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author:("Innes, michel")
1.  An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes 
Wheway, Gabrielle | Schmidts, Miriam | Mans, Dorus A. | Szymanska, Katarzyna | Nguyen, Thanh-Minh T. | Racher, Hilary | Phelps, Ian G. | Toedt, Grischa | Kennedy, Julie | Wunderlich, Kirsten A. | Sorusch, Nasrin | Abdelhamed, Zakia A. | Natarajan, Subaashini | Herridge, Warren | van Reeuwijk, Jeroen | Horn, Nicola | Boldt, Karsten | Parry, David A. | Letteboer, Stef J.F. | Roosing, Susanne | Adams, Matthew | Bell, Sandra M. | Bond, Jacquelyn | Higgins, Julie | Morrison, Ewan E. | Tomlinson, Darren C. | Slaats, Gisela G. | van Dam, Teunis J. P. | Huang, Lijia | Kessler, Kristin | Giessl, Andreas | Logan, Clare V. | Boyle, Evan A. | Shendure, Jay | Anazi, Shamsa | Aldahmesh, Mohammed | Al Hazzaa, Selwa | Hegele, Robert A. | Ober, Carole | Frosk, Patrick | Mhanni, Aizeddin A. | Chodirker, Bernard N. | Chudley, Albert E. | Lamont, Ryan | Bernier, Francois P. | Beaulieu, Chandree L. | Gordon, Paul | Pon, Richard T. | Donahue, Clem | Barkovich, A. James | Wolf, Louis | Toomes, Carmel | Thiel, Christian T. | Boycott, Kym M. | McKibbin, Martin | Inglehearn, Chris F. | Stewart, Fiona | Omran, Heymut | Huynen, Martijn A. | Sergouniotis, Panagiotis I. | Alkuraya, Fowzan S. | Parboosingh, Jillian S. | Innes, A Micheil | Willoughby, Colin E. | Giles, Rachel H. | Webster, Andrew R. | Ueffing, Marius | Blacque, Oliver | Gleeson, Joseph G. | Wolfrum, Uwe | Beales, Philip L. | Gibson, Toby | Doherty, Dan | Mitchison, Hannah M. | Roepman, Ronald | Johnson, Colin A.
Nature cell biology  2015;17(8):1074-1087.
Defects in primary cilium biogenesis underlie the ciliopathies, a growing group of genetic disorders. We describe a whole genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the primary cilium, obtaining a global resource. We identify 112 candidate ciliogenesis and ciliopathy genes, including 44 components of the ubiquitin-proteasome system, 12 G-protein-coupled receptors, and three pre-mRNA processing factors (PRPF6, PRPF8 and PRPF31) mutated in autosomal dominant retinitis pigmentosa. The PRPFs localise to the connecting cilium, and PRPF8- and PRPF31-mutated cells have ciliary defects. Combining the screen with exome sequencing data identified recessive mutations in PIBF1/CEP90 and C21orf2/LRRC76 as causes of the ciliopathies Joubert and Jeune syndromes. Biochemical approaches place C21orf2 within key ciliopathy-associated protein modules, offering an explanation for the skeletal and retinal involvement observed in individuals with C21orf2-variants. Our global, unbiased approaches provide insights into ciliogenesis complexity and identify roles for unanticipated pathways in human genetic disease.
doi:10.1038/ncb3201
PMCID: PMC4536769  PMID: 26167768
cilia; ciliopathies; reverse genetics; whole-genome siRNA screen; Jeune syndrome; Joubert syndrome
2.  Biallelic Mutations in BRCA1 Cause a New Fanconi Anemia Subtype 
Cancer discovery  2014;5(2):135-142.
Deficiency in BRCA dependent DNA inter-strand crosslink (ICL) repair is intimately connected to breast cancer susceptibility and to the rare developmental syndrome, Fanconi Anemia (FA). Bona fide FA proteins, BRCA2 (FANCD1), PALB2 (FANCN), and BRIP1 (FANCJ) interact with BRCA1 during ICL repair. However, lack of detailed phenotypic and cellular characterization of a patient with biallelic BRCA1 mutations has precluded assignment of BRCA1 as a definitive FA susceptibility gene. Here we report the presence of biallelic BRCA1 mutations in a woman with multiple congenital anomalies consistent with a FA-like disorder and breast cancer at age 23. Patient cells exhibited deficiency in BRCA1 (FANCS) and Rad51 localization to DNA damage sites, combined with radial chromosome formation and hypersensitivity to ICL inducing agents. Restoration of these functions was achieved by ectopic introduction of a BRCA1 transgene. These observations provide evidence in support of BRCA1 as a new Fanconi anemia subtype (FA-S).
doi:10.1158/2159-8290.CD-14-1156
PMCID: PMC4320660  PMID: 25472942
BRCA1; DNA repair; Fanconi Anemia
3.  Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance 
Kaiser, Frank J. | Ansari, Morad | Braunholz, Diana | Concepción Gil-Rodríguez, María | Decroos, Christophe | Wilde, Jonathan J. | Fincher, Christopher T. | Kaur, Maninder | Bando, Masashige | Amor, David J. | Atwal, Paldeep S. | Bahlo, Melanie | Bowman, Christine M. | Bradley, Jacquelyn J. | Brunner, Han G. | Clark, Dinah | Del Campo, Miguel | Di Donato, Nataliya | Diakumis, Peter | Dubbs, Holly | Dyment, David A. | Eckhold, Juliane | Ernst, Sarah | Ferreira, Jose C. | Francey, Lauren J. | Gehlken, Ulrike | Guillén-Navarro, Encarna | Gyftodimou, Yolanda | Hall, Bryan D. | Hennekam, Raoul | Hudgins, Louanne | Hullings, Melanie | Hunter, Jennifer M. | Yntema, Helger | Innes, A. Micheil | Kline, Antonie D. | Krumina, Zita | Lee, Hane | Leppig, Kathleen | Lynch, Sally Ann | Mallozzi, Mark B. | Mannini, Linda | Mckee, Shane | Mehta, Sarju G. | Micule, Ieva | Mohammed, Shehla | Moran, Ellen | Mortier, Geert R. | Moser, Joe-Ann S. | Noon, Sarah E. | Nozaki, Naohito | Nunes, Luis | Pappas, John G. | Penney, Lynette S. | Pérez-Aytés, Antonio | Petersen, Michael B. | Puisac, Beatriz | Revencu, Nicole | Roeder, Elizabeth | Saitta, Sulagna | Scheuerle, Angela E. | Schindeler, Karen L. | Siu, Victoria M. | Stark, Zornitza | Strom, Samuel P. | Thiese, Heidi | Vater, Inga | Willems, Patrick | Williamson, Kathleen | Wilson, Louise C. | Hakonarson, Hakon | Quintero-Rivera, Fabiola | Wierzba, Jolanta | Musio, Antonio | Gillessen-Kaesbach, Gabriele | Ramos, Feliciano J. | Jackson, Laird G. | Shirahige, Katsuhiko | Pié, Juan | Christianson, David W. | Krantz, Ian D. | Fitzpatrick, David R. | Deardorff, Matthew A.
Human Molecular Genetics  2014;23(11):2888-2900.
Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.
doi:10.1093/hmg/ddu002
PMCID: PMC4014191  PMID: 24403048
4.  A Shared Founder Mutation Underlies Restrictive Dermopathy in Old Colony (Dutch-German) Mennonite and Hutterite Patients in North America 
doi:10.1002/ajmg.a.35302
PMCID: PMC4247856  PMID: 22495976
restrictive dermopathy; tight skin contracture syndrome; laminopathy; lethal; Hutterite; Mennonite; ZMPSTE24
5.  Disrupted auto-regulation of the spliceosomal gene SNRPB causes cerebro–costo–mandibular syndrome 
Nature Communications  2014;5:4483.
Elucidating the function of highly conserved regulatory sequences is a significant challenge in genomics today. Certain intragenic highly conserved elements have been associated with regulating levels of core components of the spliceosome and alternative splicing of downstream genes. Here we identify mutations in one such element, a regulatory alternative exon of SNRPB as the cause of cerebro–costo–mandibular syndrome. This exon contains a premature termination codon that triggers nonsense-mediated mRNA decay when included in the transcript. These mutations cause increased inclusion of the alternative exon and decreased overall expression of SNRPB. We provide evidence for the functional importance of this conserved intragenic element in the regulation of alternative splicing and development, and suggest that the evolution of such a regulatory mechanism has contributed to the complexity of mammalian development.
Cerebro–costo–mandibular syndrome, CCMS, is a severe human multiple malformation disorder. Here, the authors report that mutations in SNRPB disrupt the normal regulation of alternative splicing at this gene, and in so doing, may be responsible for the development of CCMS.
doi:10.1038/ncomms5483
PMCID: PMC4109005  PMID: 25047197
6.  An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge 
Brownstein, Catherine A | Beggs, Alan H | Homer, Nils | Merriman, Barry | Yu, Timothy W | Flannery, Katherine C | DeChene, Elizabeth T | Towne, Meghan C | Savage, Sarah K | Price, Emily N | Holm, Ingrid A | Luquette, Lovelace J | Lyon, Elaine | Majzoub, Joseph | Neupert, Peter | McCallie Jr, David | Szolovits, Peter | Willard, Huntington F | Mendelsohn, Nancy J | Temme, Renee | Finkel, Richard S | Yum, Sabrina W | Medne, Livija | Sunyaev, Shamil R | Adzhubey, Ivan | Cassa, Christopher A | de Bakker, Paul IW | Duzkale, Hatice | Dworzyński, Piotr | Fairbrother, William | Francioli, Laurent | Funke, Birgit H | Giovanni, Monica A | Handsaker, Robert E | Lage, Kasper | Lebo, Matthew S | Lek, Monkol | Leshchiner, Ignaty | MacArthur, Daniel G | McLaughlin, Heather M | Murray, Michael F | Pers, Tune H | Polak, Paz P | Raychaudhuri, Soumya | Rehm, Heidi L | Soemedi, Rachel | Stitziel, Nathan O | Vestecka, Sara | Supper, Jochen | Gugenmus, Claudia | Klocke, Bernward | Hahn, Alexander | Schubach, Max | Menzel, Mortiz | Biskup, Saskia | Freisinger, Peter | Deng, Mario | Braun, Martin | Perner, Sven | Smith, Richard JH | Andorf, Janeen L | Huang, Jian | Ryckman, Kelli | Sheffield, Val C | Stone, Edwin M | Bair, Thomas | Black-Ziegelbein, E Ann | Braun, Terry A | Darbro, Benjamin | DeLuca, Adam P | Kolbe, Diana L | Scheetz, Todd E | Shearer, Aiden E | Sompallae, Rama | Wang, Kai | Bassuk, Alexander G | Edens, Erik | Mathews, Katherine | Moore, Steven A | Shchelochkov, Oleg A | Trapane, Pamela | Bossler, Aaron | Campbell, Colleen A | Heusel, Jonathan W | Kwitek, Anne | Maga, Tara | Panzer, Karin | Wassink, Thomas | Van Daele, Douglas | Azaiez, Hela | Booth, Kevin | Meyer, Nic | Segal, Michael M | Williams, Marc S | Tromp, Gerard | White, Peter | Corsmeier, Donald | Fitzgerald-Butt, Sara | Herman, Gail | Lamb-Thrush, Devon | McBride, Kim L | Newsom, David | Pierson, Christopher R | Rakowsky, Alexander T | Maver, Aleš | Lovrečić, Luca | Palandačić, Anja | Peterlin, Borut | Torkamani, Ali | Wedell, Anna | Huss, Mikael | Alexeyenko, Andrey | Lindvall, Jessica M | Magnusson, Måns | Nilsson, Daniel | Stranneheim, Henrik | Taylan, Fulya | Gilissen, Christian | Hoischen, Alexander | van Bon, Bregje | Yntema, Helger | Nelen, Marcel | Zhang, Weidong | Sager, Jason | Zhang, Lu | Blair, Kathryn | Kural, Deniz | Cariaso, Michael | Lennon, Greg G | Javed, Asif | Agrawal, Saloni | Ng, Pauline C | Sandhu, Komal S | Krishna, Shuba | Veeramachaneni, Vamsi | Isakov, Ofer | Halperin, Eran | Friedman, Eitan | Shomron, Noam | Glusman, Gustavo | Roach, Jared C | Caballero, Juan | Cox, Hannah C | Mauldin, Denise | Ament, Seth A | Rowen, Lee | Richards, Daniel R | Lucas, F Anthony San | Gonzalez-Garay, Manuel L | Caskey, C Thomas | Bai, Yu | Huang, Ying | Fang, Fang | Zhang, Yan | Wang, Zhengyuan | Barrera, Jorge | Garcia-Lobo, Juan M | González-Lamuño, Domingo | Llorca, Javier | Rodriguez, Maria C | Varela, Ignacio | Reese, Martin G | De La Vega, Francisco M | Kiruluta, Edward | Cargill, Michele | Hart, Reece K | Sorenson, Jon M | Lyon, Gholson J | Stevenson, David A | Bray, Bruce E | Moore, Barry M | Eilbeck, Karen | Yandell, Mark | Zhao, Hongyu | Hou, Lin | Chen, Xiaowei | Yan, Xiting | Chen, Mengjie | Li, Cong | Yang, Can | Gunel, Murat | Li, Peining | Kong, Yong | Alexander, Austin C | Albertyn, Zayed I | Boycott, Kym M | Bulman, Dennis E | Gordon, Paul MK | Innes, A Micheil | Knoppers, Bartha M | Majewski, Jacek | Marshall, Christian R | Parboosingh, Jillian S | Sawyer, Sarah L | Samuels, Mark E | Schwartzentruber, Jeremy | Kohane, Isaac S | Margulies, David M
Genome Biology  2014;15(3):R53.
Background
There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance.
Results
A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization.
Conclusions
The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
doi:10.1186/gb-2014-15-3-r53
PMCID: PMC4073084  PMID: 24667040
7.  Intellectual disability associated with a homozygous missense mutation in THOC6 
Background
We recently described a novel autosomal recessive neurodevelopmental disorder with intellectual disability in four patients from two related Hutterite families. Identity-by-descent mapping localized the gene to a 5.1 Mb region at chromosome 16p13.3 containing more than 170 known or predicted genes. The objective of this study was to identify the causative gene for this rare disorder.
Methods and results
Candidate gene sequencing followed by exome sequencing identified a homozygous missense mutation p.Gly46Arg, in THOC6. No other potentially causative coding variants were present within the critical region on chromosome 16. THOC6 is a member of the THO/TREX complex which is involved in coordinating mRNA processing with mRNA export from the nucleus. In situ hybridization showed that thoc6 is highly expressed in the midbrain and eyes. Cellular localization studies demonstrated that wild-type THOC6 is present within the nucleus as is the case for other THO complex proteins. However, mutant THOC6 was predominantly localized to the cytoplasm, suggesting that the mutant protein is unable to carry out its normal function. siRNA knockdown of THOC6 revealed increased apoptosis in cultured cells.
Conclusion
Our findings associate a missense mutation in THOC6 with intellectual disability, suggesting the THO/TREX complex plays an important role in neurodevelopment.
doi:10.1186/1750-1172-8-62
PMCID: PMC3644499  PMID: 23621916
Intellectual disability; THOC6; THO/TREX complex; mRNA export; Hutterite
8.  De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes 
Nature genetics  2012;44(8):934-940.
Megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes are sporadic overgrowth disorders associated with markedly enlarged brain size and other recognizable features1-5. We performed exome sequencing in three families with MCAP or MPPH and confirmed our initial observations in exomes from 7 MCAP and 174 control individuals, as well as in 40 additional megalencephaly subjects using a combination of Sanger sequencing, restriction-enzyme assays, and targeted deep sequencing. We identified de novo germline or postzygotic mutations in three core components of the phosphatidylinositol-3-kinase (PI3K)/AKT pathway. These include two mutations of AKT3, one recurrent mutation of PIK3R2 in 11 unrelated MPPH families, and 15 mostly postzygotic mutations of PIK3CA in 23 MCAP and one MPPH patients. Our data highlight the central role of PI3K/AKT signaling in vascular, limb and brain development, and emphasize the power of massively parallel sequencing in a challenging context of phenotypic and genetic heterogeneity combined with postzygotic mosaicism.
doi:10.1038/ng.2331
PMCID: PMC3408813  PMID: 22729224
12.  A rational approach to the child with mental retardation for the paediatrician 
Paediatrics & Child Health  2003;8(6):345-356.
Mental Retardation (MR) is a problem encountered in almost all paediatric clinical settings. The assessment of a child with MR is a common diagnostic and management dilemma for paediatricians. The field of MR research is currently in a state of flux regarding not just our understanding of the condition, but also in the language and the processes we use in naming, defining and describing MR. This article will provide a better understanding and a rational approach toward MR. Prevalence rates for MR are variable in the literature and may be attributable to the variation in major classification systems and the diversity in study operation definitions and methodologies. Etiologies of MR are diverse and include many different influences. MR most often presents during infancy or preschool years as developmental delay. There is no universally accepted approach to the etiological work-up of mental retardation. The number of medical conditions associated with MR that are completely treatable by medical means remains small. The paediatrician plays a key role establishing short and long term treatment goals, as well as providing support to families who have children with MR.
PMCID: PMC2795455  PMID: 20052328
Children; Developmental delay; Mental retardation
13.  Congenital rickets caused by maternal vitamin D deficiency 
Paediatrics & Child Health  2002;7(7):455-458.
The cases of four newborn infants with congenital rickets are reported. All infants were native Canadian: three were Cree and one was Inuit. One had a narrow chest and pulmonary hypoplasia, two had clinical and radiological signs of rickets with craniotabes, thickened wrists, and prominent costochondral junctions, and one had perinatal asphyxia and hydrops. All had hypocalcemia, hypophosphatemia and secondary hyperparathyroidism. Serum 25-hydroxyvitamin D levels were low in three of the infants. The four mothers had evidence of vitamin D deficiency. All infants recovered following treatment with 5000 IU oral vitamin D daily.
PMCID: PMC2795674  PMID: 20046322
Congenital rickets; Hyperparathyroidism; Hypocalcemia; 25-hydroxyvitamin D

Results 1-13 (13)