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Josephina?A.N. Meester Laura Southgate Anna-Barbara Stittrich Hanka Venselaar Sander?J.A. Beekmans Nicolette den?Hollander Emilia?K. Bijlsma Appolonia Helderman-van?den?Enden Joke?B.G.M. Verheij Gustavo Glusman Jared?C. Roach Anna Lehman Millan?S. Patel Bert?B.A. de?Vries Claudia Ruivenkamp Peter Itin Katrina Prescott Sheila Clarke Richard Trembath Martin Zenker Maja Sukalo Lut Van?Laer Bart Loeys Wim Wuyts 《American journal of human genetics》2015,97(3):475-482
Adams-Oliver syndrome (AOS) is a rare developmental disorder characterized by the presence of aplasia cutis congenita (ACC) of the scalp vertex and terminal limb-reduction defects. Cardiovascular anomalies are also frequently observed. Mutations in five genes have been identified as a cause for AOS prior to this report. Mutations in EOGT and DOCK6 cause autosomal-recessive AOS, whereas mutations in ARHGAP31, RBPJ, and NOTCH1 lead to autosomal-dominant AOS. Because RBPJ, NOTCH1, and EOGT are involved in NOTCH signaling, we hypothesized that mutations in other genes involved in this pathway might also be implicated in AOS pathogenesis. Using a candidate-gene-based approach, we prioritized DLL4, a critical NOTCH ligand, due to its essential role in vascular development in the context of cardiovascular features in AOS-affected individuals. Targeted resequencing of the DLL4 gene with a custom enrichment panel in 89 independent families resulted in the identification of seven mutations. A defect in DLL4 was also detected in two families via whole-exome or genome sequencing. In total, nine heterozygous mutations in DLL4 were identified, including two nonsense and seven missense variants, the latter encompassing four mutations that replace or create cysteine residues, which are most likely critical for maintaining structural integrity of the protein. Affected individuals with DLL4 mutations present with variable clinical expression with no emerging genotype-phenotype correlations. Our findings demonstrate that DLL4 mutations are an additional cause of autosomal-dominant AOS or isolated ACC and provide further evidence for a key role of NOTCH signaling in the etiology of this disorder. 相似文献
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David?A. Dyment Amanda?C. Smith Diana Alcantara Jeremy?A. Schwartzentruber Lina Basel-Vanagaite Cynthia?J. Curry I.?Karen Temple William Reardon Sahar Mansour Mushfequr?R. Haq Rodney Gilbert Ordan?J. Lehmann Megan?R. Vanstone Chandree?L. Beaulieu FORGE Canada Consortium Jacek Majewski Dennis?E. Bulman Mark O’Driscoll Kym?M. Boycott A.?Micheil Innes 《American journal of human genetics》2013,93(1):158-166
SHORT syndrome is a rare, multisystem disease characterized by short stature, anterior-chamber eye anomalies, characteristic facial features, lipodystrophy, hernias, hyperextensibility, and delayed dentition. As part of the FORGE (Finding of Rare Disease Genes) Canada Consortium, we studied individuals with clinical features of SHORT syndrome to identify the genetic etiology of this rare disease. Whole-exome sequencing in a family trio of an affected child and unaffected parents identified a de novo frameshift insertion, c.1906_1907insC (p.Asn636Thrfs∗18), in exon 14 of PIK3R1. Heterozygous mutations in exon 14 of PIK3R1 were subsequently identified by Sanger sequencing in three additional affected individuals and two affected family members. One of these mutations, c.1945C>T (p.Arg649Trp), was confirmed to be a de novo mutation in one affected individual and was also identified and shown to segregate with the phenotype in an unrelated family. The other mutation, a de novo truncating mutation (c.1971T>G [p.Tyr657∗]), was identified in another affected individual. PIK3R1 is involved in the phosphatidylinositol 3 kinase (PI3K) signaling cascade and, as such, plays an important role in cell growth, proliferation, and survival. Functional studies on lymphoblastoid cells with the PIK3R1 c.1906_1907insC mutation showed decreased phosphorylation of the downstream S6 target of the PI3K-AKT-mTOR pathway. Our findings show that PIK3R1 mutations are the major cause of SHORT syndrome and suggest that the molecular mechanism of disease might involve downregulation of the PI3K-AKT-mTOR pathway. 相似文献
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《American journal of human genetics》2012,91(5):950-957
Shprintzen-Goldberg syndrome (SGS) is characterized by severe marfanoid habitus, intellectual disability, camptodactyly, typical facial dysmorphism, and craniosynostosis. Using family-based exome sequencing, we identified a dominantly inherited heterozygous in-frame deletion in exon 1 of SKI. Direct sequencing of SKI further identified one overlapping heterozygous in-frame deletion and ten heterozygous missense mutations affecting recurrent residues in 18 of the 19 individuals screened for SGS; these individuals included one family affected by somatic mosaicism. All mutations were located in a restricted area of exon 1, within the R-SMAD binding domain of SKI. No mutation was found in a cohort of 11 individuals with other marfanoid-craniosynostosis phenotypes. The interaction between SKI and Smad2/3 and Smad 4 regulates TGF-β signaling, and the pattern of anomalies in Ski-deficient mice corresponds to the clinical manifestations of SGS. These findings define SGS as a member of the family of diseases associated with the TGF-β-signaling pathway. 相似文献
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S Thomas M Legendre S Saunier B Bessières C Alby M Bonnière A Toutain L Loeuillet K Szymanska F Jossic D Gaillard MT Yacoubi S Mougou-Zerelli A David MA Barthez Y Ville C Bole-Feysot P Nitschke S Lyonnet A Munnich CA Johnson F Encha-Razavi V Cormier-Daire C Thauvin-Robinet M Vekemans T Attié-Bitach 《American journal of human genetics》2012,91(2):372-378
Orofaciodigital syndromes (OFDSs) consist of a group of heterogeneous disorders characterized by abnormalities in the oral cavity, face, and digits and associated phenotypic abnormalities that lead to the delineation of 13 OFDS subtypes. Here, by a combined approach of homozygozity mapping and exome ciliary sequencing, we identified truncating TCTN3 mutations as the cause of an extreme form of OFD associated with bone dysplasia, tibial defect, cystic kidneys, and brain anomalies (OFD IV, Mohr-Majewski syndrome). Analysis of 184 individuals with various ciliopathies (OFD, Meckel, Joubert, and short rib polydactyly syndromes) led us to identify four additional truncating TCTN3 mutations in unrelated fetal cases with overlapping Meckel and OFD IV syndromes and one homozygous missense mutation in a family with Joubert syndrome. By exploring roles of TCTN3 in human ciliary related functions, we found that TCTN3 is necessary for transduction of the sonic hedgehog (SHH) signaling pathway, as revealed by abnormal processing of GLI3 in patient cells. These results are consistent with the suggested role of its murine ortholog, which forms a complex at the ciliary transition zone with TCTN1 and TCTN2, both of which are also implicated in the transduction of SHH signaling. Overall, our data show the involvement of the transition zone protein TCTN3 in the regulation of the key SHH signaling pathway and that its disruption causes a severe form of ciliopathy, combining features of Meckel and OFD IV syndromes. 相似文献
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Yoko Aoki Tetsuya Niihori Toshihiro Banjo Nobuhiko Okamoto Seiji Mizuno Kenji Kurosawa Tsutomu Ogata Fumio Takada Michihiro Yano Toru Ando Tadataka Hoshika Christopher Barnett Hirofumi Ohashi Hiroshi Kawame Tomonobu Hasegawa Takahiro Okutani Tatsuo Nagashima Satoshi Hasegawa Ryo Funayama Takeshi Nagashima Keiko Nakayama Shin-ichi Inoue Yusuke Watanabe Toshihiko Ogura Yoichi Matsubara 《American journal of human genetics》2013,93(1):173-180
RAS GTPases mediate a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Recent studies have revealed that germline mutations and mosaicism for classical RAS mutations, including those in HRAS, KRAS, and NRAS, cause a wide spectrum of genetic disorders. These include Noonan syndrome and related disorders (RAS/mitogen-activated protein kinase [RAS/MAPK] pathway syndromes, or RASopathies), nevus sebaceous, and Schimmelpenning syndrome. In the present study, we identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan syndrome or a related condition but with no detectable mutations in known Noonan-related genes. Clinical manifestations in the RIT1-mutation-positive individuals are consistent with those of Noonan syndrome, which is characterized by distinctive facial features, short stature, and congenital heart defects. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. Luciferase assays in NIH 3T3 cells showed that five RIT1 alterations identified in children with Noonan syndrome enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes. 相似文献
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Heon?Yung Gee Shazia Ashraf Xiaoyang Wan Virginia Vega-Warner Julian Esteve-Rudd Svjetlana Lovric Humphrey Fang Toby?W. Hurd Carolin?E. Sadowski Susan?J. Allen Edgar?A. Otto Emine Korkmaz Joseph Washburn Shawn Levy David?S. Williams Sevcan?A. Bakkaloglu Anna Zolotnitskaya Fatih Ozaltin Weibin Zhou Friedhelm Hildebrandt 《American journal of human genetics》2014,94(6):884-890
Nephrotic syndrome (NS) is a genetically heterogeneous group of diseases that are divided into steroid-sensitive NS (SSNS) and steroid-resistant NS (SRNS). SRNS inevitably leads to end-stage kidney disease, and no curative treatment is available. To date, mutations in more than 24 genes have been described in Mendelian forms of SRNS; however, no Mendelian form of SSNS has been described. To identify a genetic form of SSNS, we performed homozygosity mapping, whole-exome sequencing, and multiplex PCR followed by next-generation sequencing. We thereby detected biallelic mutations in EMP2 (epithelial membrane protein 2) in four individuals from three unrelated families affected by SRNS or SSNS. We showed that EMP2 exclusively localized to glomeruli in the kidney. Knockdown of emp2 in zebrafish resulted in pericardial effusion, supporting the pathogenic role of mutated EMP2 in human NS. At the cellular level, we showed that knockdown of EMP2 in podocytes and endothelial cells resulted in an increased amount of CAVEOLIN-1 and decreased cell proliferation. Our data therefore identify EMP2 mutations as causing a recessive Mendelian form of SSNS. 相似文献
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Anneke?T. Vulto-van?Silfhout Bert?B.A. de?Vries Bregje?W.M. van?Bon Alexander Hoischen Martina Ruiterkamp-Versteeg Christian Gilissen Fangjian Gao Marloes van?Zwam Cornelis?L. Harteveld Anthonie?J. van?Essen Ben?C.J. Hamel Tjitske Kleefstra Michèl?A.A.P. Willemsen Helger?G. Yntema Hans van?Bokhoven Han?G. Brunner Thomas?G. Boyer Arjan?P.M. de?Brouwer 《American journal of human genetics》2013,92(3):401-406
Ohdo syndrome comprises a heterogeneous group of disorders characterized by intellectual disability (ID) and typical facial features, including blepharophimosis. Clinically, these blepharophimosis-ID syndromes have been classified in five distinct subgroups, including the Maat-Kievit-Brunner (MKB) type, which, in contrast to the others, is characterized by X-linked inheritance and facial coarsening at older age. We performed exome sequencing in two families, each with two affected males with Ohdo syndrome MKB type. In the two families, MED12 missense mutations (c.3443G>A [p.Arg1148His] or c.3493T>C [p.Ser1165Pro]) segregating with the phenotype were identified. Upon subsequent analysis of an additional cohort of nine simplex male individuals with Ohdo syndrome, one additional de novo missense change (c.5185C>A [p.His1729Asn]) in MED12 was detected. The occurrence of three different hemizygous missense mutations in three unrelated families affected by Ohdo syndrome MKB type shows that mutations in MED12 are the underlying cause of this X-linked form of Ohdo syndrome. Together with the recently described KAT6B mutations resulting in Ohdo syndrome Say/Barber/Biesecker/Young/Simpson type, our findings point to aberrant chromatin modification as being central to the pathogenesis of Ohdo syndrome. 相似文献
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Christopher T. Gordon Florence Petit Peter M. Kroisel Linda Jakobsen Roseli Maria Zechi-Ceide Myriam Oufadem Christine Bole-Feysot Solenn Pruvost Cécile Masson Frédéric Tores Thierry Hieu Patrick Nitschké Pernille Lindholm Philippe Pellerin Maria Leine Guion-Almeida Nancy Mizue Kokitsu-Nakata Siulan Vendramini-Pittoli Arnold Munnich Stanislas Lyonnet Muriel Holder-Espinasse Jeanne Amiel 《American journal of human genetics》2013
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Christopher?T. Gordon Florence Petit Peter?M. Kroisel Linda Jakobsen Roseli?Maria Zechi-Ceide Myriam Oufadem Christine Bole-Feysot Solenn Pruvost Cécile Masson Frédéric Tores Thierry Hieu Patrick Nitschké Pernille Lindholm Philippe Pellerin Maria?Leine Guion-Almeida Nancy?Mizue Kokitsu-Nakata Siulan Vendramini-Pittoli Arnold Munnich Stanislas Lyonnet Muriel Holder-Espinasse Jeanne Amiel 《American journal of human genetics》2013,93(6):1118-1125
Auriculocondylar syndrome (ACS) is a rare craniofacial disorder with mandibular hypoplasia and question-mark ears (QMEs) as major features. QMEs, consisting of a specific defect at the lobe-helix junction, can also occur as an isolated anomaly. Studies in animal models have indicated the essential role of endothelin 1 (EDN1) signaling through the endothelin receptor type A (EDNRA) in patterning the mandibular portion of the first pharyngeal arch. Mutations in the genes coding for phospholipase C, beta 4 (PLCB4) and guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 3 (GNAI3), predicted to function as signal transducers downstream of EDNRA, have recently been reported in ACS. By whole-exome sequencing (WES), we identified a homozygous substitution in a furin cleavage site of the EDN1 proprotein in ACS-affected siblings born to consanguineous parents. WES of two cases with vertical transmission of isolated QMEs revealed a stop mutation in EDN1 in one family and a missense substitution of a highly conserved residue in the mature EDN1 peptide in the other. Targeted sequencing of EDN1 in an ACS individual with related parents identified a fourth, homozygous mutation falling close to the site of cleavage by endothelin-converting enzyme. The different modes of inheritance suggest that the degree of residual EDN1 activity differs depending on the mutation. These findings provide further support for the hypothesis that ACS and QMEs are uniquely caused by disruption of the EDN1-EDNRA signaling pathway. 相似文献
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Janson White Juliana?F. Mazzeu Alexander Hoischen Shalini?N. Jhangiani Tomasz Gambin Michele?Calijorne Alcino Samantha Penney Jorge?M. Saraiva Hanne Hove Flemming Skovby Hülya Kayserili Elicia Estrella Anneke?T. Vulto-van?Silfhout Marloes Steehouwer Donna?M. Muzny V.?Reid Sutton Richard?A. Gibbs Baylor-Hopkins Center for Mendelian Genomics James?R. Lupski Han?G. Brunner Bregje?W.M. van?Bon Claudia?M.B. Carvalho 《American journal of human genetics》2015,96(4):612-622
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Nadja Ehmke Almuth Caliebe Rainer Koenig Sarina?G. Kant Zornitza Stark Valérie Cormier-Daire Dagmar Wieczorek Gabriele Gillessen-Kaesbach Kirstin Hoff Amit Kawalia Holger Thiele Janine Altmüller Bj?rn Fischer-Zirnsak Alexej Knaus Na Zhu Verena Heinrich Celine Huber Izabela Harabula Malte Spielmann Denise Horn Uwe Kornak Jochen Hecht Peter?M. Krawitz Peter Nürnberg Reiner Siebert Hermann Manzke Stefan Mundlos 《American journal of human genetics》2014,95(6):763-770
Catel-Manzke syndrome is characterized by Pierre Robin sequence and a unique form of bilateral hyperphalangy causing a clinodactyly of the index finger. We describe the identification of homozygous and compound heterozygous mutations in TGDS in seven unrelated individuals with typical Catel-Manzke syndrome by exome sequencing. Six different TGDS mutations were detected: c.892A>G (p.Asn298Asp), c.270_271del (p.Lys91Asnfs∗22), c.298G>T (p.Ala100Ser), c.294T>G (p.Phe98Leu), c.269A>G (p.Glu90Gly), and c.700T>C (p.Tyr234His), all predicted to be disease causing. By using haplotype reconstruction we showed that the mutation c.298G>T is probably a founder mutation. Due to the spectrum of the amino acid changes, we suggest that loss of function in TGDS is the underlying mechanism of Catel-Manzke syndrome. TGDS (dTDP-D-glucose 4,6-dehydrogenase) is a conserved protein belonging to the SDR family and probably plays a role in nucleotide sugar metabolism. 相似文献
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Sarah B. Daly Jill E. Urquhart Emma Hilton Edward A. McKenzie Richard A. Kammerer Malcolm Lewis Bronwyn Kerr Helen Stuart Dian Donnai David A. Long Berk Burgu Ozgu Aydogdu Murat Derbent Sixto Garcia-Minaur Willie Reardon Blanca Gener Stavit Shalev Rupert Smith Adrian S. Woolf Graeme C. Black William G. Newman 《American journal of human genetics》2010,87(2):309
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Sarah B. Daly Emma Hilton Richard A. Kammerer Bronwyn Kerr Dian Donnai Berk Burgu Murat Derbent Willie Reardon Stavit Shalev Adrian S. Woolf William G. Newman 《American journal of human genetics》2010,86(6):963-674
Urinary voiding dysfunction in childhood, manifesting as incontinence, dysuria, and urinary frequency, is a common condition. Urofacial syndrome (UFS) is a rare autosomal recessive disease characterized by facial grimacing when attempting to smile and failure of the urinary bladder to void completely despite a lack of anatomical bladder outflow obstruction or overt neurological damage. UFS individuals often have reflux of infected urine from the bladder to the upper renal tract, with a risk of kidney damage and renal failure. Whole-genome SNP mapping in one affected individual defined an autozygous region of 16 Mb on chromosome 10q23-q24, within which a 10 kb deletion encompassing exons 8 and 9 of HPSE2 was identified. Homozygous exonic deletions, nonsense mutations, and frameshift mutations in five further unrelated families confirmed HPSE2 as the causative gene for UFS. Mutations were not identified in four additional UFS patients, indicating genetic heterogeneity. We show that HPSE2 is expressed in the fetal and adult central nervous system, where it might be implicated in controlling facial expression and urinary voiding, and also in bladder smooth muscle, consistent with a role in renal tract morphology and function. Our findings have broader implications for understanding the genetic basis of lower renal tract malformations and voiding dysfunction. 相似文献
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Hannah Sleven Seth J. Welsh Jing Yu Mair E.A. Churchill Caroline F. Wright Alex Henderson Rita Horvath Julia Rankin Julie Vogt Alex Magee Vivienne McConnell Andrew Green Mary D. King Helen Cox Linlea Armstrong Anna Lehman Tanya N. Nelson Andrea H. Németh 《American journal of human genetics》2017,100(1):138-150
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Fuxi Zhu Fengsong Wang Xiaoyu Yang Jingjing Zhang Huan Wu Zhou Zhang Zhiguo Zhang Xiaojin He Ping Zhou Zhaolian Wei Jozef Gecz Yunxia Cao 《American journal of human genetics》2016,99(4):942-949
Acephalic spermatozoa syndrome is a rare and severe form of teratozoospermia characterized by a predominance of headless spermatozoa in the ejaculate. Family clustering and consanguinity suggest a genetic origin; however, causative mutations have yet to be identified. We performed whole-exome sequencing in two unrelated infertile men and subsequent variant filtering identified one homozygous (c.824C>T [p.Thr275Met]) and one compound heterozygous (c.1006C>T [p.Arg356Cys] and c.485T>A [p.Met162Lys]) SUN5 (also named TSARG4) variants. Sanger sequencing of SUN5 in 15 additional unrelated infertile men revealed four compound heterozygous (c.381delA [p.Val128Serfs∗7] and c.824C>T [p.Thr275Met]; c.381delA [p.Val128Serfs∗7] and c.781G>A [p.Val261Met]; c.216G>A [p.Trp72∗] and c.1043A>T [p.Asn348Ile]; c.425+1G>A/c.1043A>T [p.Asn348Ile]) and two homozygous (c.851C>G [p.Ser284∗]; c.350G>A [p.Gly114Arg]) variants in six individuals. These 10 SUN5 variants were found in 8 of 17 unrelated men, explaining the genetic defect in 47.06% of the affected individuals in our cohort. These variants were absent in 100 fertile population-matched control individuals. SUN5 variants lead to absent, significantly reduced, or truncated SUN5, and certain variants altered SUN5 distribution in the head-tail junction of the sperm. In summary, these results demonstrate that biallelic SUN5 mutations cause male infertility due to autosomal-recessive acephalic spermatozoa syndrome. 相似文献