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13 results on '"CHROMOSOME 16P11.2"'

1. Coronin-1A: immune deficiency in humans and mice.

Author

Punwani, Divya, Pelz, Barry, Yu, Jason, Arva, Nicoleta C, Schafernak, Kristian, Kondratowicz, Karly, Makhija, Melanie, and Puck, Jennifer M

Subjects
Animals, Mice, Knockout, Humans, Mice, Leukemia, Autoimmune Diseases, Immunologic Deficiency Syndromes, Disease Models, Animal, Microfilament Proteins, Carrier Proteins, Autoimmunity, Protein Binding, Phenotype, Mutation, Protein Interaction Domains and Motifs, Genetic Association Studies, Molecular Targeted Therapy, Chromosome 16p11.2, combined immunodeficiency, immune dysregulation, epstein-barr virus, primary immunodeficiency, thymus, Knockout, Disease Models, Animal, Immunology
Published
2015

2. Phenotypes Associated with 16p11.2 Copy Number Gains and Losses at a Single Institution.

Author

Chu, Caleb, Wu, Haotian, Xu, Fangling, Ray, Joseph W, Britt, Allison, Robinson, Sally S, Lupo, Pamela J, Murphy, Christine R C, Dreyer, Charles F, Lee, Phillip D K, Hu, Peter C, and Dong, Jianli

Subjects
*CHROMOSOMES, *DEVELOPMENTAL disabilities, *DNA, *GENETICS, *GERM cells, *MEDICAL records, *MUSCLE hypotonia, *PHENOTYPES, *ACQUISITION of data methodology
Abstract

Chromosome 16p11.2 is one of the susceptible sites for recurrent copy number variations (CNVs) due to flanking near-identical segmental duplications. Five segmental duplications, named breakpoints 1 to 5 (BP1–BP5), have been defined as recombination hotspots within 16p11.2. Common CNVs on 16p11.2 include a proximal ~593 kb between BP4 and BP5, and a distal ~220 kb between BP2 and BP3. We performed a search for patients carrying 16p11.2 CNVs, as detected using chromosome microarray (CMA), in the Molecular Diagnostic Laboratory at the University of Texas Medical Branch (UTMB), in Galveston. From March 2013 through April 2018, a total of 1200 CMA results were generated for germline testing, and 14 patients tested positive for 16p11.2 CNVs, of whom 7 had proximal deletion, 2 had distal deletion, 4 had proximal duplication, and 1 had distal duplication. Herein, we provide detailed phenotype data for these patients. Our study results show that developmental delay, abnormal body weight, behavioral problems, and hypotonia are common phenotypes associated with 16p11.2 CNVs. [ABSTRACT FROM AUTHOR]

Published
2020
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3. Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a coronin-1A mutation and a chromosome 16p11.2 deletion

Author

Shiow, Lawrence R., Paris, Kenneth, Akana, Matthew C., Cyster, Jason G., Sorensen, Ricardo U., and Puck, Jennifer M.

Subjects
*SEVERE combined immunodeficiency, *ATTENTION-deficit hyperactivity disorder, *GENETIC mutation, *CHROMOSOMES, *DISEASES in girls, *ACTIN, *CYTOSKELETON, *GENETICS
Abstract

Abstract: Defects causing severe combined immunodeficiency (SCID) have been reported in pathways mediating antigen receptor rearrangement, antigen receptor and cytokine signaling, and purine metabolism. Recognizing that the actin regulator Coronin-1A is essential for development of a normal peripheral T cell compartment in mouse models, we identified absence of Coronin-1A in a girl with T−B+NK+ SCID who suffered recurrent infections including severe post-vaccination varicella at age 13 months. Murine Coronin-1A is essential for the release of T cells from the thymus, consistent with the paradoxically detectable thymus in our patient. Molecular analysis revealed a 2 bp deletion in the paternal CORO1A coding sequence paired with a 600 kb de novo deletion encompassing CORO1A on the maternal allele. This genomic region at 16p11.2 is subject to recurrent copy number variations associated with autism spectrum disorders, including attention deficit and hyperactivity, present in our patient. This case highlights the first link between actin cytoskeleton regulation and SCID. [Copyright &y& Elsevier]

Published
2009
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4. Extending the phenotype of recurrent rearrangements of 16p11.2: Deletions in mentally retarded patients without autism and in normal individuals

Author

Bijlsma, E.K., Gijsbers, A.C.J., Schuurs-Hoeijmakers, J.H.M., van Haeringen, A., Fransen van de Putte, D.E., Anderlid, B.-M., Lundin, J., Lapunzina, P., Pérez Jurado, L.A., Delle Chiaie, B., Loeys, B., Menten, B., Oostra, A., Verhelst, H., Amor, D.J., Bruno, D.L., van Essen, A.J., Hordijk, R., Sikkema-Raddatz, B., and Verbruggen, K.T.

Subjects
*GENETICS, *EMBRYOLOGY, *MENDEL'S law, *BIOLOGICAL adaptation
Abstract

Abstract: Array CGH (comparative genomic hybridization) screening of large patient cohorts with mental retardation and/or multiple congenital anomalies (MR/MCA) has led to the identification of a number of new microdeletion and microduplication syndromes. Recently, a recurrent copy number variant (CNV) at chromosome 16p11.2 was reported to occur in up to 1% of autistic patients in three large autism studies. In the screening of 4284 patients with MR/MCA with various array platforms, we detected 22 individuals (14 index patients and 8 family members) with deletions in 16p11.2, which are genomically identical to those identified in the autism studies. Though some patients shared a facial resemblance and a tendency to overweight, there was no evidence for a recognizable phenotype. Autism was not the presenting feature in our series. The assembled evidence indicates that recurrent 16p11.2 deletions are associated with variable clinical outcome, most likely arising from haploinsufficiency of one or more genes. The phenotypical spectrum ranges from MR and/or MCA, autism, learning and speech problems, to a normal phenotype. [Copyright &y& Elsevier]

Published
2009
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5. Familial juvenile hyperuricaemic nephropathy (FJHN): linkage analysis in 15 families, physical and transcriptional characterisation of the FJHN critical region on chromosome 16p11.2 and the analysis of seven candidate genes.

Author

Stiburkova, Blanka, Majewski, Jacek, Hodanova, Katerina, Ondrova, Lenka, Jerabkova, Marketa, Zikanova, Marie, Vylet'al, Petr, Sebesta, Ivan, Marinaki, Anthony, Simmonds, Anne, Matthijs, Gert, Fryns, Jean-Pierre, Torres, Rosa, Puig, Juan Garcia, Ott, Jurg, and Kmoch, Stanislav

Subjects
*HUMAN genetics, *KIDNEY diseases, *HYPERURICEMIA
Abstract

Familial juvenile hyperuricaemic nephropathy (FJHN) is an autosomal dominant renal disease characterised by juvenile onset of hyperuricaemia, gouty arthritis, and progressive renal failure at an early age. Recent studies in four kindreds showed linkage of a gene for FJHN to the same genomic interval on chromosome 16p11.2, where the gene for the phenotypically similar medullary cystic disease type 2 (MCKD2) has been Iocalised. In this study we performed linkage analysis in additional 15 FJHN families. Linkage of FJHN to 16p11.2 was confirmed in six families, which suggests that, in a large proportion of FJHN kindreds, the disease is likely to be caused by a gene or genes located outside of 16p11.2. Haplotype analysis of the new and previously analysed families provided two non-overlapping critical regions on 16p11.2-FJHN1, delimited by markers D16S499-D16S3036 and FJHN2, delimited by markers D16S412-D16S3116. Considering MCKD2 to be a distinct molecular entity, the analysis suggests that as many as three kidney disease genes may be located in close proximity on 16p11.2. From genomic databases we compiled integrated physical and transcription maps of whole critical genomic region in which 45 known genes and 129 predicted loci have been Iocalised. We selected, analysed and found no pathogenic mutations in seven candidate genes. The linkage and haplotype analysis reported here demonstrates the genetic heterogeneity of FJHN. The report of integrated physical and mostly in-silico predicted transcription maps of the FJHN critical region provides a basis for precise experimental annotation of the current transcript map, which is essential for final identification of the FJHN gene(s). [ABSTRACT FROM AUTHOR]

Published
2003

6. Copy number variations in Friesian horses and genetic risk factors for insect bite hypersensitivity

Author

Sarah C. Blott, Liesbeth Franҫois, Anneleen Stinckens, Brandon D. Velie, A. Schurink, Vinicius Henrique da Silva, Richard P. M. A. Crooijmans, Steven Janssens, Gabriella Lindgren, Nadine Buys, Bert Dibbits, Bart J. Ducro, and Animal Ecology (AnE)

Subjects
0301 basic medicine, ICELANDIC HORSES, Genome-wide association study, VARIANTS, Friesian horse, Risk Factors, Copy-number variation, Genetics (clinical), POPULATION, 2. Zero hunger, Genetics, Genetics & Heredity, education.field_of_study, biology, Copy number variations, Friesian horse, Genome-wide association study, Insect bite hypersensitivity, 04 agricultural and veterinary sciences, international, Life Sciences & Biomedicine, Animal Breeding & Genomics, Research Article, CHROMOSOME 16P11.2, lcsh:QH426-470, DNA Copy Number Variations, biology.animal_breed, Population, Single-nucleotide polymorphism, Animal Breeding and Genomics, SUMMER ECZEMA, Polymorphism, Single Nucleotide, 03 medical and health sciences, Hypersensitivity, SNP, Bio/Medical/Health - Genetics & Systems Biology, Animals, Fokkerij en Genomica, Genetic variability, Horses, Copy number variations, Fokkerij & Genomica, GENOME-WIDE ASSOCIATION, education, Genotyping, Science & Technology, IDENTIFICATION, 0402 animal and dairy science, Insect Bites and Stings, 040201 dairy & animal science, MAJOR HISTOCOMPATIBILITY COMPLEX, lcsh:Genetics, 030104 developmental biology, RESOLUTION, WIAS, Insect bite hypersensitivity, Genome wide association study, MHC
Abstract

Background Many common and relevant diseases affecting equine welfare have yet to be tested regarding structural variants such as copy number variations (CNVs). CNVs make up a substantial proportion of total genetic variability in populations of many species, resulting in more sequence differences between individuals than SNPs. Associations between CNVs and disease phenotypes have been established in several species, but equine CNV studies have been limited. Aim of this study was to identify CNVs and to perform a genome-wide association (GWA) study in Friesian horses to identify genomic loci associated with insect bite hypersensitivity (IBH), a common seasonal allergic dermatitis observed in many horse breeds worldwide. Results Genotypes were obtained using the Axiom® Equine Genotyping Array containing 670,796 SNPs. After quality control of genotypes, 15,041 CNVs and 5350 CNV regions (CNVRs) were identified in 222 Friesian horses. Coverage of the total genome by CNVRs was 11.2% with 49.2% of CNVRs containing genes. 58.0% of CNVRs were novel (i.e. so far only identified in Friesian horses). A SNP- and CNV-based GWA analysis was performed, where about half of the horses were affected by IBH. The SNP-based analysis showed a highly significant association between the MHC region on ECA20 and IBH in Friesian horses. Associations between the MHC region on ECA20 and IBH were also detected based on the CNV-based analysis. However, CNVs associated with IBH in Friesian horses were not often in close proximity to SNPs identified to be associated with IBH. Conclusions CNVs were identified in a large sample of the Friesian horse population, thereby contributing to our knowledge on CNVs in horses and facilitating our understanding of the equine genome and its phenotypic expression. A clear association was identified between the MHC region on ECA20 and IBH in Friesian horses based on both SNP- and CNV-based GWA studies. These results imply that MHC contributes to IBH sensitivity in Friesian horses. Although subsequent analyses are needed for verification, nucleotide differences, as well as more complex structural variations like CNVs, seem to contribute to IBH sensitivity. IBH should be considered as a common disease with a complex genomic architecture. Electronic supplementary material The online version of this article (10.1186/s12863-018-0657-0) contains supplementary material, which is available to authorized users.

Published
2017

7. Coronin-1A: immune deficiency in humans and mice

Author

Divya Punwani, Jason Yu, Barry J. Pelz, Jennifer M. Puck, Karly Kondratowicz, Melanie M. Makhija, Nicoleta C. Arva, and Kristian T. Schafernak

Subjects
medicine.drug_class, T cell, Knockout, Immunology, Autoimmunity, Disease, Biology, Chromosome 16p11.2, Monoclonal antibody, medicine.disease_cause, primary immunodeficiency, Article, Autoimmune Diseases, Mice, Immune system, immune dysregulation, thymus, medicine, Immunology and Allergy, Animals, Humans, combined immunodeficiency, Protein Interaction Domains and Motifs, Molecular Targeted Therapy, epstein-barr virus (EBV), B cell, Genetic Association Studies, Mice, Knockout, Leukemia, epstein-barr virus, Animal, Microfilament Proteins, Immunologic Deficiency Syndromes, combined immunodeficiency (CID), Immune dysregulation, medicine.disease, Disease Models, Animal, medicine.anatomical_structure, Phenotype, Disease Models, Mutation, Primary immunodeficiency, Carrier Proteins, Protein Binding
Abstract

Since the discovery of coronins in 1991 significant research has been carried out to understand their molecular structure and cellular mechanisms of the action. While a number of binding partners have been discovered, the precise mechanisms of action of Coronin-1A are still being elucidated, both in vitro and in vivo. The role of Coronin-1A in the development and function of the immune system is irrefutable, in both humans and mice, and deficiency of Coronin-1A results in CID. Although some immunological manifestations of Coronin-1A deficiency differed between the patients described so far, absence of Coronin-1A affected the T cell compartment in all patients. B cell numbers were lower than normal and antibody responses were impaired. Variable NK cell defects associated with absent Coronin-1A to date will require detailed analysis of further patients. HCT was curative for patients with Coronin-1A deficiency when the disease was diagnosed early, before onset of irreversible complications arising from infections and EBV associated malignancy. With new evidence about the potential of anti-Coronin-1A monoclonal antibodies to treat B cell malignancies and T cell-mediated auto-inflammatory diseases, Coronin-1A can now be said to be involved in the overall regulation of the immune system, and inappropriate expression can lead to either immune deficiency or autoimmunity.

Published
2015
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8. Familial Juvenile Hyperuricemic Nephropathy: Localization of the Gene on Chromosome 16p11.2—and Evidence for Genetic Heterogeneity

Author

Ivan Sebesta, Blanka Stibůrková, Stanislav Kmoch, Jurg Ott, Jacek Majewski, and Wenyong Zhang

Subjects
Adult, Male, Thyroid Hormones, Adolescent, Gout, Penetrance, Locus (genetics), Chromosome 16p11.2, Biology, Medullary cystic kidney disease, Renal disease, Genetic Heterogeneity, Mucoproteins, Genetic linkage, Genetic heterogeneity, FJHN, Uromodulin, Genetics, medicine, Humans, Genetics(clinical), Crossing Over, Genetic, Renal Insufficiency, Age of Onset, Child, Genetics (clinical), Czech Republic, Genes, Dominant, Familial juvenile hyperuricemic nephropathy, Genetic heterogeneity, Haplotype, Chromosome Mapping, Membrane Proteins, Middle Aged, medicine.disease, Pedigree, Uric Acid, Haplotypes, Female, Lod Score, Age of onset, Carrier Proteins, Chromosomes, Human, Pair 16, Research Article
Abstract

Familial juvenile hyperuricemic nephropathy (FJHN), is an autosomal dominant renal disease characterized by juvenile onset of hyperuricemia, gouty arthritis, and progressive renal failure at an early age. Using a genomewide linkage analysis in three Czech affected families, we have identified, on chromosome 16p11.2, a locus for FJHN and have found evidence for genetic heterogeneity and reduced penetrance of the disease. The maximum two-point LOD score calculated with allowance for heterogeneity (HLOD) was 4.70, obtained at recombination fraction 0, with marker D16S3036; multipoint linkage analysis yielded a maximum HLOD score of 4.76 at the same location. Haplotype analysis defined a 10-cM candidate region between flanking markers D16S501 and D16S3113, exhibiting crossover events with the disease locus. The candidate interval contains several genes expressed in the kidney, two of which—uromodulin and NADP-regulated thyroid-hormone–binding protein—represent promising candidates for further analysis.

Published
2000
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9. Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity

Author

D. L. Cousminer, D. J. Berry, N. J. Timpson, W. Ang, E. Thiering, E. M. Byrne, H. R. Taal, V. Huikari, J. P. Bradfield, M. Kerkhof, M. M. Groen Blokhuis, E. Kreiner Moller, M. Marinelli, C. Holst, J. T. Leinonen, J. R. B. Perry, I. Surakka, O. Pietilainen, J. Kettunen, V. Anttila, M. Kaakinen, U. Sovio, A. Pouta, S. Das, V. Lagou, C. Power, I. Prokopenko, D. M. Evans, J. P. Kemp, B. St Pourcain, S. Ring, A. Palotie, E. Kajantie, C. Osmond, T. Lehtimaki, J. S. Viikari, M. Kahonen, N. M. Warrington, S. J. Lye, L. J. Palmer, C. M. T. Tiesler, C. Flexeder, G. W. Montgomery, S. E. Medland, A. Hofman, H. Hakonarson, M. Guxens, M. Bartels, V. Salomaa, J. M. Murabito, J. Kaprio, T. I. A. Sorensen, F. Ballester, H. Bisgaard, D. I. Boomsma, G. H. Koppelman, S. F. A. Grant, V. W. V. Jaddoe, N. G. Martin, J. Heinrich, C. E. Pennell, O. T. Raitakari, J. G. Eriksson, G. D. Smith, E. Hypponen, M. R. Jarvelin, M. I. McCarthy, S. Ripatti, E. Widen, Adair LS, Ang W, Atalay M, van Beijsterveldt T, Bergen N, Benke K, Berry DJ, Boomsma DI, Bradfield JP, Charoen P, Coin L, Cooper C, Cousminer DL, Das S, Davis OS, Dedoussis GV, Elliott P, Estivill X, Evans DM, Feenstra B, Flexeder C, Frayling T, Freathy RM, Gaillard R, Geller F, Gillman M, Grant SF, Groen Blokhuis M, Goh LK, Guxens M, Hakonarson H, Hattersley AT, Haworth CM, Hadley D, Hedebrand J, Heinrich J, Hinney A, Hirschhorn JN, Hocher B, Holloway JW, Holst C, Hottenga JJ, Horikoshi M, Huikari V, Hypponen E, Iñiguez C, Jaddoe VW, Jarvelin MR, Kaakinen M, Kilpeläinen TO, Kirin M, Kowgier M, Lakka HM, Lakka TA, Lange LA, Lawlor DA, Lehtimäki T, Lewin A, Lindgren C, Lindi V, Maggi R, Marsh J, McCarthy MI, Melbye M, Middeldorp C, Millwood I, Mohlke KL, Mook Kanamori DO, Murray JC, Nivard M, Nohr EA, Ntalla I, Oken E, Ong KK, O'Reilly PF, Palmer LJ, Panoutsopoulou K, Pararajasingham J, Pearson ER, Pennell CE, Power C, Price TS, Prokopenko I, Raitakari OT, Rodriguez A, Salem RM, Saw SM, Scherag A, Sebert S, Siitonen N, Simell O, Sørensen TI, Sovio U, Pourcain BS, Strachan DP, Sunyer J, Taal HR, Teo YY, Thiering E, Tiesler C, Timpson NJ, Uitterlinden AG, Valcárcel B, Warrington NM, White S, Widén E, Willemsen G, Wilson JF, Yaghootkar H, Zeggini E, Elks CE, Perry JR, Sulem P, Chasman DI, Franceschini N, He C, Lunetta KL, Visser JA, Byrne EM, Gudbjartsson DF, Esko T, Koller DL, Kutalik Z, Lin P, Mangino M, Marongiu M, McArdle PF, Smith AV, Stolk L, van Wingerden SH, Zhao JH, Albrecht E, Corre T, Ingelsson E, Hayward C, Magnusson PK, Smith EN, Ulivi S, Warrington M, Zgaga L, Alavere H, Amin N, Aspelund T, Bandinelli S, Barroso I, Berenson GS, Bergmann S, Blackburn H, Boerwinkle E, Buring JE, Busonero F, Campbell H, Chanock SJ, Chen W, Cornelis MC, Couper D, Coviello AD, de Faire U, de Geus EJ, Deloukas P, Döring A, Davey Smith G, Easton DF, Eiriksdottir G, Emilsson V, Eriksson J, Ferrucci L, Folsom AR, Foroud T, Garcia M, GASPARINI, PAOLO, Gieger C, Gudnason V, Hall P, Hankinson SE, Ferreli L, Heath AC, Hernandez DG, Hofman A, Hu FB, Illig T, Järvelin MR, Johnson AD, Karasik D, Khaw KT, Kiel DP, Kolcic I, Kraft P, Launer LJ, Laven JS, Li S, Liu J, Levy D, Martin NG, McArdle WL, Mooser V, Murray SS, Nalls MA, Navarro P, Nelis M, Ness AR, Northstone K, Oostra BA, Peacock M, Palotie A, Paré G, Parker AN, Pedersen NL, Peltonen L, Pharoah P, Polasek O, Plump AS, Pouta A, Porcu E, Rafnar T, Rice JP, Ring SM, Rivadeneira F, Rudan I, Sala C, Salomaa V, Sanna S, Schlessinger D, Schork NJ, Scuteri A, Segrè AV, Shuldiner AR, Soranzo N, Srinivasan SR, Tammesoo ML, Tikkanen E, Toniolo D, Tsui K, Tryggvadottir L, Tyrer J, Uda M, van Dam RM, van Meurs JB, Vollenweider P, Waeber G, Wareham NJ, Waterworth DM, Weedon MN, Wichmann HE, Wright AF, Young L, Zhai G, Zhuang WV, Bierut LJ, Boyd HA, Crisponi L, Demerath EW, van Duijn CM, Econs MJ, Harris TB, Hunter DJ, Loos RJ, Metspalu A, Montgomery GW, Ridker PM, Spector TD, Streeten EA, Stefansson K, Thorsteinsdottir U, Widen E, Murabito JM, Murray A., D'ADAMO, ADAMO PIO, Cousminer, Diana L, Berry, Diane J, Timpson, Nicholas J, Ang, Wei, Hyppönen, Elina, Widen, Elisabéth, ReproGen Consortium, Early Growth Genetics (EGG) Consortium, Pediatrics, Epidemiology, Internal Medicine, D. L., Cousminer, D. J., Berry, N. J., Timpson, W., Ang, E., Thiering, E. M., Byrne, H. R., Taal, V., Huikari, J. P., Bradfield, M., Kerkhof, M. M., Groen Blokhui, E., Kreiner Moller, M., Marinelli, C., Holst, J. T., Leinonen, J. R. B., Perry, I., Surakka, O., Pietilainen, J., Kettunen, V., Anttila, M., Kaakinen, U., Sovio, A., Pouta, S., Da, V., Lagou, C., Power, I., Prokopenko, D. M., Evan, J. P., Kemp, B., St Pourcain, S., Ring, A., Palotie, E., Kajantie, C., Osmond, T., Lehtimaki, J. S., Viikari, M., Kahonen, N. M., Warrington, S. J., Lye, L. J., Palmer, C. M. T., Tiesler, C., Flexeder, G. W., Montgomery, S. E., Medland, A., Hofman, H., Hakonarson, M., Guxen, M., Bartel, V., Salomaa, J. M., Murabito, J., Kaprio, T. I. A., Sorensen, F., Ballester, H., Bisgaard, D. I., Boomsma, G. H., Koppelman, S. F. A., Grant, V. W. V., Jaddoe, N. G., Martin, J., Heinrich, C. E., Pennell, O. T., Raitakari, J. G., Eriksson, G. D., Smith, E., Hypponen, M. R., Jarvelin, M. I., Mccarthy, S., Ripatti, E., Widen, Adair, L, Ang, W, Atalay, M, van Beijsterveldt, T, Bergen, N, Benke, K, Berry, Dj, Boomsma, Di, Bradfield, Jp, Charoen, P, Coin, L, Cooper, C, Cousminer, Dl, Das, S, Davis, O, Dedoussis, Gv, Elliott, P, Estivill, X, Evans, Dm, Feenstra, B, Flexeder, C, Frayling, T, Freathy, Rm, Gaillard, R, Geller, F, Gillman, M, Grant, Sf, Groen Blokhuis, M, Goh, Lk, Guxens, M, Hakonarson, H, Hattersley, At, Haworth, Cm, Hadley, D, Hedebrand, J, Heinrich, J, Hinney, A, Hirschhorn, Jn, Hocher, B, Holloway, Jw, Holst, C, Hottenga, Jj, Horikoshi, M, Huikari, V, Hypponen, E, Iñiguez, C, Jaddoe, Vw, Jarvelin, Mr, Kaakinen, M, Kilpeläinen, To, Kirin, M, Kowgier, M, Lakka, Hm, Lakka, Ta, Lange, La, Lawlor, Da, Lehtimäki, T, Lewin, A, Lindgren, C, Lindi, V, Maggi, R, Marsh, J, Mccarthy, Mi, Melbye, M, Middeldorp, C, Millwood, I, Mohlke, Kl, Mook Kanamori, Do, Murray, Jc, Nivard, M, Nohr, Ea, Ntalla, I, Oken, E, Ong, Kk, O'Reilly, Pf, Palmer, Lj, Panoutsopoulou, K, Pararajasingham, J, Pearson, Er, Pennell, Ce, Power, C, Price, T, Prokopenko, I, Raitakari, Ot, Rodriguez, A, Salem, Rm, Saw, Sm, Scherag, A, Sebert, S, Siitonen, N, Simell, O, Sørensen, Ti, Sovio, U, Pourcain, B, Strachan, Dp, Sunyer, J, Taal, Hr, Teo, Yy, Thiering, E, Tiesler, C, Timpson, Nj, Uitterlinden, Ag, Valcárcel, B, Warrington, Nm, White, S, Widén, E, Willemsen, G, Wilson, Jf, Yaghootkar, H, Zeggini, E, Elks, Ce, Perry, Jr, Sulem, P, Chasman, Di, Franceschini, N, He, C, Lunetta, Kl, Visser, Ja, Byrne, Em, Gudbjartsson, Df, Esko, T, Koller, Dl, Kutalik, Z, Lin, P, Mangino, M, Marongiu, M, Mcardle, Pf, Smith, Av, Stolk, L, van Wingerden, Sh, Zhao, Jh, Albrecht, E, Corre, T, Ingelsson, E, Hayward, C, Magnusson, Pk, Smith, En, Ulivi, S, Warrington, M, Zgaga, L, Alavere, H, Amin, N, Aspelund, T, Bandinelli, S, Barroso, I, Berenson, G, Bergmann, S, Blackburn, H, Boerwinkle, E, Buring, Je, Busonero, F, Campbell, H, Chanock, Sj, Chen, W, Cornelis, Mc, Couper, D, Coviello, Ad, D'Adamo, ADAMO PIO, de Faire, U, de Geus, Ej, Deloukas, P, Döring, A, Davey Smith, G, Easton, Df, Eiriksdottir, G, Emilsson, V, Eriksson, J, Ferrucci, L, Folsom, Ar, Foroud, T, Garcia, M, Gasparini, Paolo, Gieger, C, Gudnason, V, Hall, P, Hankinson, Se, Ferreli, L, Heath, Ac, Hernandez, Dg, Hofman, A, Hu, Fb, Illig, T, Järvelin, Mr, Johnson, Ad, Karasik, D, Khaw, Kt, Kiel, Dp, Kolcic, I, Kraft, P, Launer, Lj, Laven, J, Li, S, Liu, J, Levy, D, Martin, Ng, Mcardle, Wl, Mooser, V, Murray, S, Nalls, Ma, Navarro, P, Nelis, M, Ness, Ar, Northstone, K, Oostra, Ba, Peacock, M, Palotie, A, Paré, G, Parker, An, Pedersen, Nl, Peltonen, L, Pharoah, P, Polasek, O, Plump, A, Pouta, A, Porcu, E, Rafnar, T, Rice, Jp, Ring, Sm, Rivadeneira, F, Rudan, I, Sala, C, Salomaa, V, Sanna, S, Schlessinger, D, Schork, Nj, Scuteri, A, Segrè, Av, Shuldiner, Ar, Soranzo, N, Srinivasan, Sr, Tammesoo, Ml, Tikkanen, E, Toniolo, D, Tsui, K, Tryggvadottir, L, Tyrer, J, Uda, M, van Dam, Rm, van Meurs, Jb, Vollenweider, P, Waeber, G, Wareham, Nj, Waterworth, Dm, Weedon, Mn, Wichmann, He, Wright, Af, Young, L, Zhai, G, Zhuang, Wv, Bierut, Lj, Boyd, Ha, Crisponi, L, Demerath, Ew, van Duijn, Cm, Econs, Mj, Harris, Tb, Hunter, Dj, Loos, Rj, Metspalu, A, Montgomery, Gw, Ridker, Pm, Spector, Td, Streeten, Ea, Stefansson, K, Thorsteinsdottir, U, Widen, E, Murabito, Jm, Murray, A., Hedebrand, Johannes (Beitragende*r), Hinney, Anke (Beitragende*r), Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, Neuroscience Campus Amsterdam - Brain Imaging Technology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Faculteit Medische Wetenschappen/UMCG, Groningen Research Institute of Pharmacy, and Groningen Research Institute for Asthma and COPD (GRIAC)

Subjects
Male, Netherlands Twin Register (NTR), Genetic Linkage, Medizin, Gene Expression, Genome-wide association study, VARIANTS, Body Mass Index, 0302 clinical medicine, genetic linkage, Transforming Growth Factor beta, Neoplasms, molecular biology, genetics, Child, Genetics (clinical), Adiposity, 2. Zero hunger, 0303 health sciences, adiposity, Mitogen-Activated Protein Kinase 3, Association Studies Articles, Age Factors, ACHONDROPLASIA, General Medicine, Genome-Wide Association Study, pubertal height growth, pubertal timing, Phenotype, OBESITY, Menarche, body height, Female, Signal Transduction, medicine.medical_specialty, age factors, CHROMOSOME 16P11.2, Adolescent, BIRTH, Quantitative Trait Loci, 030209 endocrinology & metabolism, Context (language use), Biology, Childhood obesity, MENARCHE, Young Adult, 03 medical and health sciences, AGE, SDG 3 - Good Health and Well-being, Prepuberty, Internal medicine, Genetics, medicine, Humans, Molecular Biology, 030304 developmental biology, Sign, FACTOR RECEPTOR-3, MUTATIONS, Puberty, ta3121, medicine.disease, Obesity, Body Height, Genetic architecture, Endocrinology, POPULATION COHORT, gene expression, Body mass index, Follow-Up Studies
Abstract

The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P

Published
2013
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10. Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity

Author

François Pattou, Robert Sladek, Flore Zufferey, Matthias Nauck, Kari Stefansson, Unnur Thorsteinsdottir, Robin G. Walters, Katrin Männik, Tõnu Esko, Sébastien Jacquemont, Peter Vollenweider, Jaana Laitinen, Adam J. de Smith, Claudia Schurmann, Danielle Martinet, Anna-Liisa Hartikainen, Gérard Waeber, David Meyre, Julia S. El-Sayed Moustafa, Armand Valsesia, Lachlan J. M. Coin, Philippe Froguel, Alexandra I. F. Blakemore, Henry Völzke, Marjo-Riitta Järvelin, Jacques S. Beckmann, Gudmar Thorleifsson, Aimo Ruokonen, Andres Metspalu, Paul Elliott, Beverley Balkau, and Medical Research Council (MRC)

Subjects
Male, False discovery rate, Heredity, Kinesins, lcsh:Medicine, Genome-wide association study, Adolescent Adult Aged Body Mass Index Child Child, Preschool *Chromosome Deletion Chromosomes, Human, Pair 16/*genetics Cohort Studies Female Forkhead Transcription Factors/genetics *Genetic Loci Genome-Wide Association Study Humans Kinesin/genetics Male Middle Aged Obesity/*genetics, Body Mass Index, Cohort Studies, HIDDEN-MARKOV MODEL, Missing heritability problem, WIDE ASSOCIATION, Copy-number variation, Child, lcsh:Science, Genetics, education.field_of_study, Multidisciplinary, Forkhead Transcription Factors, Kinesin, Genomics, Middle Aged, Child, Preschool, Cohort, Science & Technology - Other Topics, Medicine, Female, CHILDHOOD OBESITY, Chromosome Deletion, Research Article, Adult, CHROMOSOME 16P11.2, Adolescent, General Science & Technology, Clinical Research Design, Population, EARLY-ONSET, Biology, MD Multidisciplinary, Humans, COHORT, Obesity, education, SNP GENOTYPING DATA, Genetic Association Studies, COPY NUMBER VARIATION, Aged, Nutrition, Science & Technology, MULTIDISCIPLINARY SCIENCES, Complex Traits, lcsh:R, Computational Biology, Human Genetics, Odds ratio, BODY-MASS INDEX, CIRCULAR BINARY SEGMENTATION, Genetic Loci, Case-Control Studies, Genetics of Disease, Multiple comparisons problem, Structural Genomics, lcsh:Q, Chromosomes, Human, Pair 16, Genome-Wide Association Study
Abstract

The limited ability of common variants to account for the genetic contribution to complex disease has prompted searches for rare variants of large effect, to partly explain the 'missing heritability'. Analyses of genome-wide genotyping data have identified genomic structural variants (GSVs) as a source of such rare causal variants. Recent studies have reported multiple GSV loci associated with risk of obesity. We attempted to replicate these associations by similar analysis of two familial-obesity case-control cohorts and a population cohort, and detected GSVs at 11 out of 18 loci, at frequencies similar to those previously reported. Based on their reported frequencies and effect sizes (OR≥25), we had sufficient statistical power to detect the large majority (80%) of genuine associations at these loci. However, only one obesity association was replicated. Deletion of a 220 kb region on chromosome 16p11.2 has a carrier population frequency of 2×10(-4) (95% confidence interval [9.6×10(-5)-3.1×10(-4)]); accounts overall for 0.5% [0.19%-0.82%] of severe childhood obesity cases (P = 3.8×10(-10); odds ratio = 25.0 [9.9-60.6]); and results in a mean body mass index (BMI) increase of 5.8 kg.m(-2) [1.8-10.3] in adults from the general population. We also attempted replication using BMI as a quantitative trait in our population cohort; associations with BMI at or near nominal significance were detected at two further loci near KIF2B and within FOXP2, but these did not survive correction for multiple testing. These findings emphasise several issues of importance when conducting rare GSV association, including the need for careful cohort selection and replication strategy, accurate GSV identification, and appropriate correction for multiple testing and/or control of false discovery rate. Moreover, they highlight the potential difficulty in replicating rare CNV associations across different populations. Nevertheless, we show that such studies are potentially valuable for the identification of variants making an appreciable contribution to complex disease.

Published
2013

11. Reciprocal Effects on Neurocognitive and Metabolic Phenotypes in Mouse Models of 16p11.2 Deletion and Duplication Syndromes

Author

Maksym V. Kopanitsa, Claire Chevalier, Yann Herault, Belinda S. Cowling, Marie-France Champy, Thomas Arbogast, Abdel-Mouttalib Ouagazzal, Eugenia Migliavacca, Nurudeen O. Afinowi, Alexandre Reymond, Marie-Christine Birling, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Synome Ltd [Cambridge, Royaume-Uni], Babraham Research Campus [Cambridge, Royaume-Uni], Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Université de Lausanne = University of Lausanne (UNIL), French National Infrastructure for Mouse Phenogenomics (PHENOMIN), Institut Clinique de la Souris (ICS), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work has been supported by the National Centre for Scientific Research (CNRS), the French National Institute of Health and Medical Research (INSERM), the University of Strasbourg (UDS), the 'Centre Européen de Recherche en Biologie et en Médecine', the European commission (AnEUploidy project to YH, LSHG-CT-2006-037627) with a fellowship from the 'Fondation pour la Recherche Médicale' to TA (FDT20130928080). This study also received support from French state funds through the 'Agence Nationale de la Recherche' under the frame programmes 'Investissements d’Avenir' labelled ANR-10-IDEX-0002-02, ANR-10-LABX-0030-INRT, ANR-10-INBS-07 PHENOMIN as well as by grants from the Simons Foundation (SFARI274424), the Swiss National Science Foundation (31003A_160203 and CRSII33-133044) to AR, the EU FP7 large-scale integrated project GENCODYS (FP7-COLLABORATION PROJECT-2009-2.1.1‐1/241995) m to YH and MK and the INTERREG offensive Science program to YH., ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-10-INBS-0007,PHENOMIN,INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS(2010), European Project: 38928,ANEUPLOIDY, European Project: 241995,EC:FP7:HEALTH,FP7-HEALTH-2009-two-stage,GENCODYS(2010), Bodescot, Myriam, Initiative d'excellence - Par-delà les frontières, l'Université de Strasbourg - - UNISTRA2010 - ANR-10-IDEX-0002 - IDEX - VALID, Infrastructures - INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS - - PHENOMIN2010 - ANR-10-INBS-0007 - INBS - VALID, AnEUploidy: understanding the importance of gene dosage imbalance in human health using genetics, functional genomics and systems biology. - ANEUPLOIDY - 38928 - OLD, Genetic and Epigenetic Networks in Cognitive Dysfunction - GENCODYS - - EC:FP7:HEALTH2010-05-01 - 2015-04-30 - 241995 - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), and Université de Lausanne (UNIL)

Subjects
Social Sciences, Synaptic Transmission, Craniofacial Abnormalities, Transcriptome, Mice, Cognition, Learning and Memory, 0302 clinical medicine, SCHIZOPHRENIA, Psychology, GENE-EXPRESSION, Adiposity, Genetics & Heredity, Mammals, ADIPOCYTE DIFFERENTIATION, Behavior, Animal, Brain, Eukaryota, Penetrance, Phenotypes, Chromosome Deletion, CHROMOSOME 16P11.2, Locus (genetics), Weaning, Diet, High-Fat, 03 medical and health sciences, Memory, Genetics, Homologous chromosome, MICRODELETION, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Molecular Biology, Alleles, Ecology, Evolution, Behavior and Systematics, 0604 Genetics, Behavior, Science & Technology, Biological Locomotion, Organisms, Biology and Life Sciences, Chromosomes, Mammalian, Mice, Inbred C57BL, 030104 developmental biology, 030217 neurology & neurosurgery, Developmental Biology, Neuroscience, 0301 basic medicine, Cancer Research, Physiology, Hippocampus, Chromosome Duplication, Gene duplication, Medicine and Health Sciences, Genetics (clinical), Gene Rearrangement, Object Recognition, 2. Zero hunger, Animal Behavior, DE-NOVO CNVS, Syndrome, Animal Models, Arylsulfotransferase, Phenotype, Experimental Organism Systems, OBESITY, Vertebrates, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Life Sciences & Biomedicine, Research Article, lcsh:QH426-470, Mouse Models, Motor Activity, Biology, Research and Analysis Methods, Rodents, Model Organisms, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene, Nutrition, AUTISM SPECTRUM DISORDER, Gene Expression Profiling, Body Weight, Cognitive Psychology, Diet, lcsh:Genetics, Disease Models, Animal, SYNAPTIC-TRANSMISSION, Gene Expression Regulation, Amniotes, dup, Cognitive Science, RECOGNITION MEMORY, Perception, Zoology
Abstract

The 16p11.2 600 kb BP4-BP5 deletion and duplication syndromes have been associated with developmental delay; autism spectrum disorders; and reciprocal effects on the body mass index, head circumference and brain volumes. Here, we explored these relationships using novel engineered mouse models carrying a deletion (Del/+) or a duplication (Dup/+) of the Sult1a1-Spn region homologous to the human 16p11.2 BP4-BP5 locus. On a C57BL/6N inbred genetic background, Del/+ mice exhibited reduced weight and impaired adipogenesis, hyperactivity, repetitive behaviors, and recognition memory deficits. In contrast, Dup/+ mice showed largely opposite phenotypes. On a F1 C57BL/6N × C3B hybrid genetic background, we also observed alterations in social interaction in the Del/+ and the Dup/+ animals, with other robust phenotypes affecting recognition memory and weight. To explore the dosage effect of the 16p11.2 genes on metabolism, Del/+ and Dup/+ models were challenged with high fat and high sugar diet, which revealed opposite energy imbalance. Transcriptomic analysis revealed that the majority of the genes located in the Sult1a1-Spn region were sensitive to dosage with a major effect on several pathways associated with neurocognitive and metabolic phenotypes. Whereas the behavioral consequence of the 16p11 region genetic dosage was similar in mice and humans with activity and memory alterations, the metabolic defects were opposite: adult Del/+ mice are lean in comparison to the human obese phenotype and the Dup/+ mice are overweight in comparison to the human underweight phenotype. Together, these data indicate that the dosage imbalance at the 16p11.2 locus perturbs the expression of modifiers outside the CNV that can modulate the penetrance, expressivity and direction of effects in both humans and mice., Author Summary The 16p11.2 BP4-BP5 deletion and duplication syndromes are frequent copy number variants in humans, and are associated with developmental delay and autism spectrum disorders, with a reciprocal effect on head circumference and body mass index. Here we explored gene dosage effect in mouse models and found that the deletion and duplication induced opposite behavioral phenotypes. Notably, we observed that some behavioral phenotypes, such as social interaction, were sensitive to the genetic background. For the metabolism, the energy imbalance and adipocyte phenotypes were mirrored in the deletion and duplication carriers but opposite to the human phenotypes, the deletion mouse carriers were lean whereas the individuals with the deletion were obese. The main cause of the phenotypic features is the copy number variation of the 16p11.2 region with many genetic pathways altered in the striatum and the liver. Thus the final consequences of the rearrangement are likely governed by the interplay between many cellular pathways in both human cases and mouse models.

Published
2016
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12. Extending the phenotype of recurrent rearrangements of 16p11.2: Deletions in mentally retarded patients without autism and in normal individuals

Author

L.A. Pérez Jurado, Ann Oostra, D. E. Fransen van de Putte, Pablo Lapunzina, Bart Loeys, B. Delle Chiaie, Marjolijn C.J. Jongmans, Johanna Lundin, K. T. Verbruggen, Rolph Pfundt, Emilia K. Bijlsma, Björn Menten, Birgit Sikkema-Raddatz, H.M. Reeser, David J. Amor, Claudia A. L. Ruivenkamp, Helene Verhelst, A. van Haeringen, Britt-Marie Anderlid, Roel Hordijk, Damien L. Bruno, Antoinet C.J. Gijsbers, Martijn H. Breuning, A. J. van Essen, Janneke H M Schuurs-Hoeijmakers, and Faculteit Medische Wetenschappen/UMCG

Subjects
Male, MICRODUPLICATION 22Q11.2, Genetics and epigenetic pathways of disease [NCMLS 6], DNA Mutational Analysis, Microdeletion syndrome, Heritability of autism, Copy-number variation, Child, Genetics (clinical), Genetics, Comparative Genomic Hybridization, medicine.diagnostic_test, Learning Disabilities, General Medicine, Child, Preschool, Female, Chromosome Deletion, Haploinsufficiency, Adult, Adolescent, DISORDERS, Chromosome 16p11.2, Variable phenotype, Speech Disorders, Genomic disorders and inherited multi-system disorders [IGMD 3], Young Adult, Intellectual Disability, medicine, Humans, Abnormalities, Multiple, MICRODELETION, Genetic Testing, Autistic Disorder, Genetic testing, Family Health, business.industry, Infant, medicine.disease, POLYMORPHISM, MICROARRAYS, Developmental disorder, DISCOVERY, Autism, business, LEUKEMIA, RETARDATION, Chromosomes, Human, Pair 16, Comparative genomic hybridization
Abstract

Pérez-Jurado, Luis A. [et al.], Array CGH (comparative genomic hybridization) screening of large patient cohorts with mental retardation and/or multiple congenital anomalies (MR/MCA) has led to the identification of a number of new microdeletion and microduplication syndromes. Recently, a recurrent copy number variant (CNV) at chromosome 16p11.2 was reported to occur in up to 1% of autistic patients in three large autism studies. In the screening of 4284 patients with MR/MCA with various array platforms, we detected 22 individuals (14 index patients and 8 family members) with deletions in 16p11.2, which are genomically identical to those identified in the autism studies. Though some patients shared a facial resemblance and a tendency to overweight, there was no evidence for a recognizable phenotype. Autism was not the presenting feature in our series. The assembled evidence indicates that recurrent 16p11.2 deletions are associated with variable clinical outcome, most likely arising from haploinsufficiency of one or more genes. The phenotypical spectrum ranges from MR and/or MCA, autism, learning and speech problems, to a normal phenotype. © 2009 Elsevier Masson SAS. All rights reserved.

Published
2009

13. Sequencing of the TBX6 Gene in Families with Familial Idiopathic Scoliosis.

Author

Baschal EE, Swindle K, Justice CM, Baschal RM, Perera A, Wethey CI, Poole A, Pourquié O, Tassy O, and Miller NH

Abstract

Study Design: A hypothesis-driven study was conducted in a familial cohort to determine the potential association between variants within the TBX6 gene and Familial Idiopathic Scoliosis (FIS)., Objective: To determine if variants within exons of the TBX6 gene segregate with the FIS phenotype within a sample of families with FIS., Summary of Background Data: Idiopathic Scoliosis (IS) is a structural curvature of the spine whose underlying genetic etiology has not been established. IS has been reported to occur at a higher rate than expected in family members of individuals with congenital scoliosis (CS), suggesting that the two diseases might have a shared etiology. The TBX6 gene on chromosome 16p, essential to somite development, has been associated with CS in a Chinese population. Previous studies have identified linkage to this locus in families with FIS, and specifically with rs8060511, located in an intron of the TBX6 gene., Methods: Parent-offspring trios from 11 families (13 trios, 42 individuals) with FIS were selected for Sanger sequencing of the TBX6 gene. Trios were selected from a large population of families with FIS in which a genome-wide scan had resulted in linkage to 16p., Results: Sequencing analyses of the subset of families resulted in the identification of five coding variants. Three of the five variants were novel; the remaining two variants were previously characterized and account for 90% of the observed variants in these trios. In all cases, there was no correlation between transmission of the TBX6 variant allele and FIS phenotype. However, an analysis of regulatory markers in osteoblasts showed that rs8060511 is in a putative enhancer element., Conclusions: Although this study did not identify any TBX6 coding variants that segregate with FIS, we identified a variant that is located in a potential TBX6 enhancer element. Therefore, further investigation of the region is needed.

Published
2015
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