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ABSTRACT: Spondyloepimetaphyseal dysplasia (SEMD), Pakistani type, is a skeletal dysplasia characterized by platyspondyly, delayed epiphyseal ossification, mild metaphyseal abnormalities, short stature, and short and bowed legs, and is caused by mutations in PAPSS2. In a single Turkish patient also hyperandrogenism was reported. We describe five patients from a Turkish family with SEMD Pakistani type with homozygosity for a nonsense mutation (p.R329X) leading to a stop codon in PAPSS2. Plasma levels of dehydroepiandrosterone (DHEA) and androstenedione were normal, but DHEA sulfate levels were low in four of the patients. Two patients and a mother had history of pubertal hyperandrogenism. Testosterone level was mildly elevated in one of the female patients, and insulin resistance was not detected in any of the patients. The patients also had precocious costal calcification, small iliac bones, short femoral necks, coxa vara, short halluces and fused vertebral bodies, none of which has been reported previously in this entity. (c) 2013 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A 04/2013; · 2.39 Impact Factor
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Stephan J Sanders,
Michael T Murtha,
Abha R Gupta,
John D Murdoch,
Melanie J Raubeson,
A Jeremy Willsey,
A Gulhan Ercan-Sencicek,
Nicholas M DiLullo,
Neelroop N Parikshak,
Jason L Stein, [......],
Kyle A Meyer,
Kaya Bilguvar,
Shrikant M Mane,
Nenad Sestan,
Richard P Lifton, Murat Günel,
Kathryn Roeder,
Daniel H Geschwind,
Bernie Devlin,
Matthew W State
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ABSTRACT: Multiple studies have confirmed the contribution of rare de novo copy number variations to the risk for autism spectrum disorders. But whereas de novo single nucleotide variants have been identified in affected individuals, their contribution to risk has yet to be clarified. Specifically, the frequency and distribution of these mutations have not been well characterized in matched unaffected controls, and such data are vital to the interpretation of de novo coding mutations observed in probands. Here we show, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, we demonstrate that multiple independent de novo single nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, α subunit), a result that is highly unlikely by chance.
Nature 04/2012; 485(7397):237-41. · 36.28 Impact Factor
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Emília Ilona Gaál,
Perttu Salo,
Kati Kristiansson,
Karola Rehnström,
Johannes Kettunen,
Antti-Pekka Sarin,
Mika Niemelä,
Antti Jula,
Olli T Raitakari,
Terho Lehtimäki, [......],
Mitja Kurki,
Mikael von und Zu Fraunberg,
Juha E Jääskeläinen,
Juha Hernesniemi,
Marjo-Riitta Järvelin,
Anneli Pouta,
Christopher Newton-Cheh,
Veikko Salomaa,
Aarno Palotie,
Markus Perola
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ABSTRACT: Although genome-wide association studies (GWAS) have identified hundreds of complex trait loci, the pathomechanisms of most remain elusive. Studying the genetics of risk factors predisposing to disease is an attractive approach to identify targets for functional studies. Intracranial aneurysms (IA) are rupture-prone pouches at cerebral artery branching sites. IA is a complex disease for which GWAS have identified five loci with strong association and a further 14 loci with suggestive association. To decipher potential underlying disease mechanisms, we tested whether there are IA loci that convey their effect through elevating blood pressure (BP), a strong risk factor of IA. We performed a meta-analysis of four population-based Finnish cohorts (n(FIN) = 11 266) not selected for IA, to assess the association of previously identified IA candidate loci (n = 19) with BP. We defined systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure as quantitative outcome variables. The most significant result was further tested for association in the ICBP-GWAS cohort of 200 000 individuals. We found that the suggestive IA locus at 5q23.2 in PRDM6 was significantly associated with SBP in individuals of European descent (p(FIN) = 3.01E-05, p(ICBP-GWAS) = 0.0007, p(ALL) = 8.13E-07). The risk allele of IA was associated with higher SBP. PRDM6 encodes a protein predominantly expressed in vascular smooth muscle cells. Our study connects a complex disease (IA) locus with a common risk factor for the disease (SBP). We hypothesize that common variants in PRDM6 can contribute to altered vascular wall structure, hence increasing SBP and predisposing to IA. True positive associations often fail to reach genome-wide significance in GWAS. Our findings show that analysis of traditional risk factors as intermediate phenotypes is an effective tool for deciphering hidden heritability. Further, we demonstrate that common disease loci identified in a population isolate may bear wider significance.
PLoS Genetics 03/2012; 8(3):e1002563. · 8.69 Impact Factor
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Thomas V Fernandez,
Stephan J Sanders,
Ilana R Yurkiewicz,
A Gulhan Ercan-Sencicek,
Young-Shin Kim,
Daniel O Fishman,
Melanie J Raubeson,
Youeun Song,
Katsuhito Yasuno,
Winson S C Ho, [......],
Robert A King,
Donald L Gilbert,
Gary A Heiman,
Jay A Tischfield,
Pieter J Hoekstra,
Bernie Devlin,
Hakon Hakonarson,
Shrikant M Mane, Murat Günel,
Matthew W State
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ABSTRACT: Studies of copy number variation (CNV) have characterized loci and molecular pathways in a range of neuropsychiatric conditions. We analyzed rare CNVs in Tourette syndrome (TS) to identify novel risk regions and relevant pathways, to evaluate burden of structural variation in cases versus controls, and to assess overlap of identified variations with those in other neuropsychiatric syndromes.
We conducted a case-control study of 460 individuals with TS, including 148 parent-child trios and 1131 controls. CNV analysis was undertaken using 370 K to 1 M probe arrays, and genotyping data were used to match cases and controls for ancestry. CNVs present in < 1% of the population were evaluated.
While there was no significant increase in the number of de novo or transmitted rare CNVs in cases versus controls, pathway analysis using multiple algorithms showed enrichment of genes within histamine receptor (subtypes 1 and 2) signaling pathways (p = 5.8 × 10(-4) - 1.6 × 10(-2)), as well as axon guidance, cell adhesion, nervous system development, and synaptic structure and function processes. Genes mapping within rare CNVs in TS showed significant overlap with those previously identified in autism spectrum disorders but not intellectual disability or schizophrenia. Three large, likely pathogenic, de novo events were identified, including one disrupting multiple gamma-aminobutyric acid receptor genes.
We identify further evidence supporting recent findings regarding the involvement of histaminergic and gamma-aminobutyric acidergic mechanisms in the etiology of TS and show an overlap of rare CNVs in TS and autism spectrum disorders.
Biological psychiatry 12/2011; 71(5):392-402. · 8.93 Impact Factor
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Katsuhito Yasuno,
Mehmet Bakırcıoğlu,
Siew-Kee Low,
Kaya Bilgüvar,
Emília Gaál,
Ynte M Ruigrok,
Mika Niemelä,
Akira Hata,
Philippe Bijlenga,
Hidetoshi Kasuya, [......],
Helmuth Steinmetz,
Juha Hernesniemi,
Karl Schaller,
Hitoshi Zembutsu,
Ituro Inoue,
Aarno Palotie,
François Cambien,
Yusuke Nakamura,
Richard P Lifton, Murat Günel
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ABSTRACT: The pathogenesis of intracranial aneurysm (IA) formation and rupture is complex, with significant contribution from genetic factors. We previously reported genome-wide association studies based on European discovery and Japanese replication cohorts of 5,891 cases and 14,181 controls that identified five disease-related loci. These studies were based on testing replication of genomic regions that contained SNPs with posterior probability of association (PPA) greater than 0.5 in the discovery cohort. To identify additional IA risk loci, we pursued 14 loci with PPAs in the discovery cohort between 0.1 and 0.5. Twenty-five SNPs from these loci were genotyped using two independent Japanese cohorts, and the results from discovery and replication cohorts were combined by meta-analysis. The results demonstrated significant association of IA with rs6841581 on chromosome 4q31.23, immediately 5' of the endothelin receptor type A with P = 2.2 × 10(-8) [odds ratio (OR) = 1.22, PPA = 0.986]. We also observed substantially increased evidence of association for two other regions on chromosomes 12q22 (OR = 1.16, P = 1.1 × 10(-7), PPA = 0.934) and 20p12.1 (OR = 1.20, P = 6.9 × 10(-7), PPA = 0.728). Although endothelin signaling has been hypothesized to play a role in various cardiovascular disorders for over two decades, our results are unique in providing genetic evidence for a significant association with IA and suggest that manipulation of the endothelin pathway may have important implications for the prevention and treatment of IA.
Proceedings of the National Academy of Sciences 11/2011; 108(49):19707-12. · 9.68 Impact Factor
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Stephan J Sanders,
A Gulhan Ercan-Sencicek,
Vanessa Hus,
Rui Luo,
Michael T Murtha,
Daniel Moreno-De-Luca,
Su H Chu,
Michael P Moreau,
Abha R Gupta,
Susanne A Thomson, [......],
Eric Fombonne,
Catherine Lord,
Christa Lese Martin,
Andrew I Brooks,
James S Sutcliffe,
Edwin H Cook,
Daniel Geschwind,
Kathryn Roeder,
Bernie Devlin,
Matthew W State
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ABSTRACT: We have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6-12.0, p = 2.4 × 10(-7)). We estimate there are 130-234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1.
Neuron 06/2011; 70(5):863-85. · 14.74 Impact Factor
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Tanyeri Barak,
Kenneth Y Kwan,
Angeliki Louvi,
Veysi Demirbilek,
Serap Saygı,
Beyhan Tüysüz,
Murim Choi,
Hüseyin Boyacı,
Katja Doerschner,
Ying Zhu, [......],
Ergin Atalar,
Cengiz Yalçınkaya,
Alp Dinçer,
Richard A Bronen,
Shrikant Mane,
Tayfun Ozçelik,
Richard P Lifton,
Nenad Sestan,
Kaya Bilgüvar, Murat Günel
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ABSTRACT: The biological basis for regional and inter-species differences in cerebral cortical morphology is poorly understood. We focused on consanguineous Turkish families with a single affected member with complex bilateral occipital cortical gyration abnormalities. By using whole-exome sequencing, we initially identified a homozygous 2-bp deletion in LAMC3, the laminin γ3 gene, leading to an immediate premature termination codon. In two other affected individuals with nearly identical phenotypes, we identified a homozygous nonsense mutation and a compound heterozygous mutation. In human but not mouse fetal brain, LAMC3 is enriched in postmitotic cortical plate neurons, localizing primarily to the somatodendritic compartment. LAMC3 expression peaks between late gestation and late infancy, paralleling the expression of molecules that are important in dendritogenesis and synapse formation. The discovery of the molecular basis of this unusual occipital malformation furthers our understanding of the complex biology underlying the formation of cortical gyrations.
Nature Genetics 06/2011; 43(6):590-4. · 35.53 Impact Factor
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ABSTRACT: Communication between neural cells and the vasculature is integral to the proper development and later function of the central nervous system. A mechanistic understanding of the interactions between components of the neurovascular unit has implications for various disorders, including cerebral cavernous malformations (CCMs) in which focal vascular lesions form throughout the central nervous system. Loss of function mutations in three genes with proven endothelial cell autonomous roles, CCM1/krev1 interaction trapped gene 1, CCM2, and CCM3/programmed cell death 10, cause familial CCM. By using neural specific conditional mouse mutants, we show that Ccm3 has both neural cell autonomous and nonautonomous functions. Gfap- or Emx1-Cre-mediated Ccm3 neural deletion leads to increased proliferation, increased survival, and activation of astrocytes through cell autonomous mechanisms involving activated Akt signaling. In addition, loss of neural CCM3 results in a vascular phenotype characterized by diffusely dilated and simplified cerebral vasculature along with formation of multiple vascular lesions that closely resemble human cavernomas through cell nonautonomous mechanisms. RNA sequencing of the vascular lesions shows abundant expression of molecules involved in cytoskeletal remodeling, including protein kinase A and Rho-GTPase signaling. Our findings implicate neural cells in the pathogenesis of CCMs, showing the importance of this pathway in neural/vascular interactions within the neurovascular unit.
Proceedings of the National Academy of Sciences 02/2011; 108(9):3737-42. · 9.68 Impact Factor
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Kaya Bilgüvar,
Ali Kemal Oztürk,
Angeliki Louvi,
Kenneth Y Kwan,
Murim Choi,
Burak Tatli,
Dilek Yalnizoğlu,
Beyhan Tüysüz,
Ahmet Okay Cağlayan,
Sarenur Gökben, [......],
Shrikant Mane,
Mehmet Necmettin Pamir,
Cengiz Yalçinkaya,
Sefer Kumandaş,
Meral Topçu,
Meral Ozmen,
Nenad Sestan,
Richard P Lifton,
Matthew W State, Murat Günel
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ABSTRACT: The development of the human cerebral cortex is an orchestrated process involving the generation of neural progenitors in the periventricular germinal zones, cell proliferation characterized by symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in six highly ordered, functionally specialized layers. An understanding of the molecular mechanisms guiding these intricate processes is in its infancy, substantially driven by the discovery of rare mutations that cause malformations of cortical development. Mapping of disease loci in putative Mendelian forms of malformations of cortical development has been hindered by marked locus heterogeneity, small kindred sizes and diagnostic classifications that may not reflect molecular pathogenesis. Here we demonstrate the use of whole-exome sequencing to overcome these obstacles by identifying recessive mutations in WD repeat domain 62 (WDR62) as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients with mutations in WDR62 had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities. In mice and humans, WDR62 transcripts and protein are enriched in neural progenitors within the ventricular and subventricular zones. Expression of WDR62 in the neocortex is transient, spanning the period of embryonic neurogenesis. Unlike other known microcephaly genes, WDR62 does not apparently associate with centrosomes and is predominantly nuclear in localization. These findings unify previously disparate aspects of cerebral cortical development and highlight the use of whole-exome sequencing to identify disease loci in settings in which traditional methods have proved challenging.
Nature 09/2010; 467(7312):207-10. · 36.28 Impact Factor
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Katsuhito Yasuno,
Kaya Bilguvar,
Philippe Bijlenga,
Siew Kee Low,
Boris Krischek,
Georg Auburger,
Matthias Simon,
Dietmar Krex,
Zulfikar Arlier,
Nikhil Nayak, [......],
Juha E Jääskeläinen,
Juha Hernesniemi,
Gabriel J E Rinkel,
Hitoshi Zembutsu,
Ituro Inoue,
Aarno Palotie,
François Cambien,
Yusuke Nakamura,
Richard P Lifton, Murat Günel
Nature Genetics 05/2010; · 35.53 Impact Factor
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Katsuhito Yasuno,
Kaya Bilguvar,
Philippe Bijlenga,
Siew-Kee Low,
Boris Krischek,
Georg Auburger,
Matthias Simon,
Dietmar Krex,
Zulfikar Arlier,
Nikhil Nayak, [......],
Juha E Jääskeläinen,
Juha Hernesniemi,
Gabriel J E Rinkel,
Hitoshi Zembutsu,
Ituro Inoue,
Aarno Palotie,
François Cambien,
Yusuke Nakamura,
Richard P Lifton, Murat Günel
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ABSTRACT: Saccular intracranial aneurysms are balloon-like dilations of the intracranial arterial wall; their hemorrhage commonly results in severe neurologic impairment and death. We report a second genome-wide association study with discovery and replication cohorts from Europe and Japan comprising 5,891 cases and 14,181 controls with approximately 832,000 genotyped and imputed SNPs across discovery cohorts. We identified three new loci showing strong evidence for association with intracranial aneurysms in the combined dataset, including intervals near RBBP8 on 18q11.2 (odds ratio (OR) = 1.22, P = 1.1 x 10(-12)), STARD13-KL on 13q13.1 (OR = 1.20, P = 2.5 x 10(-9)) and a gene-rich region on 10q24.32 (OR = 1.29, P = 1.2 x 10(-9)). We also confirmed prior associations near SOX17 (8q11.23-q12.1; OR = 1.28, P = 1.3 x 10(-12)) and CDKN2A-CDKN2B (9p21.3; OR = 1.31, P = 1.5 x 10(-22)). It is noteworthy that several putative risk genes play a role in cell-cycle progression, potentially affecting the proliferation and senescence of progenitor-cell populations that are responsible for vascular formation and repair.
Nature Genetics 04/2010; 42(5):420-5. · 35.53 Impact Factor
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Kaya Bilguvar,
Katsuhito Yasuno,
Mika Niemelä,
Ynte M Ruigrok,
Mikael von Und Zu Fraunberg,
Cornelia M van Duijn,
Leonard H van den Berg,
Shrikant Mane,
Christopher E Mason,
Murim Choi, [......],
Monique M B Breteler,
Cisca Wijmenga,
Matthew W State,
Gabriel J E Rinkel,
Juha Hernesniemi,
Juha E Jääskeläinen,
Aarno Palotie,
Ituro Inoue,
Richard P Lifton, Murat Günel
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ABSTRACT: Stroke is the world's third leading cause of death. One cause of stroke, intracranial aneurysm, affects approximately 2% of the population and accounts for 500,000 hemorrhagic strokes annually in mid-life (median age 50), most often resulting in death or severe neurological impairment. The pathogenesis of intracranial aneurysm is unknown, and because catastrophic hemorrhage is commonly the first sign of disease, early identification is essential. We carried out a multistage genome-wide association study (GWAS) of Finnish, Dutch and Japanese cohorts including over 2,100 intracranial aneurysm cases and 8,000 controls. Genome-wide genotyping of the European cohorts and replication studies in the Japanese cohort identified common SNPs on chromosomes 2q, 8q and 9p that show significant association with intracranial aneurysm with odds ratios 1.24-1.36. The loci on 2q and 8q are new, whereas the 9p locus was previously found to be associated with arterial diseases, including intracranial aneurysm. Associated SNPs on 8q likely act via SOX17, which is required for formation and maintenance of endothelial cells, suggesting a role in development and repair of the vasculature; CDKN2A at 9p may have a similar role. These findings have implications for the pathophysiology, diagnosis and therapy of intracranial aneurysm.
Nature Genetics 01/2009; 40(12):1472-7. · 35.53 Impact Factor
