype of an individual and for predicting reciprocal consequences. It enables face shape to be used as a relatively simple and inexpensive functional analysis of the gene(s) involved.

Rapamycin inhibits smooth muscle cell proliferation and obstructive arteriopathy attributable to elastin deficiency.

OBJECTIVE: Patients with elastin deficiency attributable to gene mutation (supravalvular aortic stenosis) or chromosomal microdeletion (Williams syndrome) are characterized by obstructive arteriopathy resulting from excessive smooth muscle cell (SMC) proliferation, mural expansion, and inadequate vessel size. We investigated whether rapamycin, an inhibitor of the cell growth regulator mammalian target of rapamycin (mTOR) and effective against other SMC proliferative disorders, is of therapeutic benefit in experimental models of elastin deficiency. APPROACH AND RESULTS: As previously reported, Eln(-/-) mice demonstrated SMC hyperplasia and severe stenosis of the aorta, whereas Eln(+/-) mice exhibited a smaller diameter aorta with more numerous but thinner elastic lamellae. Increased mTOR signaling was detected in elastin-deficient aortas of newborn pups that was inhibited by maternal administration of rapamycin. mTOR inhibition reduced SMC proliferation and aortic obstruction in Eln(-/-) pups and prevented medial hyperlamellation in Eln(+/-) weanlings without compromising aortic size. However, rapamycin did not prolong the survival of Eln(-/-) pups, and it retarded the somatic growth of juvenile Eln(+/-) and Eln(+/+) mice. In cell cultures, rapamycin inhibited prolonged mTOR activation and enhanced proliferation of SMC derived from patients with supravalvular aortic stenosis and with Williams syndrome. CONCLUSIONS: mTOR inhibition may represent a pharmacological strategy to treat diffuse arteriopathy resulting from elastin deficiency.

A role for transcription factor GTF2IRD2 in executive function in Williams-Beuren syndrome.

Executive functions are amongst the most heritable cognitive traits with twin studies indicating a strong genetic origin. However genes associated with this domain are unknown. Our research into the neurodevelopmental disorder Williams-Beuren syndrome (WBS) has identified a gene within the causative recurrent 1.5/1.6 Mb heterozygous microdeletion on chromosome 7q11.23, which may be involved in executive functioning. Comparative genome array screening of 55 WBS patients revealed a larger ∼1.8 Mb microdeletion in 18% of cases, which results in the loss of an additional gene, the transcription factor GTF2IRD2. The GTF gene family of transcription factors (GTF2I, GTF2IRD1 and GTF2IRD2) are all highly expressed in the brain, and GTF2I and GTF2IRD1 are involved in the pathogenesis of the cognitive and behavioural phenotypes associated with WBS. A multi-level analysis of cognitive, behavioural and psychological functioning in WBS patients showed that those with slightly larger deletions encompassing GTF2IRD2 were significantly more cognitively impaired in the areas of spatial functioning, social reasoning, and cognitive flexibility (a form of executive functioning). They also displayed significantly more obsessions and externalizing behaviours, a likely manifestation of poor cognitive flexibility and executive dysfunction. We provide the first evidence for a role for GTF2IRD2 in higher-level (executive functioning) abilities and highlight the importance of integrating detailed molecular characterisation of patients with comprehensive neuropsychological profiling to uncover additional genotype-phenotype correlations. The identification of specific genes which contribute to executive function has important neuropsychological implications in the treatment of patients with conditions like WBS, and will allow further studies into their mechanism of action.

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.

Anxious, hypoactive phenotype combined with motor deficits in Gtf2ird1 null mouse model relevant to Williams syndrome.

Williams-Beuren syndrome (WBS) is a rare genetic disorder caused by a hemizygous deletion of around 28 genes on the long arm of chromosome 7 (7q11.23), characterized by a unique spectrum of behavioral impairments, including mental retardation, deficits in visuospatial constructive cognition, hypersociability, anxiety and simple phobias. Physical characteristics include dysmorphic faces, short stature, oculomotor deficits, gross and fine coordination impairments, diminished control of balance and mild extrapyramidal signs as well as gait abnormalities resembling gait hypokinesia. Genes near the distal deletion breakpoint appear to contribute most to the WBS cognitive and behavioral profile and include the GTF family of transcription factors: GTF2I, GTF2IRD1, GTF2IRD2. We have previously shown that heterozygous deletions of GTF2IRD1 in humans and homozygous deletion in mice contributes to craniofacial abnormalities. Here we show an important role of this gene in motor coordination and anxiety ascertained from extensive behavioral mouse phenotyping. Gtf2ird1 null mice showed lower body weight, decreased spontaneous and circadian locomotor activity, diminished motor coordination and strength, gait abnormalities, increased anxiety and an elevated endocrinological response to stress. Gtf2ird1 heterozygous mice displayed lower body weight and decreased circadian activity, but only minor motor coordination and anxiety-related behavioral dysfunctions. Our study strongly supports a role for GTF2IRD1 in the motoric and anxiety-related abnormalities seen in Williams-Beuren syndrome, and suggests basal ganglia and potentially cerebellar abnormalities in Gtf2ird1 mice.

DNA copy number variations at chromosome 7p14.1 and chromosome 14q11.2 are associated with dupuytren's disease: potential role for MMP and Wnt signaling pathway.

BACKGROUND: Dupuytren's disease is a common fibroproliferative disorder with an unknown etiology. Emerging evidence suggests a strong genetic component involved in the manifestation of the disease. This study aims to investigate the potential involvement of copy number variations in Dupuytren's disease pathogenesis. METHODS: Array-based comparative genomic hybridization (NimbleGen Human CGH 2.1 M) was utilized to compare DNA from (1) nodules versus internal control (patient's blood; n = 4) and (2) nodules (n = 4) versus external control (commercial reference DNA pooled from 10 donors). Analysis was carried out using Nexus 5.1 (BioDiscovery, El Segundo, Calif.) with the inclusion of additional results from previously published array-based comparative genomic hybridization. Copy number variations were considered to be common in Dupuytren's disease if the overlap was statistically significant and they were present in the majority (75 to 87.5 percent when compared with controls) of Dupuytren's disease nodules. The copy number variations loci were also compared with recently published genome wide-association studies. Common copy number variations were further validated using quantitative polymerase chain reaction. DNA from 25 Dupuytren's disease cases and 30 external controls were used in the quantitative polymerase chain reaction validation. In addition, gene expression was compared between Dupuytren's disease nodules and internal controls (transverse palmar fascia; n = 7). RESULTS: Five common copy number variations, on chromosome 17q12, 1p31.1, 20p13, 7p14.1, and 14q11.2, were identified by array-based comparative genomic hybridization. Significantly higher copy numbers of copy number variations at chromosome 7p14.1 and 14q11.2 in Dupuytren's disease were confirmed in quantitative polymerase chain reaction validation. Matrix metalloproteinase-14 and secreted frizzled-related protein 4 (near a polymorphism recently associated with Dupuytren's disease) were significantly up-regulated in nodules. CONCLUSION: This study demonstrated an association between Dupuytren's disease and copy number variations at chromosomes 7p14.1 and 14q11.2.

Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome.

Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS or Ohdo syndrome) is a multiple anomaly syndrome characterized by severe intellectual disability, blepharophimosis, and a mask-like facial appearance. A number of individuals with SBBYSS also have thyroid abnormalities and cleft palate. The condition usually occurs sporadically and is therefore presumed to be due in most cases to new dominant mutations. In individuals with SBBYSS, a whole-exome sequencing approach was used to demonstrate de novo protein-truncating mutations in the highly conserved histone acetyltransferase gene KAT6B (MYST4/MORF)) in three out of four individuals sequenced. Sanger sequencing was used to confirm truncating mutations of KAT6B, clustering in the final exon of the gene in all four individuals and in a further nine persons with typical SBBYSS. Where parental samples were available, the mutations were shown to have occurred de novo. During mammalian development KAT6B is upregulated specifically in the developing central nervous system, facial structures, and limb buds. The phenotypic features seen in the Qkf mouse, a hypomorphic Kat6b mutant, include small eyes, ventrally placed ears and long first digits that mirror the human phenotype. This is a further example of how perturbation of a protein involved in chromatin modification might give rise to a multisystem developmental disorder.

Claudin 13, a member of the claudin family regulated in mouse stress induced erythropoiesis.

Mammals are able to rapidly produce red blood cells in response to stress. The molecular pathways used in this process are important in understanding responses to anaemia in multiple biological settings. Here we characterise the novel gene Claudin 13 (Cldn13), a member of the Claudin family of tight junction proteins using RNA expression, microarray and phylogenetic analysis. We present evidence that Cldn13 appears to be co-ordinately regulated as part of a stress induced erythropoiesis pathway and is a mouse-specific gene mainly expressed in tissues associated with haematopoietic function. CLDN13 phylogenetically groups with its genomic neighbour CLDN4, a conserved tight junction protein with a putative role in epithelial to mesenchymal transition, suggesting a recent duplication event. Mechanisms of mammalian stress erythropoiesis are of importance in anaemic responses and expression microarray analyses demonstrate that Cldn13 is the most abundant Claudin in spleen from mice infected with Trypanosoma congolense. In mice prone to anaemia (C57BL/6), its expression is reduced compared to strains which display a less severe anaemic response (A/J and BALB/c) and is differentially regulated in spleen during disease progression. Genes clustering with Cldn13 on microarrays are key regulators of erythropoiesis (Tal1, Trim10, E2f2), erythrocyte membrane proteins (Rhd and Gypa), associated with red cell volume (Tmcc2) and indirectly associated with erythropoietic pathways (Cdca8, Cdkn2d, Cenpk). Relationships between genes appearing co-ordinately regulated with Cldn13 post-infection suggest new insights into the molecular regulation and pathways involved in stress induced erythropoiesis and suggest a novel, previously unreported role for claudins in correct cell polarisation and protein partitioning prior to erythroblast enucleation.

Genome-wide high-resolution screening in Dupuytren's disease reveals common regions of DNA copy number alterations.

PURPOSE: Dupuytren's disease (DD) is a familial disorder with a high genetic susceptibility in white people; however, its etiopathogenesis remains unknown. Previous comparative genomic hybridization studies using lower-resolution, 44-k oligonucleotide-based arrays revealed no copy number variation (CNV) changes in DD. In this study, we used a higher-resolution genome-wide screening (next-generation microarrays) comprising 963,331 human sequences (3 kb spacing between probes) for whole genome DNA variation analysis. The objective was to detect cryptic chromosomal imbalances in DD. METHODS: Agilent SurePrint G3 microarrays, one million format (Agilent Technologies, Santa Clara, CA), were used to detect CNV regions (CNVRs) in DNA extracted from nodules of 4 white men with DD (age, 69 +/- 4 y). Reference samples were from the DNA of 10 men who served as control patients. Copy number variations that were common to greater than 3 assessed DD individuals (p < .05) were selected as candidate loci for DD etiology. In addition, quantitative polymerase chain reactions (qPCR) assays were designed for selected CNVRs on DNA from 13 DD patients and 11 control patients. Independent t-tests and Fisher's exact tests were carried out for statistical analysis. RESULTS: Three novel CNVs previously unreported in the phenotypically normal population were detected in 3 DD cases, located at 10q22, 16p12.1, and 17p12. Nine polymorphic CNVRs potentially associated with DD were determined using our strategic selection criteria, locating to chromosomes 1q31, 6p21, 7p14, 8p11, 12p13, 14q11, 17q21 and 20p13. More than 3 of the DD cases tested had a CNVR located to a small region on 6p21 and 4 CNVRs within 6p21-22 of the human leukocyte antigen (HLA) genes. CONCLUSIONS: Three novel copy number alterations were observed in 3 unrelated patients with sporadic (no known family history) DD. Nine polymorphic CNVRs were found to be common among the DD cases. These variants might contain genes involved in DD formation, indicating that important gene networks expressed within the palmar fascia might contribute to genetic susceptibility of DD.

Inefficient search of large-scale space in Williams syndrome: further insights on the role of LIMK1 deletion in deficits of spatial cognition.

Williams syndrome (WS) is a genetic disorder associated with impairments of spatial cognition. This has primarily been studied in small-scale space, and rarely in large-scale environments. In order to fully characterise the spatial deficits in WS, and also to address claims that the deletion of LIM-kinase 1 (LIMK1) on chromosome 7 is responsible for those deficits, we report an automated large-scale search task for humans that places the participant egocentrically within the search space. Search locations were defined as lights and switches embedded in the floor, and participants attempted to locate a hidden target by pressing the switch at potential locations. We compared individuals with WS to patients with smaller deletions (including LIMK1) in the critical region on chromosome 7. Whilst partial-deletion participants performed efficiently on the task, participants with WS demonstrated inefficient search profiles: their search slopes were steeper and they made significantly more erroneous revisits to previously inspected locations. Our findings indicate that spatial deficits associated with WS also affect large-scale spatial processing and suggest that hemizygous deletion of LIMK1 is not sufficient to account for any of the spatial deficits associated with WS.

Gerodermia osteodysplastica is caused by mutations in SCYL1BP1, a Rab-6 interacting golgin.

Gerodermia osteodysplastica is an autosomal recessive disorder characterized by wrinkly skin and osteoporosis. Here we demonstrate that gerodermia osteodysplastica is caused by loss-of-function mutations in SCYL1BP1, which is highly expressed in skin and osteoblasts. The protein localizes to the Golgi apparatus and interacts with Rab6, identifying SCYL1BP1 as a golgin. These results associate abnormalities of the secretory pathway with age-related changes in connective tissues.

Geroderma osteodysplastica maps to a 4 Mb locus on chromosome 1q24.

Important insights into the etiology of osteoporosis have been gained by the study of single gene disorders, including osteogenesis imperfecta. We report on the genetic mapping of geroderma osteodysplastica (GO), a rare autosomal recessive disorder of the connective tissue, characterized by wrinkly skin and severe osteoporosis. We undertook autozygosity mapping in one Libyan and four consanguineous Pakistani families with a total of 10 affected individuals to define a 4 Mb homozygous region on chromosome 1q24, which harbors the GO causative gene. No obvious candidate genes that encode known protein constituents of the extracellular matrix are found in the linked region. Importantly, our study demonstrates that GO is not allelic to wrinkly skin syndrome caused by mutations in ATP6V0A2.