Han G Brunner

..Our study supports a role for rare CNVs in schizophrenia susceptibility and identifies at least three candidate genes for this complex disorder...

..9 Mb (98 genes) in common with the 5.4 Mb MRT11 locus (195 genes). These data support that homozygosity mapping in outbred families may contribute to identification of novel AR-MR genes...

..Here we examine whether co-expression across multiple species is also a better prioritizer of disease genes than is co-expression between human genes alone...

..NMYC and SOX2 are transcription factors, whereas CHD7 is encoded by a chromodomain helicase DNA-binding gene, important for chromatin structure and gene expression. These new genes broaden our view of human foregut development...

..WDR35 is homologous to TULP4 (from the Tubby superfamily) and has previously been characterized as an intraflagellar transport component, confirming that Sensenbrenner syndrome is a ciliary disorder...

..The distribution of mutations over the various p63 protein domains and the structural and functional implications of these mutations establish a clear genotype-phenotype correlation...

..This finding demonstrates that LARGE gene mutations can give rise to a wide clinical spectrum, similar as for other genes that have a role in the post-translational modification of the alpha-dystroglycan protein...

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..3 Mb located within 18q22.3-q23. Molecular characterization of more patients will ultimately lead to a further delineation of the critical regions and thus to the identification of candidate genes for these specific traits...

..Our data suggest the existence of a disease spectrum of CMD including brain and eye abnormalities resulting from POMT1 mutations...

..The identification of novel human and mouse mutations for ectrodactyly will enhance our understanding of AER functions and the pathogenesis of ectrodactyly...

..These two families showed parent-to-child transmission. Phenotypically milder forms of CHARGE syndrome have a higher risk of transmission to multiple family members...

..We suggest that the presence of brachymesophalangy and toe syndactyly in combination with microcephaly is enough to justify MYCN analysis...

..Trp241X) and c.946_947delinsA (p.Pro316ThrfsX16), and both mutations predicted a loss of function. Together, these results demonstrate that hemizygosity of TSHZ1 leads to congenital aural atresia as a result of haploinsufficiency...

..Consistent with this syndrome-specific mutational pattern, the functional consequences of mutations on the p63 proteins also vary, invoking dominant-negative and gain-of-function mechanisms rather than a simple loss of function...

..These results indicate that this classification method will be of value for objectively prioritizing CNVs in clinical research and diagnostics...

..We expect that, ultimately, genomic copy number scanning of all 250,000 exons in the human genome will enable immediate disease gene discovery in cases exhibiting single exon duplications and/or deletions...

..Together with de novo copy number variation, de novo point mutations of large effect could explain the majority of all mental retardation cases in the population...

..These results implicate ISPD in a-dystroglycan glycosylation in maintaining sarcolemma integrity in vertebrates...

..The causes of intellectual disability remain largely unknown because of extensive clinical and genetic heterogeneity...

..These results expand the spectrum of clinical phenotypes known to be due to mutations in the XNP gene, and indicate that XNP mutation analysis should not be restricted to patients with severe MR and characteristic facial features...

..Additional research is needed to further establish the role of genes from the 5q35.1 region in brain and limb development and to determine the prevalence of copy number gain in the 5q35.1 region among HPE patients...

..2% (71.9% losses, 19.6% gains, 8.5% complex) could be identified, reflecting the overall diagnostic yield of clinically significant CNVs in individuals with unexplained mental retardation...

..In total, 7 out of 13 subjects with a Bohring-Opitz phenotype had de novo ASXL1 mutations, suggesting that the syndrome is genetically heterogeneous...

..Sequence analysis of genes located in this region detected mutations in the gene CHD7 in 10 of 17 individuals with CHARGE syndrome without microdeletions, accounting for the disease in most affected individuals...

..The deletions encompass the MAPT and CRHR1 genes and are associated with a common inversion polymorphism...

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..Met1?) should not be considered as a regular pathogenic mutation that leads to a strongly increased cancer risk, though it possibly contributes to a more severe phenotype when combined with a truncating mutation on the other allele...

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..These data suggest that rare pathogenic microdeletions and tandem duplications do not occur at random genome sequences, but are stimulated and potentially catalyzed by various genomic architectural features...

..We also identified SETBP1 mutations in eight additional cases using Sanger sequencing. All mutations clustered to a highly conserved 11-bp exonic region, suggesting a dominant-negative or gain-of-function effect...

..All mutations are predicted to disrupt both the full-length protein and a new shortened MYCN isoform, suggesting that multiple aspects of early embryogenesis and postnatal brain growth in humans are tightly regulated by MYCN dosage...

..We propose a highly conserved epigenetic network that underlies cognition in health and disease. This network should allow the design of strategies to treat the growing group of ID pathologies that are caused by epigenetic defects...

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..The study provides presumptive evidence that educational-support group participants decide to undergo prophylactic mastectomy earlier than non-attendees...

..This is illustrated by the different phenotypes that are seen for the five-hotspot mutations that explain almost 90% of all EEC syndrome patients...

..RNA sequencing studies in cell lines derived from affected individuals and the presence of learning deficits in Drosophila melanogaster mutants suggest a role for KANSL1 in neuronal processes...

..Furthermore, it interacts with the LIS1 gene of which haploinsufficiency causes a severe neuronal migration disorder in humans, known as classical lissencephaly or Miller-Dieker syndrome...

..These findings identify the genetic basis of Cantú syndrome and suggest that this is a new member of the potassium channelopathies...

..Exome sequencing is revolutionizing Mendelian disease gene identification. This results in improved clinical diagnosis, more accurate genotype-phenotype correlations and new insights into the role of rare genomic variation in disease...

..These data provide a proof-of-concept that the catalogue of p63 binding sites identified in this study may be of relevance to the studies of SHFM and other congenital malformations that resemble the p63-associated phenotypes...

..Mutation screening of the LHFPL5 homologs LHFPL3 and LHFPL4 did not reveal any disease causing mutation. Our findings indicate that LHFPL5 is essential for normal function of the human cochlea...

..Our results indicate that the diagnostic yield of this approach in the general population of patients with MR is at least twice as high as that of standard GTG-banded karyotyping...

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..These mutations, although individually rare, may capture a significant part of the heritability for complex genetic diseases that is not detectable by genome-wide association studies...

..Exome sequencing is likely to become the most commonly used tool for Mendelian disease gene identification for the coming years...

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..1 microdeletion present with a variable phenotype and the diagnosis should be considered in mentally retarded children with coarse facies, seizures, disturbed sleeping patterns and additional specific behavioural problems...

..CEP290 mutations therefore represent one of the most frequent causes of LCA identified so far...

..4004-2A-->G) was recently reported that resulted in a 39-nucleotide exon 8 in-frame deletion. We investigated whether CSPG2/Versican was mutated in six Dutch families and one Chinese family with Wagner disease and in a family with ERVR...

..Depending on the expression pattern of the neighboring gene that lacks its normal polyadenylation signal, this may cause either generalized or mosaic patterns of epigenetic inactivation...

..Sensenbrenner syndrome is a heterogeneous ciliopathy that is characterised by skeletal and ectodermal anomalies, accompanied by chronic renal failure, heart defects, liver fibrosis and other features...

..From this we conclude that IL-4R and CD11B in the IBD1 region and STAT6 in the IBD2 region are not involved in Crohn's disease in this Dutch cohort...

..These results establish that haploinsufficiency of EHMT1 is causative for 9q subtelomeric deletion syndrome...

..To elucidate the mechanisms by which such effects on psychiatric disease are brought about by genetic factors, we investigated the influence of CACNA1C polymorphisms on brain structure...

..We found presumptive evidence that specific subgroups of patients with CRC are more vulnerable for genetic-testing-related distress...

..Finally, in an affected male who did not have a mutation in any of the CHM exons or their splice sites, the deletion of a complete exon from the CHM mRNA was observed...

..The implication of O-mannosylation in MEB and WWS suggests new lines of study in understanding the molecular basis of neuronal migration...

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..This work identifies RPGRIP1L as a gene responsible for JBTS and establishes a central role for cilia and basal bodies in the pathophysiology of this disorder...

..Reciprocal deletions lead to speech and language delay, mild facial dysmorphisms and, in some individuals, to cerebellar, breast developmental and cardiac defects...

..We are currently expanding the tool by adding other databases. The GeneSeeker is available via the web-interface (http://www.cmbi.kun.nl/GeneSeeker/)...

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..This high-resolution assay will facilitate the identification of novel genes involved in human mental retardation and/or malformation syndromes and will provide insight into the flexibility and plasticity of the human genome...

..Our results further show that p63 contains a second transactivation domain which is normally repressed and can become activated by mutations in the DNA binding domain of p63...

..However, tumors with low-level MSI show unfavorable pathological characteristics compared to tumors with no and tumors with high-level MSI. These differences suggest a distinct underlying biology of CRC with low-level MSI...

..These results are consistent with an autosomal recessive condition that is similar to, but likely distinct from, Coffin-Siris syndrome...

..The true frequency of MECP2 mutations in the mentally retarded has probably been overestimated. Based on our data, the frequency of MECP2 mutations in mentally retarded males is 0.2% (1/475)...

..These results indicate a single origin of the 2588G>C mutation which, to our best estimate, occurred between 2400 and 3000 years ago...

..The robustness and simplicity of this array-based telomere copy-number screening make it highly suited for introduction into the clinic as a rapid and sensitive automated diagnostic procedure...

..Taken together, these results lead to the exclusion of the PLEXIN-D1 gene as the causative gene in Möbius syndrome 2, and in isolated Möbius syndrome...

..Our results define microdeletion of 15q24 as a novel recurrent genomic disorder...

..Together, our data indicate that also nonsense mutations in DFNB59 cause nonsyndromic hearing loss, but that mutations in DFNB59 are not a major cause of nonsyndromic hearing impairment in the Turkish and Dutch population...

..Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified...

..A PTPN11 mutation was identified in a family inheriting Noonan-like/multiple giant-cell lesion syndrome, extending the phenotypic range of disease associated with this gene...

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..These findings extend the role of acetylcholine receptor dysfunction in human disease and provide new insights into the pathogenesis and management of fetal akinesia syndromes...

..We therefore conclude that it is highly unlikely that Plexin-A1 is involved in the pathogenicity of hereditary congenital facial paresis...

..Such predictions will further improve if a unified system of phenotype descriptors is developed. The phenotype similarity data are accessible through a web interface at http://www.cmbi.ru.nl/MimMiner/...

..These findings increase the spectrum of anomalies associated with abnormal FGF signaling...

..The genes PODXL2, PLEXIN-D1, GATA-2, and TMCC1 are also located within the smaller critical interval of the Pakistani HCFP family. Based on the results obtained, all seven genes could be excluded as causative genes in HCFP...

..In addition, we have documented a gain-of-function effect on the dNp63gamma isoform caused by this mutation. We discuss the possible relevance of oral squamous cell carcinoma in one patient, who carries this p63 germline mutation...

..However, the variability in phenotype severity did account for striking differences in endogenous GH secretion...

..These findings further demonstrate the genetic heterogeneity associated with HPE, as well as showing that mutations in different components of a single signaling pathway can result in the same clinical condition...

..Atrial fibrillation, previously reported in three individuals with CSX/NKX2-5 mutations, was observed in three patients...

..Two genes, LPL and BCKDHA, are common to these two sets. We also present a set of secondary candidates for T2D (94 genes) and for obesity (116 genes) with 58 genes in common to both diseases...

..These results highlight the importance of considering possible origins of mutation in the counseling of families with CFNS and provide a generally applicable approach to the combined analysis of mosaic and germline mutations...

..Absence of PCNT results in disorganized mitotic spindles and missegregation of chromosomes. Mutations in related genes are known to cause primary microcephaly (MCPH1, CDK5RAP2, ASPM, and CENPJ)...

..Our data indicate that ESRRB is essential for inner-ear development and function. To our knowledge, this is the first report of pathogenic mutations of an estrogen-related receptor gene...

..Their results imply that the human phenome can be viewed as a landscape of interrelated diseases, reflecting overlapping molecular causation...

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..Such in silico prioritisation methods may further improve by completion of datasets, by development of standardised ontologies across databases and species and, ultimately, by the integration of different strategies...