@article {526, title = {The coexistence of copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) at a locus can result in distorted calculations of the significance in associating SNPs to disease.}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Jul}, pages = {553-567}, abstract = {

With the recent advance in genome-wide association studies (GWAS), disease-associated single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) have been extensively reported. Accordingly, the issue of incorrect identification of recombination events that can induce the distortion of multi-allelic or hemizygous variants has received more attention. However, the potential distorted calculation bias or significance of a detected association in a GWAS due to the coexistence of CNVs and SNPs in the same genomic region may remain under-recognized. Here we performed the association study within a congenital scoliosis (CS) cohort whose genetic etiology was recently elucidated as a compound inheritance model, including mostly one rare variant deletion CNV null allele and one common variant non-coding hypomorphic haplotype of the TBX6 gene. We demonstrated that the existence of a deletion in TBX6 led to an overestimation of the contribution of the SNPs on the hypomorphic allele. Furthermore, we generalized a model to explain the calculation bias, or distorted significance calculation for an association study, that can be {\textquoteright}induced{\textquoteright} by CNVs at a locus. Meanwhile, overlapping between the disease-associated SNPs from published GWAS and common CNVs (overlap 10\%) and pathogenic/likely pathogenic CNVs (overlap 99.69\%) was significantly higher than the random distribution (p < 1 {\texttimes} 10 and p = 0.034, respectively), indicating that such co-existence of CNV and SNV alleles might generally influence data interpretation and potential outcomes of a GWAS. We also verified and assessed the influence of colocalizing CNVs to the detection sensitivity of disease-associated SNP variant alleles in another adolescent idiopathic scoliosis (AIS) genome-wide association study. We proposed that detecting co-existent CNVs when evaluating the association signals between SNPs and disease traits could improve genetic model analyses and better integrate GWAS with robust Mendelian principles.

}, keywords = {Adolescent, Congenital Abnormalities, DNA Copy Number Variations, Female, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Genomics, Genotype, Haplotypes, Humans, Phenotype, Polymorphism, Single Nucleotide, Scoliosis}, issn = {1432-1203}, doi = {10.1007/s00439-018-1910-3}, author = {Liu, Jiaqi and Zhou, Yangzhong and Liu, Sen and Song, Xiaofei and Yang, Xin-Zhuang and Fan, Yanhui and Chen, Weisheng and Akdemir, Zeynep Coban and Yan, Zihui and Zuo, Yuzhi and Du, Renqian and Liu, Zhenlei and Yuan, Bo and Zhao, Sen and Liu, Gang and Chen, Yixin and Zhao, Yanxue and Lin, Mao and Zhu, Qiankun and Niu, Yuchen and Liu, Pengfei and Ikegawa, Shiro and Song, You-Qiang and Posey, Jennifer E and Qiu, Guixing and Zhang, Feng and Wu, Zhihong and Lupski, James R and Wu, Nan} } @article {27, title = {Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.}, journal = {J Allergy Clin Immunol}, volume = {139}, year = {2017}, month = {2017 Jan}, pages = {232-245}, abstract = {

BACKGROUND: Primary 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.

OBJECTIVE: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs.

METHODS: Patients 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.

RESULTS: A 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.

CONCLUSION: This 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.

}, keywords = {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}, issn = {1097-6825}, doi = {10.1016/j.jaci.2016.05.042}, author = {Stray-Pedersen, Asbj{\o}rg and Sorte, Hanne S{\o}rmo and Samarakoon, Pubudu and Gambin, Tomasz and Chinn, Ivan K and Coban Akdemir, Zeynep H and Erichsen, Hans Christian and Forbes, Lisa R and Gu, Shen and Yuan, Bo and Jhangiani, Shalini N and Muzny, Donna M and R{\o}dningen, Olaug Kristin and Sheng, Ying and Nicholas, Sarah K and Noroski, Lenora M and Seeborg, Filiz O and Davis, Carla M and Canter, Debra L and Mace, Emily M and Vece, Timothy J and Allen, Carl E and Abhyankar, Harshal A and Boone, Philip M and Beck, Christine R and Wiszniewski, Wojciech and Fevang, B{\o}rre and Aukrust, P{\r a}l and Tj{\o}nnfjord, Geir E and Gedde-Dahl, Tobias and Hjorth-Hansen, Henrik and Dybedal, Ingunn and Nord{\o}y, Ingvild and J{\o}rgensen, Silje F and Abrahamsen, Tore G and {\O}verland, Torstein and Bechensteen, Anne Grete and Skogen, Vegard and Osnes, Liv T N and Kulseth, Mari Ann and Prescott, Trine E and Rustad, Cecilie F and Heimdal, Ketil R and Belmont, John W and Rider, Nicholas L and Chinen, Javier and Cao, Tram N and Smith, Eric A and Caldirola, Maria Soledad and Bezrodnik, Liliana and Lugo Reyes, Saul Oswaldo and Espinosa Rosales, Francisco J and Guerrero-Cursaru, Nina Denisse and Pedroza, Luis Alberto and Poli, Cecilia M and Franco, Jose L and Trujillo Vargas, Claudia M and Aldave Becerra, Juan Carlos and Wright, Nicola and Issekutz, Thomas B and Issekutz, Andrew C and Abbott, Jordan and Caldwell, Jason W and Bayer, Diana K and Chan, Alice Y and Aiuti, Alessandro and Cancrini, Caterina and Holmberg, Eva and West, Christina and Burstedt, Magnus and Karaca, Ender and Yesil, G{\"o}zde and Artac, Hasibe and Bayram, Yavuz and Atik, Mehmed Musa and Eldomery, Mohammad K and Ehlayel, Mohammad S and Jolles, Stephen and Flat{\o}, Berit and Bertuch, Alison A and Hanson, I Celine and Zhang, Victor W and Wong, Lee-Jun and Hu, Jianhong and Walkiewicz, Magdalena and Yang, Yaping and Eng, Christine M and Boerwinkle, Eric and Gibbs, Richard A and Shearer, William T and Lyle, Robert and Orange, Jordan S and Lupski, James R} } @article {170, title = {Alu-mediated diverse and complex pathogenic copy-number variants within human chromosome 17 at p13.3.}, journal = {Hum Mol Genet}, volume = {24}, year = {2015}, month = {2015 Jul 15}, pages = {4061-77}, abstract = {

Alu repetitive elements are known to be major contributors to genome instability by generating Alu-mediated copy-number variants (CNVs). Most of the reported Alu-mediated CNVs are simple deletions and duplications, and the mechanism underlying Alu-Alu-mediated rearrangement has been attributed to non-allelic homologous recombination (NAHR). Chromosome 17 at the p13.3 genomic region lacks extensive low-copy repeat architecture; however, it is highly enriched for Alu repetitive elements, with a fraction of 30\% of total sequence annotated in the human reference genome, compared with the 10\% genome-wide and 18\% on chromosome 17. We conducted mechanistic studies of the 17p13.3 CNVs by performing high-density oligonucleotide array comparative genomic hybridization, specifically interrogating the 17p13.3 region with \~{}150 bp per probe density; CNV breakpoint junctions were mapped to nucleotide resolution by polymerase chain reaction and Sanger sequencing. Studied rearrangements include 5 interstitial deletions, 14 tandem duplications, 7 terminal deletions and 13 complex genomic rearrangements (CGRs). Within the 17p13.3 region, Alu-Alu-mediated rearrangements were identified in 80\% of the interstitial deletions, 46\% of the tandem duplications and 50\% of the CGRs, indicating that this mechanism was a major contributor for formation of breakpoint junctions. Our studies suggest that Alu repetitive elements facilitate formation of non-recurrent CNVs, CGRs and other structural aberrations of chromosome 17 at p13.3. The common observation of Alu-mediated rearrangement in CGRs and breakpoint junction sequences analysis further demonstrates that this type of mechanism is unlikely attributed to NAHR, but rather may be due to a recombination-coupled DNA replicative repair process.

}, keywords = {Alleles, Alu Elements, Base Sequence, Chromosomes, Human, Pair 17, Comparative Genomic Hybridization, DNA Copy Number Variations, Female, Gene Duplication, Gene Rearrangement, Genome, Human, Genomic Instability, Genomics, Homologous Recombination, Humans, Male, Molecular Sequence Data, Segmental Duplications, Genomic, Sequence Deletion}, issn = {1460-2083}, doi = {10.1093/hmg/ddv146}, author = {Gu, Shen and Yuan, Bo and Campbell, Ian M and Beck, Christine R and Carvalho, Claudia M B and Nagamani, Sandesh C S and Erez, Ayelet and Patel, Ankita and Bacino, Carlos A and Shaw, Chad A and Stankiewicz, Pawe{\l} and Cheung, Sau Wai and Bi, Weimin and Lupski, James R} } @article {120, title = {Nonrecurrent 17p11.2p12 Rearrangement Events that Result in Two Concomitant Genomic Disorders: The PMP22-RAI1 Contiguous Gene Duplication Syndrome.}, journal = {Am J Hum Genet}, volume = {97}, year = {2015}, month = {2015 Nov 05}, pages = {691-707}, abstract = {

The genomic duplication associated with Potocki-Lupski syndrome (PTLS) maps in close proximity to the duplication associated with Charcot-Marie-Tooth disease type 1A (CMT1A). PTLS is characterized by hypotonia, failure to thrive, reduced body weight, intellectual disability, and autistic features. CMT1A is a common autosomal dominant distal symmetric peripheral polyneuropathy. The key dosage-sensitive genes RAI1 and PMP22 are respectively associated with PTLS and CMT1A. Recurrent duplications accounting for the majority of subjects with these conditions are mediated by nonallelic homologous recombination between distinct low-copy repeat (LCR) substrates. The LCRs flanking a contiguous genomic interval encompassing both RAI1 and PMP22 do not share extensive homology; thus, duplications encompassing both loci are rare and potentially generated by a different mutational mechanism. We characterized genomic rearrangements that simultaneously duplicate PMP22 and RAI1, including nine potential complex genomic rearrangements, in 23 subjects by high-resolution array comparative genomic hybridization and breakpoint junction sequencing. Insertions and microhomologies were found at the breakpoint junctions, suggesting potential replicative mechanisms for rearrangement formation. At the breakpoint junctions of these nonrecurrent rearrangements, enrichment of repetitive DNA sequences was observed, indicating that they might predispose to genomic instability and rearrangement. Clinical evaluation revealed blended PTLS and CMT1A phenotypes with a potential earlier onset of neuropathy. Moreover, additional clinical findings might be observed due to the extra duplicated material included in the rearrangements. Our genomic analysis suggests replicative mechanisms as a predominant mechanism underlying PMP22-RAI1 contiguous gene duplications and provides further evidence supporting the role of complex genomic architecture in genomic instability.

}, keywords = {Abnormalities, Multiple, Charcot-Marie-Tooth Disease, Child, Child, Preschool, Chromosome Disorders, Chromosome Duplication, Chromosomes, Human, Pair 17, Comparative Genomic Hybridization, Female, Follow-Up Studies, Gene Duplication, Gene Rearrangement, Genome, Human, Genomics, Humans, Infant, Male, Models, Genetic, Myelin Proteins, Phenotype, Prognosis, Recombination, Genetic, Transcription Factors}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.10.003}, author = {Yuan, Bo and Harel, Tamar and Gu, Shen and Liu, Pengfei and Burglen, Lydie and Chantot-Bastaraud, Sandra and Gelowani, Violet and Beck, Christine R and Carvalho, Claudia M B and Cheung, Sau Wai and Coe, Andrew and Malan, Val{\'e}rie and Munnich, Arnold and Magoulas, Pilar L and Potocki, Lorraine and Lupski, James R} } @article {229, title = {Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Aug 07}, pages = {173-82}, abstract = {

New human mutations are thought to originate in germ cells, thus making a recurrence of the same mutation in a sibling exceedingly rare. However, increasing sensitivity of genomic technologies has anecdotally revealed mosaicism for mutations in somatic tissues of apparently healthy parents. Such somatically mosaic parents might also have germline mosaicism that can potentially cause unexpected intergenerational recurrences. Here, we show that somatic mosaicism for transmitted mutations among parents of children with simplex genetic disease is more common than currently appreciated. Using the sensitivity of individual-specific breakpoint PCR, we prospectively screened 100 families with children affected by genomic disorders due to rare deletion copy-number variants (CNVs) determined to be de novo by clinical analysis of parental DNA. Surprisingly, we identified four cases of low-level somatic mosaicism for the transmitted CNV in DNA isolated from parental blood. Integrated probabilistic modeling of gametogenesis developed in response to our observations predicts that mutations in parental blood increase recurrence risk substantially more than parental mutations confined to the germline. Moreover, despite the fact that maternally transmitted mutations are the minority of alleles, our model suggests that sexual dimorphisms in gametogenesis result in a greater proportion of somatically mosaic transmitting mothers who are thus at increased risk of recurrence. Therefore, somatic mosaicism together with sexual differences in gametogenesis might explain a considerable fraction of unexpected recurrences of X-linked recessive disease. Overall, our results underscore an important role for somatic mosaicism and mitotic replicative mutational mechanisms in transmission genetics.

}, keywords = {Cell Division, DNA Copy Number Variations, Female, Gametogenesis, Genetic Diseases, Inborn, Genomics, Germ Cells, Germ-Line Mutation, Humans, Male, Models, Genetic, Mosaicism, Mutation, Pedigree, Prospective Studies, Recurrence, Risk, Sex Characteristics, Smith-Magenis Syndrome}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.07.003}, author = {Campbell, Ian M and Yuan, Bo and Robberecht, Caroline and Pfundt, Rolph and Szafranski, Przemyslaw and McEntagart, Meriel E and Nagamani, Sandesh C S and Erez, Ayelet and Bartnik, Magdalena and Wi{\'s}niowiecka-Kowalnik, Barbara and Plunkett, Katie S and Pursley, Amber N and Kang, Sung-Hae L and Bi, Weimin and Lalani, Seema R and Bacino, Carlos A and Vast, Mala and Marks, Karen and Patton, Michael and Olofsson, Peter and Patel, Ankita and Veltman, Joris A and Cheung, Sau Wai and Shaw, Chad A and Vissers, Lisenka E L M and Vermeesch, Joris R and Lupski, James R and Stankiewicz, Pawe{\l}} }