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1. Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders

Author

Stray-Pedersen, Asbjørg, Sorte, Hanne Sørmo, Samarakoon, Pubudu, Gambin, Tomasz, Chinn, Ivan K, Akdemir, Zeynep H Coban, Erichsen, Hans Christian, Forbes, Lisa R, Gu, Shen, Yuan, Bo, Jhangiani, Shalini N, Muzny, Donna M, Rødningen, Olaug Kristin, Sheng, Ying, Nicholas, Sarah K, Noroski, Lenora M, Seeborg, Filiz O, Davis, Carla M, Canter, Debra L, Mace, Emily M, Vece, Timothy J, Allen, Carl E, Abhyankar, Harshal A, Boone, Philip M, Beck, Christine R, Wiszniewski, Wojciech, Fevang, Børre, Aukrust, Pål, Tjønnfjord, Geir E, Gedde-Dahl, Tobias, Hjorth-Hansen, Henrik, Dybedal, Ingunn, Nordøy, Ingvild, Jørgensen, Silje F, Abrahamsen, Tore G, Øverland, Torstein, Bechensteen, Anne Grete, Skogen, Vegard, Osnes, Liv TN, Kulseth, Mari Ann, Prescott, Trine E, Rustad, Cecilie F, Heimdal, Ketil R, Belmont, John W, Rider, Nicholas L, Chinen, Javier, Cao, Tram N, Smith, Eric A, Caldirola, Maria Soledad, Bezrodnik, Liliana, Reyes, Saul Oswaldo Lugo, Rosales, Francisco J Espinosa, Guerrero-Cursaru, Nina Denisse, Pedroza, Luis Alberto, Poli, Cecilia M, Franco, Jose L, Vargas, Claudia M Trujillo, Becerra, Juan Carlos Aldave, Wright, Nicola, Issekutz, Thomas B, Issekutz, Andrew C, Abbott, Jordan, Caldwell, Jason W, Bayer, Diana K, Chan, Alice Y, Aiuti, Alessandro, Cancrini, Caterina, Holmberg, Eva, West, Christina, Burstedt, Magnus, Karaca, Ender, Yesil, Gözde, Artac, Hasibe, Bayram, Yavuz, Atik, Mehmed Musa, Eldomery, Mohammad K, Ehlayel, Mohammad S, Jolles, Stephen, Flatø, Berit, Bertuch, Alison A, Hanson, I Celine, Zhang, Victor W, Wong, Lee-Jun, Hu, Jianhong, Walkiewicz, Magdalena, Yang, Yaping, Eng, Christine M, Boerwinkle, Eric, Gibbs, Richard A, Shearer, William T, Lyle, Robert, Orange, Jordan S, and Lupski, James R

Subjects
Biomedical and Clinical Sciences, Immunology, Human Genome, Prevention, Clinical Research, Genetic Testing, Genetics, Rare Diseases, 2.1 Biological and endogenous factors, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Aetiology, Good Health and Well Being, Adolescent, Adult, Aged, Child, Child, Preschool, DNA Copy Number Variations, Female, Genomics, High-Throughput Nucleotide Sequencing, Humans, Immunologic Deficiency Syndromes, Infant, Male, Middle Aged, Young Adult, Primary immunodeficiency disease, whole-exome sequencing, copy number variants, Allergy
Abstract

BackgroundPrimary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions.ObjectiveWe sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs.MethodsPatients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping.ResultsA likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays.ConclusionThis high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.

Published
2017

2. Mechanisms for Complex Chromosomal Insertions.

Author

Gu, Shen, Szafranski, Przemyslaw, Akdemir, Zeynep Coban, Yuan, Bo, Cooper, Mitchell L., Magriñá, Maria A., Bacino, Carlos A., Lalani, Seema R., Breman, Amy M., Smith, Janice L., Patel, Ankita, Song, Rodger H., Bi, Weimin, Cheung, Sau Wai, Carvalho, Claudia M. B., Stankiewicz, Paweł, and Lupski, James R.

Subjects
*CHROMOSOMES, *IN situ hybridization, *CHROMOSOMAL rearrangement, *DNA copy number variations, *HIGH-density lipoprotein receptors
Abstract

Chromosomal insertions are genomic rearrangements with a chromosome segment inserted into a non-homologous chromosome or a non-adjacent locus on the same chromosome or the other homologue, constituting ~2% of nonrecurrent copy-number gains. Little is known about the molecular mechanisms of their formation. We identified 16 individuals with complex insertions among 56,000 individuals tested at Baylor Genetics using clinical array comparative genomic hybridization (aCGH) and fluorescence in situ hybridization (FISH). Custom high-density aCGH was performed on 10 individuals with available DNA, and breakpoint junctions were fine-mapped at nucleotide resolution by long-range PCR and DNA sequencing in 6 individuals to glean insights into potential mechanisms of formation. We observed microhomologies and templated insertions at the breakpoint junctions, resembling the breakpoint junction signatures found in complex genomic rearrangements generated by replication-based mechanism(s) with iterative template switches. In addition, we analyzed 5 families with apparently balanced insertion in one parent detected by FISH analysis and found that 3 parents had additional small copy-number variants (CNVs) at one or both sides of the inserting fragments as well as at the inserted sites. We propose that replicative repair can result in interchromosomal complex insertions generated through chromothripsis-like chromoanasynthesis involving two or three chromosomes, and cause a significant fraction of apparently balanced insertions harboring small flanking CNVs. [ABSTRACT FROM AUTHOR]

Published
2016
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3. Hutterite-type cataract maps to chromosome 6p21.32-p21.31, cosegregates with a homozygous mutation in LEMD2, and is associated with sudden cardiac death.

Author

Boone, Philip M., Yuan, Bo, Gu, Shen, Ma, Zhiwei, Gambin, Tomasz, Gonzaga‐Jauregui, Claudia, Jain, Mahim, Murdock, Todd J., White, Janson J., Jhangiani, Shalini N., Walker, Kimberly, Wang, Qiaoyan, Muzny, Donna M., Gibbs, Richard A., Hejtmancik, J. Fielding, Lupski, James R., Posey, Jennifer E., and Lewis, Richard A.

Subjects
CATARACT, CATARACT in children, EXOMES, MISSENSE mutation, POINT mutation (Biology), GENETICS
Abstract

Background Juvenile-onset cataracts are known among the Hutterites of North America. Despite being identified over 30 years ago, this autosomal recessive condition has not been mapped, and the disease gene is unknown. Methods We performed whole exome sequencing of three Hutterite-type cataract trios and follow-up genotyping and mapping in four extended kindreds. Results Trio exomes enabled genome-wide autozygosity mapping, which localized the disease gene to a 9.5-Mb region on chromosome 6p. This region contained two candidate variants, LEMD2 c.T38G and MUC21 c.665delC. Extended pedigrees recruited for variant genotyping revealed multiple additional relatives with juvenile-onset cataract, as well as six deceased relatives with both cataracts and sudden cardiac death. The candidate variants were genotyped in 84 family members, including 17 with cataracts; only the variant in LEMD2 cosegregated with cataracts ( LOD = 9.62). SNP-based fine mapping within the 9.5 Mb linked region supported this finding by refining the cataract locus to a 0.5- to 2.9-Mb subregion (6p21.32-p21.31) containing LEMD2 but not MUC21. LEMD2 is expressed in mouse and human lenses and encodes a LEM domain-containing protein; the c.T38G missense mutation is predicted to mutate a highly conserved residue within this domain (p.Leu13Arg). Conclusion We performed a genetic and genomic study of Hutterite-type cataract and found evidence for an association of this phenotype with sudden cardiac death. Using combined genetic and genomic approaches, we mapped cataracts to a small portion of chromosome 6 and propose that they result from a homozygous missense mutation in LEMD2. [ABSTRACT FROM AUTHOR]

Published
2016
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4. Molecular Mechanisms of Regulation and Action of microRNA-199a in Testicular Germ Cell Tumor and Glioblastomas.

Author

Gu, Shen, Cheung, Hoi Hung, Lee, Tin Lap, Lu, Gang, Poon, Wai Sang, and Chan, Wai Yee

Subjects
*MOLECULAR biology, *MICRORNA, *GENETIC regulation, *GERM cell tumors, *GLIOBLASTOMA multiforme, *LOCUS (Genetics)
Abstract

MicroRNA-199a (miRNA-199a) has been shown to have comprehensive functions and behave differently in different systems and diseases. It is encoded by two loci in the human genome, miR-199a-1 in chromosome 19 and miR-199a-2 in chromosome 1. Both loci give rise to the same miRNAs (miR-199a-5p and miR-199a-3p). The cause of the diverse action of the miRNA in different systems is not clear. However, it is likely due to different regulation of the two genomic loci and variable targets of the miRNA in different cells and tissues. Here we studied promoter methylation of miR-199a in testicular germ cell tumors (TGCTs) and glioblastomas (gliomas) and discovered that hypermethylation in TGCTs of both miR-199a-1 and -2 resulted in its reduced expression, while hypomethylation of miR-199a-2 but not -1 in gliomas may be related to its elevated expression. We also identified a common regulator, REST, which preferentially bound to the methylated promoters of both miR-199a-1 and miR-199a-2. The action of miR-199a is dependent on its downstream targets. We identified MAFB as a putative target of miRNA-199a-5p in TGCTs and confirmed that the tumor suppression activity of the microRNA is mediated by its target MAFB. By studying the mechanisms that control the expressions of miR-199a and its various downstream targets, we hope to use miR-199a as a model to understand the complexity of miRNA biology. [ABSTRACT FROM AUTHOR]

Published
2013
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5. Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics

Author

Loviglio, Maria Nicla, Beck, Christine R., White, Janson J., Leleu, Marion, Harel, Tamar, Guex, Nicolas, Niknejad, Anne, Bi, Weimin, Chen, Edward S., Crespo, Isaac, Yan, Jiong, Charng, Wu-Lin, Gu, Shen, Fang, Ping, Coban-Akdemir, Zeynep, Shaw, Chad A., Jhangiani, Shalini N., Muzny, Donna M., Gibbs, Richard A., Rougemont, Jacques, Xenarios, Ioannis, Lupski, James R., and Reymond, Alexandre

Subjects
Male, Text mining, lcsh:QH426-470, Intellectual disability, lcsh:Medicine, Real-Time Polymerase Chain Reaction, Disease network, Mice, Genetics, Animals, Humans, Exome, Gene Regulatory Networks, Chromatin conformation, Diagnostic, Genetics(clinical), RNA, Messenger, Molecular Biology, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Research, lcsh:R, Genomics, Embryo, Mammalian, Mice, Inbred C57BL, lcsh:Genetics, Phenotype, Mutation, Trans-Activators, Molecular Medicine, Female, Smith-Magenis Syndrome, Transcriptome, Transcription Factors
Abstract

Background Smith-Magenis syndrome (SMS) is a developmental disability/multiple congenital anomaly disorder resulting from haploinsufficiency of RAI1. It is characterized by distinctive facial features, brachydactyly, sleep disturbances, and stereotypic behaviors. Methods We investigated a cohort of 15 individuals with a clinical suspicion of SMS who showed neither deletion in the SMS critical region nor damaging variants in RAI1 using whole exome sequencing. A combination of network analysis (co-expression and biomedical text mining), transcriptomics, and circularized chromatin conformation capture (4C-seq) was applied to verify whether modified genes are part of the same disease network as known SMS-causing genes. Results Potentially deleterious variants were identified in nine of these individuals using whole-exome sequencing. Eight of these changes affect KMT2D, ZEB2, MAP2K2, GLDC, CASK, MECP2, KDM5C, and POGZ, known to be associated with Kabuki syndrome 1, Mowat-Wilson syndrome, cardiofaciocutaneous syndrome, glycine encephalopathy, mental retardation and microcephaly with pontine and cerebellar hypoplasia, X-linked mental retardation 13, X-linked mental retardation Claes-Jensen type, and White-Sutton syndrome, respectively. The ninth individual carries a de novo variant in JAKMIP1, a regulator of neuronal translation that was recently found deleted in a patient with autism spectrum disorder. Analyses of co-expression and biomedical text mining suggest that these pathologies and SMS are part of the same disease network. Further support for this hypothesis was obtained from transcriptome profiling that showed that the expression levels of both Zeb2 and Map2k2 are perturbed in Rai1 –/– mice. As an orthogonal approach to potentially contributory disease gene variants, we used chromatin conformation capture to reveal chromatin contacts between RAI1 and the loci flanking ZEB2 and GLDC, as well as between RAI1 and human orthologs of the genes that show perturbed expression in our Rai1 –/– mouse model. Conclusions These holistic studies of RAI1 and its interactions allow insights into SMS and other disorders associated with intellectual disability and behavioral abnormalities. Our findings support a pan-genomic approach to the molecular diagnosis of a distinctive disorder. Electronic supplementary material The online version of this article (doi:10.1186/s13073-016-0359-z) contains supplementary material, which is available to authorized users.

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6. The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance

Author

Maja Hempel, Jennifer E. Posey, Yavuz Bayram, Eric Boerwinkle, Katta M. Girisha, Ender Karaca, Timur Yildirim, Anju Shukla, Jaya Punetha, Ilhan A. Bayhan, Harsha Doddapaneni, Christopher M. Grochowski, Davut Gul, Aysegul Bursali, Davut Pehlivan, Elif Yilmaz Gulec, Richard A. Gibbs, Zeynep Ocak, Jawid M Fatih, Ibrahim Sahin, Gozde Yesil, Burhan Balta, Onur Yildiz, Alper Gezdirici, Tatjana Bierhals, James R. Lupski, Zafer Yüksel, Hatice Mutlu Albayrak, Donna M. Muzny, Jianhong Hu, Fatma Silan, Zeynep Coban Akdemir, Shen Gu, Öztürk Özdemir, Haktan Bağış Erdem, Periyasamy Radhakrishnan, Burcu Tabakci, Beyhan Tüysüz, Nilay Güneş, Shalini N. Jhangiani, Osman Yeşilbaş, Yavuz Sahin, Nursel Elcioglu, Muhsin Elmas, Konstantinos Tsiakas, Sedat Isikay, Pehlivan, Davut, Bayram, Yavuz, Gunes, Nilay, Akdemir, Zeynep Coban, Shukla, Anju, Bierhals, Tatjana, Tabakci, Burcu, Sahin, Yavuz, Gezdirici, Alper, Fatih, Jawid M., Gulec, Elif Yilmaz, Yesil, Gozde, Punetha, Jaya, Ocak, Zeynep, Grochowski, Christopher M., Karaca, Ender, Albayrak, Hatice Mutlu, Radhakrishnan, Periyasamy, Erdem, Haktan Bagis, Sahin, Ibrahim, Yildirim, Timur, Bayhan, Ilhan A., Bursali, Aysegul, Elmas, Muhsin, Yuksel, Zafer, Ozdemir, Ozturk, Silan, Fatma, Yildiz, Onur, Yesilbas, Osman, Isikay, Sedat, Balta, Burhan, Gu, Shen, Jhangiani, Shalini N., Doddapaneni, Harsha, Hu, Jianhong, Muzny, Donna M., Boerwinkle, Eric, Gibbs, Richard A., Tsiakas, Konstantinos, Hempel, Maja, Girisha, Katta Mohan, Gul, Davut, Posey, Jennifer E., Elcioglu, Nursel H., Tuysuz, Beyhan, Lupski, James R., HKÜ, Sağlık Bilimleri Fakültesi, Fizyoterapi ve Rehabilitasyon Bölümü, YEŞİL, Gözde, İÜC, Cerrahpaşa Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, and OMÜ

Subjects
Male, 0301 basic medicine, Multifactorial Inheritance, Candidate gene, Vesicular Transport Proteins, DE-NOVO, DISEASE, Cohort Studies, MYOPATHY, MULTIPLEX CONGENITA, SKELETAL-MUSCLE, MUTATIONS, PATIENT, FAT1, MECHANISMS, DELETION, 0302 clinical medicine, Candidate Genes and Further Evidence for Oligogenic Inheritance-, AMERICAN JOURNAL OF HUMAN GENETICS, cilt.105, ss.132-150, 2019 [Pehlivan D., Bayram Y., Gunes N., Akdemir Z. C. , Shukla A., Bierhals T., TABAKCI B., Sahin Y., Gezdirici A., Fatih J. M. , et al., -The Genomics of Arthrogryposis, a Complex Trait], Connectin, Copy-number variation, Child, Genetics (clinical), Exome sequencing, Arthrogryposis, Genetics, Mosaicism, Oligogenic Inheritance, Genomics, Pedigree, 3. Good health, Child, Preschool, Female, medicine.symptom, Adult, Genetic Markers, Adolescent, DNA Copy Number Variations, Gestational Age, Locus (genetics), Biology, Article, Young Adult, 03 medical and health sciences, Exome Sequencing, medicine, Humans, Genetic heterogeneity, Infant, Newborn, Infant, Ryanodine Receptor Calcium Release Channel, 030104 developmental biology, Mutation, 030217 neurology & neurosurgery, Comparative genomic hybridization
Abstract

Erdem, Haktan Bagis/0000-0002-4391-1387; Albayrak, Hatice Mutlu/0000-0001-5624-3878; isikay, sedat/0000-0003-0103-9612; Grochowski, Christopher/0000-0002-3884-7720; Gezdirici, Alper/0000-0002-2432-9279; KM, Girisha/0000-0002-0139-8239; Gu, Shen/0000-0003-3107-1218; YESIL, GOZDE/0000-0003-1964-6306; Gezdirici, Alper/0000-0002-2432-9279; Tuysuz, Beyhan/0000-0002-9620-5021; Fatih, Jawid/0000-0002-3927-2711; YUKSEL, Zafer/0000-0002-2085-5773; Balta, Burhan/0000-0003-2672-2493; Posey, Jennifer/0000-0003-4814-6765; Bayhan, Ilhan/0000-0001-8308-1309; Punetha, Jaya/0000-0002-6774-4464; YILDIRIM, Timur/0000-0003-0291-7632 WOS:000473723000011 PubMed ID: 31230720 Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members. National Human Genome Research Institute (NHGRI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [UM1 HG006542]; National Heart, Lung, and Blood Institute (NHLBI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [UM1 HG006542]; NHGRIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [K08 HG008986]; National Institutes of Health - Brain Disorders and Development Training Grant [T32 NS043124-17]; Clinical Research Training Scholarship in Neuromuscular Disease; Tubitak project, TurkeyTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [217S675]; Indian Council of Medical Research, New Delhi, IndiaIndian Council of Medical Research (ICMR) [5/13/58/2015/NCD-III]; [R35 NS105078]; [512848]; NATIONAL HUMAN GENOME RESEARCH INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI) [K08HG008986, UM1HG006542, K08HG008986, UM1HG006542, UM1HG006542, UM1HG006542, K08HG008986, UM1HG006542] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [R35NS105078, T32NS043124, T32NS043124, T32NS043124, R35NS105078, T32NS043124, T32NS043124, R35NS105078, T32NS043124, T32NS043124, T32NS043124, R35NS105078] Funding Source: NIH RePORTER This work was supported in part by R35 NS105078 and MDA#512848 to J.R.L. and a jointly funded National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute (NHLBI) grant to the Baylor-Hopkins Center for Mendelian Genomics (UM1 HG006542). J.E.P. is supported by NHGRI K08 HG008986. D.P. is supported by the National Institutes of Health - Brain Disorders and Development Training Grant (T32 NS043124-17) and a Clinical Research Training Scholarship in Neuromuscular Disease partnered by the American Brain Foundation (ABF) and Muscle Study Group (MSG). This study is partly funded by Tubitak project number 217S675, Turkey to N.E. and B.T.. This study is partly funded by Indian Council of Medical Research, New Delhi, India with File no.: No. 5/13/58/2015/NCD-III to A.S.

Published
2019

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