CNV Analysis in Monozygotic Twin Pairs Discordant for Urorectal Malformations

2013 ◽  
Vol 16 (4) ◽  
pp. 802-807 ◽  
Author(s):  
Friederike Baudisch ◽  
Markus Draaken ◽  
Enrika Bartels ◽  
Eberhard Schmiedeke ◽  
Soyhan Bagci ◽  
...  
Keyword(s):  
De Novo ◽  
Bladder Exstrophy ◽  
Anorectal Malformations ◽  
Monozygotic Twin ◽  
Regulatory Elements ◽  
Copy Number Variations ◽  
Molecular Karyotyping ◽  
Genetic Changes ◽  
Coding Regions ◽  
Whole Exome

Early post-twinning mutational events can account for discordant phenotypes in monozygotic (MZ) twin pairs. Such mutational events may comprise genomic alterations of different sizes, ranging from single nucleotides to large copy-number variations (CNVs). Anorectal malformations (ARM) and the bladder exstrophy-epispadias complex (BEEC) represent the most severe end of the urorectal malformation spectrum. Recently, CNV studies in patients with sporadic ARM and the BEEC have identified de novo events that occur in specific chromosomal regions. We hypothesized that early arising, post-twinning CNVs might contribute to discordance in MZ twin pairs with ARM or the BEEC; knowledge of such CNVs might help to identify additional chromosomal regions involved in the development of these malformations. We investigated four discordant MZ twin pairs (three ARM and one BEEC) using molecular karyotyping arrays comprising 1,140,419 markers with a median marker spacing of 1.5 kb. Filtering the coding regions for possible disease-causing post-twinning de novo CNVs present only in the affected twin, but not in the unaffected twin or the parents, identified a total of 136 CNVs. These 136 CNVs were then filtered against publicly available databases and finally re-evaluated visually. No potentially causative CNV remained after applying these filter criteria. Our results suggest that post-twinning CNV events that affect coding regions of the genome did not contribute to the discordant phenotypes in MZ twin pairs that we investigated. Possible causes for the discordant phenotypes include changes in regulatory elements or smaller genetic changes within coding regions which may be detectable by whole-exome sequencing.

scholarly journals Genomic alterations caused by HPV integration in a cohort of Chinese endocervical adenocarcinomas

2021 ◽  
Author(s):  
Wenhui Li ◽  
Wanjun Lei ◽  
Xiaopei Chao ◽  
Xiaochen Song ◽  
Yalan Bi ◽  
...  
Keyword(s):  
Copy Number ◽  
Somatic Mutations ◽  
Hpv Infection ◽  
Copy Number Variations ◽  
Cervical Adenocarcinoma ◽  
Structural Variations ◽  
Driver Genes ◽  
Genetic Changes ◽  
Genomic Changes ◽  
Whole Exome

AbstractThe association between human papillomavirus (HPV) integration and relevant genomic changes in uterine cervical adenocarcinoma is poorly understood. This study is to depict the genomic mutational landscape in a cohort of 20 patients. HPV+ and HPV− groups were defined as patients with and without HPV integration in the host genome. The genetic changes between these two groups were described and compared by whole-genome sequencing (WGS) and whole-exome sequencing (WES). WGS identified 2916 copy number variations and 743 structural variations. WES identified 6113 somatic mutations, with a mutational burden of 2.4 mutations/Mb. Six genes were predicted as driver genes: PIK3CA, KRAS, TRAPPC12, NDN, GOLGA6L4 and BAIAP3. PIK3CA, NDN, GOLGA6L4, and BAIAP3 were recognized as significantly mutated genes (SMGs). HPV was detected in 95% (19/20) of patients with cervical adenocarcinoma, 7 of whom (36.8%) had HPV integration (HPV+ group). In total, 1036 genes with somatic mutations were confirmed in the HPV+ group, while 289 genes with somatic mutations were confirmed in the group without HPV integration (HPV− group); only 2.1% were shared between the two groups. In the HPV+ group, GOLGA6L4 and BAIAP3 were confirmed as SMGs, while PIK3CA, NDN, KRAS, FUT1, and GOLGA6L64 were identified in the HPV− group. ZDHHC3, PKD1P1, and TGIF2 showed copy number amplifications after HPV integration. In addition, the HPV+ group had significantly more neoantigens. HPV integration rather than HPV infection results in different genomic changes in cervical adenocarcinoma.

scholarly journals Lessons Learned from CNV Analysis of Major Birth Defects

2020 ◽  
Vol 21 (21) ◽  
pp. 8247
Author(s):  
Alina Christine Hilger ◽  
Gabriel Clemens Dworschak ◽  
Heiko Martin Reutter
Keyword(s):  
Birth Defects ◽  
Copy Number ◽  
Congenital Malformations ◽  
De Novo ◽  
Copy Number Variations ◽  
Lessons Learned ◽  
Organ System ◽  
Molecular Karyotyping ◽  
The Past ◽  
Single Organ

The treatment of major birth defects are key concerns for child health. Hitherto, for the majority of birth defects, the underlying cause remains unknown, likely to be heterogeneous. The implicated mortality and/or reduced fecundity in major birth defects suggest a significant fraction of mutational de novo events among the affected individuals. With the advent of systematic array-based molecular karyotyping, larger cohorts of affected individuals have been screened over the past decade. This review discusses the identification of disease-causing copy-number variations (CNVs) among individuals with different congenital malformations. It highlights the differences in findings depending on the respective congenital malformation. It looks at the differences in findings of CNV analysis in non-isolated complex congenital malformations, associated with central nervous system malformations or intellectual disabilities, compared to isolated single organ-system malformations. We propose that the more complex an organ system is, and the more genes involved during embryonic development, the more likely it is that mutational de novo events, comprising CNVs, will confer to the expression of birth defects of this organ system.

scholarly journals Love the one you’re with: replicate viral adaptations converge on the same phenotypic change

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2227 ◽  
Author(s):  
Craig R. Miller ◽  
Anna C. Nagel ◽  
LuAnn Scott ◽  
Matt Settles ◽  
Paul Joyce ◽  
...  
Keyword(s):  
De Novo ◽  
Regulatory Elements ◽  
Host Cells ◽  
Phenotypic Change ◽  
De Novo Mutations ◽  
Promoter Mutation ◽  
Genetic Changes ◽  
Evolutionary Forces ◽  
Parallel Change ◽  
The One

Parallelism is important because it reveals how inherently stochastic adaptation is. Even as we come to better understand evolutionary forces, stochasticity limits how well we can predict evolutionary outcomes. Here we sought to quantify parallelism and some of its underlying causes by adapting a bacteriophage (ID11) with nine different first-step mutations, each with eight-fold replication, for 100 passages. This was followed by whole-genome sequencing five isolates from each endpoint. A large amount of variation arose—281 mutational events occurred representing 112 unique mutations. At least 41% of the mutations and 77% of the events were adaptive. Within wells, populations generally experienced complex interference dynamics. The genome locations and counts of mutations were highly uneven: mutations were concentrated in two regulatory elements and three genes and, while 103 of the 112 (92%) of the mutations were observed in ≤4 wells, a few mutations arose many times. 91% of the wells and 81% of the isolates had a mutation in the D-promoter. Parallelism was moderate compared to previous experiments with this system. On average, wells shared 27% of their mutations at the DNA level and 38% when the definition of parallel change is expanded to include the same regulatory feature or residue. About half of the parallelism came from D-promoter mutations. Background had a small but significant effect on parallelism. Similarly, an analyses of epistasis between mutations and their ancestral background was significant, but the result was mostly driven by four individual mutations. A second analysis of epistasis focused on de novo mutations revealed that no isolate ever had more than one D-promoter mutation and that 56 of the 65 isolates lacking a D-promoter mutation had a mutation in genes D and/or E. We assayed time to lysis in four of these mutually exclusive mutations (the two most frequent D-promoter and two in gene D) across four genetic backgrounds. In all cases lysis was delayed. We postulate that because host cells were generally rare (i.e., high multiplicity of infection conditions developed), selection favored phage that delayed lysis to better exploit their current host (i.e., ‘love the one you’re with’). Thus, the vast majority of wells (at least 64 of 68, or 94%) arrived at the same phenotypic solution, but through a variety of genetic changes. We conclude that answering questions about the range of possible adaptive trajectories, parallelism, and the predictability of evolution requires attention to the many biological levels where the process of adaptation plays out.

Whole Exome Analysis of Relapsing Patients with Acute Promyelocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2892-2892 ◽  
Author(s):  
Cecile Bally ◽  
Jacqueline Lehmann-Che ◽  
Bruno Cassinat ◽  
Lionel Ades ◽  
Eric Letouze ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Research Funding ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Mapk Signaling ◽  
Copy Number Variations ◽  
Leukemic Cells ◽  
De Novo Mutation ◽  
Whole Exome

Abstract Background : APL is, in the vast majority of cases, driven by t(15 ;17) translocation, which leads to PML/RARA rearrangement. Remarkably, APL is an uncommon genetically simple disease and only few additional alterations, cooperating with PML/RAR, have been described at diagnostic (Welch et al, Cell 2012). Most APL can be cured with targeted therapy combining all-trans retinoic acid (ATRA) and chemotherapy (CT). However, genetic mechanisms underlying the 10-15% relapses observed with this regimen remain unclear. The goal of the present study was to identify mutations that cooperate with PML/RAR and those responsible for acquired resistance to ATRA-CT treatment in APL patients by whole-exome sequencing of diagnostic/ remission/relapse trios. Methods: Newly diagnosed APL patients included in clinical trials of the French Swiss Belgian APL group between 1994 and 2008, treated with ATRA-CT, before the introduction of first-line ATO, who experienced at least one relapse and had adequate material, were studied. We collected retrospectively 64 samples from 23 patients, including 23 diagnostic samples, 18 at first complete remission (CR) and 23 at relapse (22 first relapse and 1 second relapse). Whole exome-sequencing was performed on all samples. DNA libraries were prepared with the SureSelect human v5 kit (Agilent) and sequenced on Hiseq1000 (Illumina). The bioinformatic analysis was performed by GECO/integragen using CASAVA variant calling (Illumina) and dedicated pipeline. 18 trios and 5 duos passed the stringent quality control and were analyzed for somatic variants and copy number variations (CNV). Results : After elimination of polymorphisms, the median number of somatic variants corresponding to de novo mutation at diagnosis was 14, while only 3 new somatic variants appeared at relapse (figure 1). Notably, we failed to detect oncogene alterations other than PML/RARA in 7/23 (30%) patients. At diagnostic, 39% of patients (9/23) presented the common FLT3 alterations and at relapse 22% (5/23) of patients presented the known RARA mutations. Moreover, recurrent alterations were observed in activators of the MAPK signaling (22%): NRAS (2 patients), BRAF (1 patient), KRAS (1 patient), SPRY1 (1 patient). Mutations in the NT5C2 gene (3 patients), coding a 5'nucleotidase implicated in resistance to nucleoside-analog therapy, were solely observed at relapse, as in acute lymphoblastic leukemia (ALL). Abnormalities of epigenetic regulators were also detected at diagnostic and/or relapse: WT1 (7 patients, 30%), NSD1 (2 patients), TET2 (1 patient), ASXL1 (1 patient) and MED12 (2 patients). Homozygote WT1 inactivation by mutation plus neutral copy LOH occurred in 3 patients at relapse. The genetic markers identified allowed us to construct several evolution models. In 8 patients (35%), the diagnostic and relapse clones were clearly distinct, supporting the fact that they independently derived from pre-leukemic cells that survived ATRA/chemotherapy. In contrast, other relapses appeared to derive from the diagnostic clone. Conclusion: Our data highlight the genetic simplicity of APL with very few alterations detected and 30% patients without identified mutations in addition to PML/RARa. Our results support the existence of two prototypic mechanisms of relapse: re-emergence of a new APL from persisting pre-leukemic cells and relapse from APLs often expressing strong oncogenes at diagnosis, impeding therapy response and favoring the acquisition of resistance mutations at relapse, including PML/RARA or NT5C2. It will be interesting to assess the prevalence of those two mechanisms in the exceptional cases of relapse in patients treated with more recent frontline regimens that combine ATRA and arsenic in APL. Disclosures Ades: Celgene, Takeda, Novartis, Astex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding.

scholarly journals Identification of novel CSNK2A1 variants and the genotype–phenotype relationship in patients with Okur–Chung neurodevelopmental syndrome: a case report and systematic literature review

2021 ◽  
Vol 49 (5) ◽  
pp. 030006052110170
Author(s):  
Ruo-hao Wu ◽  
Wen-ting Tang ◽  
Kun-yin Qiu ◽  
Xiao-juan Li ◽  
Dan-xia Tang ◽  
...  
Keyword(s):  
De Novo ◽  
Facial Dysmorphism ◽  
Comprehensive Overview ◽  
Protein Coding ◽  
Coding Regions ◽  
Gtp Binding ◽  
Phenotypic Spectrum ◽  
Whole Exome ◽  
First Time ◽  
Binding Loop

De novo germline variants of the casein kinase 2α subunit (CK2α) gene ( CSNK2A1) have been reported in individuals with the congenital neuropsychiatric disorder Okur–Chung neurodevelopmental syndrome (OCNS). Here, we report on two unrelated children with OCNS and review the literature to explore the genotype–phenotype relationship in OCNS. Both children showed facial dysmorphism, growth retardation, and neuropsychiatric disorders. Using whole-exome sequencing, we identified two novel de novo CSNK2A1 variants: c.479A>G p.(H160R) and c.238C>T p.(R80C). A search of the literature identified 12 studies that provided information on 35 CSNK2A1 variants in various protein-coding regions of CK2α. By quantitatively analyzing data related to these CSNK2A1 variants and their corresponding phenotypes, we showed for the first time that mutations in protein-coding CK2α regions appear to influence the phenotypic spectrum of OCNS. Mutations altering the ATP/GTP-binding loop were more likely to cause the widest range of phenotypes. Therefore, any assessment of clinical spectra for this disorder should be extremely thorough. This study not only expands the mutational spectrum of OCNS, but also provides a comprehensive overview to improve our understanding of the genotype–phenotype relationship in OCNS.

scholarly journals Whole-exome sequencing of de novo genetic variants in a Chinese family with a sporadic case of congenital nonsyndromic hearing loss

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 61
Author(s):  
Sijing Hu ◽  
Hao Zhang ◽  
Yunqiang Liu ◽  
Mohan Liu ◽  
Jingjing Li ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Genetic Variants ◽  
Cellular Localization ◽  
De Novo ◽  
Copy Number Variations ◽  
Occurrence Rate ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Functional Assay ◽  
Whole Exome

Background: We examined the genetic variants of a Chinese family with a 22-month-old infant with sporadic non-syndromic sensorineural hearing loss (NSHL). Methods: The whole-exome sequence data in the family, especially the de novo variants presented in the patient, were analyzed and the effect of the disease-causing genetic variants on the protein expression level and cellular localization were examined by cell-based functional assay. Results: The infant had no known NSHL-causing variants, except two compound heterozygous variants in connexin26 gene GJB2; one was the c.79G>A, c.341A>G haplotype from the asymptomatic mother which was benign, and the other was a de novo pathogenic c.262G>C (p.A88P). In vitro, GJB2 with c.262G>C was weakly expressed and displayed a punctate distribution in the cytoplasm and cytomembrane, while wild type GJB2 was robustly expressed in the cytomembrane. We deduced that the de novo pathogenic GJB2 c.262G>C exacerbated loss-of-function in the context of leaky variants c.79G>A, c.341A>G in the patient. Interestingly, further analysis of exome sequences revealed that the occurrence of de novo pathogenic variants in the infant was frequent. Among the total~47,000 variants, 143 were de novo in the patient, whereas among all 74 variants predicted to be pathogenic/likely pathogenic, 21 were heterozygous and two were homozygous de novo. The occurrence rate of de novo deleterious variants was much higher (31.1%, 23/74) than that in total (0.34%, 143/47,000). It is notable that most genes with de novo deleterious variants were environment-sensitive, such as GJB2, MNK1, MNK2, MUC4, RAD21 and DNA copy number variations. Conclusions: The full picture of genetic variants in the exome might help us to interpret the NSHL-causing variants. More research is needed into the causes of de novo deleterious variants and gene-environment interactions in congenital NSHL.

scholarly journals Genetic causes of severe childhood obesity: a remarkably high prevalence (≥49%) in an inbred population of Pakistan

2020 ◽  
Author(s):  
Ada Admin ◽  
Sadia Saeed ◽  
Muhammad Arslan ◽  
Jaida Manzoor ◽  
Sadia M. Din ◽  
...  
Keyword(s):  
Simultaneous Detection ◽  
Point Mutations ◽  
Copy Number Variations ◽  
Coding Regions ◽  
New Genes ◽  
Whole Exome ◽  
High Prevalence ◽  
Severely Obese ◽  
Prevalence Of Obesity ◽  
Obese Subjects

Monogenic forms of obesity have been identified in ≤10% of severely obese European patients. However, the overall spectrum of deleterious variants (point mutations and structural variants) responsible for childhood severe obesity remains elusive. In this study, we genetically screened 225 severely obese children from consanguineous Pakistani families through a combination of techniques including an in-house developed augmented whole-exome sequencing (CoDE-seq) enabling simultaneous detection of whole exome copy number variations (CNVs) and of point mutations in coding regions. We identified 110 probands (49%) carrying 55 different pathogenic point mutations and CNVs in 13 genes/loci responsible for non-syndromic and syndromic monofactorial obesity. CoDE-seq also identified 28 rare or novel CNVs associated with intellectual disability in 22 additional obese subjects (10%). Additionally, we highlight variants in candidate genes for obesity warranting further investigation. Altogether, 59% of the studied cohort are likely to have a discrete genetic cause with 13% of these due to CNVs demonstrating a remarkably higher prevalence of monofactorial obesity than hitherto reported and a plausible over lapping of obesity and intellectual disabilities in several cases. Finally, inbred populations with high prevalence of obesity, provide a unique genetically enriched material in quest of new genes/variants influencing energy balance.

scholarly journals Rates of contributory de novo mutation in high and low-risk autism families

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Seungtai Yoon ◽  
Adriana Munoz ◽  
Boris Yamrom ◽  
Yoon-ha Lee ◽  
Peter Andrews ◽  
...  
Keyword(s):  
High Risk ◽  
De Novo ◽  
Low Risk ◽  
Whole Genome Sequence ◽  
De Novo Mutation ◽  
Coding Regions ◽  
Simons Simplex Collection ◽  
Whole Exome ◽  
Autism Genetic Resource Exchange ◽  
Multiplex Families

AbstractAutism arises in high and low-risk families. De novo mutation contributes to autism incidence in low-risk families as there is a higher incidence in the affected of the simplex families than in their unaffected siblings. But the extent of contribution in low-risk families cannot be determined solely from simplex families as they are a mixture of low and high-risk. The rate of de novo mutation in nearly pure populations of high-risk families, the multiplex families, has not previously been rigorously determined. Moreover, rates of de novo mutation have been underestimated from studies based on low resolution microarrays and whole exome sequencing. Here we report on findings from whole genome sequence (WGS) of both simplex families from the Simons Simplex Collection (SSC) and multiplex families from the Autism Genetic Resource Exchange (AGRE). After removing the multiplex samples with excessive cell-line genetic drift, we find that the contribution of de novo mutation in multiplex is significantly smaller than the contribution in simplex. We use WGS to provide high resolution CNV profiles and to analyze more than coding regions, and revise upward the rate in simplex autism due to an excess of de novo events targeting introns. Based on this study, we now estimate that de novo events contribute to 52–67% of cases of autism arising from low risk families, and 30–39% of cases of all autism.

scholarly journals Case report: a de-novo 7p12.3 microduplication detected in an infant with perineal hamartoma and imperforate anus

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Ayca Kocaaga ◽  
Sevgi Yimenicioglu ◽  
Cigdem Arslan Alıcı
Keyword(s):  
Imperforate Anus ◽  
De Novo ◽  
Neonatal Period ◽  
Wide Spectrum ◽  
Anorectal Malformations ◽  
Sacrococcygeal Teratoma ◽  
Anal Atresia ◽  
Whole Exome ◽  
Laboratory Investigations ◽  
Magnetic Resonance Imaging Mri

Abstract Background Anorectal malformations (ARM) represent a wide spectrum of defects. Caudal and genitourinary malformations can associate with anorectal malformations. Genetic factors may play role in the development of anorectal malformations. Perineal masses like sacrococcygeal teratoma, rectal prolapse, or duplication cysts were reported before, but their association with perineal hamartoma and anal atresia is extremely rare. Case presentation Here, we report an 11-month-old female infant. She had 551 kb duplication at 7p12.3 with perineal hamartoma and anal atresia consisting a cystic lesion with a diameter of 4 mm at the filum terminale (L2 vertebra) on lumbar magnetic resonance imaging (MRI) in neonatal period. She presented with hypotonia. She had anorectal anomaly and external perineal mass bulging from left major labium extending across anal region with imperforate anus. There was 1 × 1 cm polyp-like protrusion on it. She was operated in neonatal period. Genetic laboratory investigations showed karyotype 46, XX. The microduplication of the chromosome 7p12.3 was detected by microarray analysis. There were not any significant homozygous or heterozygous variants determined  by whole-exome sequencing. Conclusions To the best of our knowledge, this is the first report of a patient with a microduplication of the chromosome 7p12.3, and second case with perineal hamartoma and imperforate anus. Clinicians should pay attention to microdeletions and microduplications while giving genetic counseling to patients with urogenital and anorectal abnormalities.

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