Case Report: Neuroblastoma Breakpoint Family Genes Associate With 1q21 Copy Number Variation Disorders

Microduplications and reciprocal microdeletions of chromosome 1q21. 1 and/or 1q21.2 have been linked to variable clinical features, but the underlying pathogenic gene(s) remain unclear. Here we report that distinct microduplications were detected on chromosome 1q21.2 (GRCh37/hg19) in a mother (255 kb in size) and her newborn daughter (443 kb in size), while the same paternal locus was wild-type. Although the two microduplications largely overlap in genomic sequence (183 kb overlapping), the mother showed no clinical phenotype while the daughter presented with several features that are commonly observed on 1q21 microduplication or microdeletion patients, including developmental delay, craniofacial dysmorphism, congenital heart disease and sensorineural hearing loss. NBPF15 and NBPF16, two involved genes that are exclusively duplicated in the proband, may be the cause of the clinical manifestations. This study supports an association between NBPF genes and 1q21 copy number variation disorders.

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A 44-kb deleted-type copy number variation is associated with decreasing complement component activity and calf mortality in Japanese Black cattle

BMC Genomics ◽

10.1186/s12864-021-07415-6 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Shinji Sasaki ◽

Youko Miki ◽

Takayuki Ibi ◽

Hiroyuki Wakaguri ◽

Yuichi Yoshida ◽

...

Keyword(s):

Infectious Disease ◽

Copy Number Variation ◽

Copy Number ◽

Risk Allele ◽

Wild Type ◽

Japanese Black Cattle ◽

Complement Activity ◽

Categorical Trait ◽

Number Variation ◽

Calf Mortality

Abstract Background Calf mortality generally occurs in calves prior to weaning, which is a serious problem in cattle breeding. Several causative variants of monogenic Mendelian disorders in calf mortality have been identified, whereas genetic factors affecting the susceptibility of calves to death are not well known. To identify variants associated with calf mortality in Japanese Black cattle, we evaluated calf mortality as a categorical trait with a threshold model and performed a genome-wide copy number variation (CNV) association study on calf mortality. Results We identified a 44-kb deleted-type CNV ranging from 103,317,687 to 103,361,802 bp on chromosome 5, which was associated with the mortality of 1–180-day-old calves. The CNV harbored C1RL, a pseudogene, and an IncRNA localized in the C1R and C1S gene cluster, which is a component of the classical complement activation pathway for immune complexes for infectious pathogens. The average complement activity in CNVR_221 homozygotes at postnatal day 7 was significantly lower than that of wild-type animals and heterozygotes. The frequency of the risk allele in dead calves suffering from diarrhea and pneumonia and in healthy cows was 0.35 and 0.28, respectively (odds ratio = 2.2, P = 0.016), suggesting that CNVR_221 was associated with the mortality of Japanese Black calves suffering from an infectious disease. Conclusions This study identified a deleted-type CNV associated with the mortality of 1–180-day-old calves. The complement activity in CNVR_221 homozygotes was significantly lower than that in heterozygotes and wild type animals. The frequency of the risk allele was higher in dead calves suffering from an infectious disease than in healthy cows. These results suggest that the existence of CNVR_221 in calves could be attributed to a reduction in complement activity, which in turn leads to susceptibility to infections. Thus, the risk allele could serve as a useful marker to reduce the mortality of infected Japanese Black calves.

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DNA methylation and copy number variation profiling of T-cell lymphoblastic leukemia and lymphoma

Blood Cancer Journal ◽

10.1038/s41408-020-0310-9 ◽

2020 ◽

Vol 10 (4) ◽

Cited By ~ 1

Author(s):

Zahra Haider ◽

Mattias Landfors ◽

Irina Golovleva ◽

Martin Erlanson ◽

Kjeld Schmiegelow ◽

...

Keyword(s):

Dna Methylation ◽

T Cell ◽

Copy Number Variation ◽

Copy Number ◽

Cpg Island ◽

Lymphoblastic Leukemia ◽

Clinical Manifestations ◽

Cpg Island Methylator Phenotype ◽

Genetic Landscape ◽

Number Variation

AbstractDespite having common overlapping immunophenotypic and morphological features, T-cell lymphoblastic leukemia (T-ALL) and lymphoma (T-LBL) have distinct clinical manifestations, which may represent separate diseases. We investigated and compared the epigenetic and genetic landscape of adult and pediatric T-ALL (n = 77) and T-LBL (n = 15) patient samples by high-resolution genome-wide DNA methylation and Copy Number Variation (CNV) BeadChip arrays. DNA methylation profiling identified the presence of CpG island methylator phenotype (CIMP) subgroups within both pediatric and adult T-LBL and T-ALL. An epigenetic signature of 128 differentially methylated CpG sites was identified, that clustered T-LBL and T-ALL separately. The most significant differentially methylated gene loci included the SGCE/PEG10 shared promoter region, previously implicated in lymphoid malignancies. CNV analysis confirmed overlapping recurrent aberrations between T-ALL and T-LBL, including 9p21.3 (CDKN2A/CDKN2B) deletions. A significantly higher frequency of chromosome 13q14.2 deletions was identified in T-LBL samples (36% in T-LBL vs. 0% in T-ALL). This deletion, encompassing the RB1, MIR15A and MIR16-1 gene loci, has been reported as a recurrent deletion in B-cell malignancies. Our study reveals epigenetic and genetic markers that can distinguish between T-LBL and T-ALL, and deepen the understanding of the biology underlying the diverse disease localization.

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Synaptonemal complex-deficient Drosophila melanogaster females exhibit rare DSB repair events, recurrent copy number variation, and an increased rate of de novo transposable element movement

10.1101/814186 ◽

2019 ◽

Author(s):

Danny E. Miller

Keyword(s):

Drosophila Melanogaster ◽

Copy Number Variation ◽

Transposable Element ◽

Synaptonemal Complex ◽

Copy Number ◽

De Novo ◽

Wild Type ◽

Dsb Repair ◽

Number Variation ◽

Element Movement

ABSTRACTGenetic stability depends on the maintenance of a variety of chromosome structures and the precise repair of DNA breaks. During meiosis, programmed double-strand breaks (DSBs) made in prophase I are normally repaired as gene conversions or crossovers. Additionally, DSBs are made by the movement of transposable elements (TEs), which must also be resolved. Incorrect repair of these DNA lesions can lead to mutations, copy number variations, translocations, and/or aneuploid gametes. In Drosophila melanogaster, as in most organisms, meiotic DSB repair occurs in the presence of a rapidly evolving multiprotein structure called the synaptonemal complex (SC). Here, whole-genome sequencing is used to investigate the fate of meiotic DSBs in D. melanogaster mutant females lacking functional SC, to assay for de novo CNV formation, and to examine the role of the SC in transposable element movement in flies. The data indicate that, in the absence of SC, copy number variation still occurs but meiotic DSB repair by gene conversion may occur only rarely. Remarkably, an 856-kilobase de novo CNV was observed in two unrelated individuals of different genetic backgrounds and was identical to a CNV recovered in a previous wild-type study, suggesting that recurrent formation of large CNVs occurs in Drosophila. In addition, the rate of novel TE insertion was markedly higher than wild type in one of two SC mutants tested, suggesting that SC proteins may contribute to the regulation of TE movement and insertion in the genome. Overall, this study provides novel insight into the role that the SC plays in genome stability and provides clues as to why SC proteins are among the most rapidly evolving in any organism.

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Synaptonemal Complex-Deficient Drosophila melanogaster Females Exhibit Rare DSB Repair Events, Recurrent Copy-Number Variation, and an Increased Rate of de Novo Transposable Element Movement

G3 Genes|Genome|Genetics ◽

10.1534/g3.119.400853 ◽

2019 ◽

Vol 10 (2) ◽

pp. 525-537 ◽

Cited By ~ 4

Author(s):

Danny E. Miller

Keyword(s):

Drosophila Melanogaster ◽

Copy Number Variation ◽

Transposable Element ◽

Synaptonemal Complex ◽

Copy Number ◽

De Novo ◽

Wild Type ◽

Dsb Repair ◽

Number Variation ◽

Element Movement

Genetic stability depends on the maintenance of a variety of chromosome structures and the precise repair of DNA breaks. During meiosis, programmed double-strand breaks (DSBs) made in prophase I are normally repaired as gene conversions or crossovers. DSBs can also be made by other mechanisms, such as the movement of transposable elements (TEs), which must also be resolved. Incorrect repair of these DNA lesions can lead to mutations, copy-number changes, translocations, and/or aneuploid gametes. In Drosophila melanogaster, as in most organisms, meiotic DSB repair occurs in the presence of a rapidly evolving multiprotein structure called the synaptonemal complex (SC). Here, whole-genome sequencing is used to investigate the fate of meiotic DSBs in D. melanogaster mutant females lacking functional SC, to assay for de novo CNV formation, and to examine the role of the SC in transposable element movement in flies. The data indicate that, in the absence of SC, copy-number variation still occurs and meiotic DSB repair by gene conversion occurs infrequently. Remarkably, an 856-kilobase de novo CNV was observed in two unrelated individuals of different genetic backgrounds and was identical to a CNV recovered in a previous wild-type study, suggesting that recurrent formation of large CNVs occurs in Drosophila. In addition, the rate of novel TE insertion was markedly higher than wild type in one of two SC mutants tested, suggesting that SC proteins may contribute to the regulation of TE movement and insertion in the genome. Overall, this study provides novel insight into the role that the SC plays in genome stability and provides clues as to why the sequence, but not structure, of SC proteins is rapidly evolving.

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Chromosome 1q21 gains confer inferior outcomes in multiple myeloma treated with bortezomib but copy number variation and percentage of plasma cells involved have no additional prognostic value

Haematologica ◽

10.3324/haematol.2013.088211 ◽

2013 ◽

Vol 99 (2) ◽

pp. 353-359 ◽

Cited By ~ 44

Author(s):

G. An ◽

Y. Xu ◽

L. Shi ◽

Z. Shizhen ◽

S. Deng ◽

...

Keyword(s):

Multiple Myeloma ◽

Copy Number Variation ◽

Copy Number ◽

Prognostic Value ◽

Plasma Cells ◽

Number Variation ◽

Chromosome 1Q21

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Chromosome 1q21 Gains Confer Inferior Outcomes In Multiple Myeloma Treated With Bortezomib But Copy Number Variation and Percentage Of Plasma Cells Involved Have No Additional Prognostic Value

Blood ◽

10.1182/blood.v122.21.1992.1992 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1992-1992

Author(s):

Gang An ◽

Yan Xu ◽

Shuhui Deng ◽

Dehui Zou ◽

Weiwei Sui ◽

...

Keyword(s):

Multiple Myeloma ◽

Copy Number Variation ◽

Copy Number ◽

Prognostic Value ◽

Plasma Cells ◽

Negative Impact ◽

Newly Diagnosed ◽

Copy Numbers ◽

Number Variation ◽

Chromosome 1Q21

Abstract Background Chromosome 1q21 aberrations have not been implemented into the routine clinical test yet, and their effect in multiple myeloma is still under investigation. Heterogeneity exists among patients presenting 1q21 gains, e.g., variation in the copy numbers and the size of clone carrying 1q21 gains. The prognostic value of copy number variation and percentage of plasma cells involved remained unclear. Materials and Methods In the present study, we analyzed the prognostic value of 1q21 in a in a series of 290 cases of newly diagnosed multiple myeloma treated in a prospective, nonrandomized clinical trial (BDH 2008/02). Results The incidence of patients carrying at least three copies of 1q21 was significantly higher in relapsed MM than in newly diagnosed MM (73 out of 107 [68.2%] vs. 142 out of 290 [48.9%], p=0.001). Among the whole cohort, 278 newly diagnosed MM and 102 relapsed MM had copy number variation information. No statistical difference in the frequency of three, four, or at least five copies copies of 1q21 was found between relapsed and initially diagnosed cases. 1q21 gains showed a profoundly negative impact on survival in patients receiving bortezomib treatment. Patients with 1q21 gains had a significantly shortened PFS (13.5 months vs. 43.0 months, p<0.001) and OS (24.0 months vs. 54.0 months, p<0.001) than patients with two copies of 1q21. Further investigation of the impact of copy number variation on survival indicated that the median PFS of patients who had three, four, or at least five copies of 1q21 were 14.0 months (95% CI: 8.07-19.93), 14.0 months (95% CI: 5.47-22.53), and 10.0 months (95% CI: 4.12-15.88), respectively. The median OS of patients who had three and four copies were 24.0 months (95% CI: 11.85-36.14) and 30.0 months (95% CI: 18.14-41.85) respectively, while the OS of patients with at least five copies was not obtained due to the small sample size; no statistically significant differences were found. When the patients with four and five copies were analyzed as a whole, i.e., as one group of patients with at least four copies, patients with at least four copies of 1q21 also exhibited a comparable PFS (14.0 months vs.10.0 months, p=0.737) and OS (24.0 months vs. 30.0 months, p=0.382), compared with patients harboring three copies of 1q21. Patients with 1q21 gains were divided into two groups according to the percentage of plasma cells involved, i.e., 20%-50% and >50%, which were seen respectively in 28/290 (9.7%) and 114/290 (43.8%) patients with newly diagnosed MM. The median PFS was 6.0 months (95% CI: 1.00-21.5) and 13.5 months (95% CI: 8.87-18.14) respectively, and median OS was 6.0 months (95% CI: 1.00-21.49) and 24.0 months (95% CI: 18.94-29.05) respectively. The difference in PFS and OS were not statistically significant between the two groups (p=0.753 and 0.273 respectively;). No statistically significant differences were found in patients harboring 1q21 gains between bortezomib-based and thalidomide-based chemotherapy groups, and the median PFS and OS in patients receiving bortezomib-based regimens were 13.5 months (vs. 20.0 months; p=0.176) and 24.0 months (vs. 21.0 months; p=0.773) respectively. Therefore, bortezomib was unable to overcome the negative impact of 1q21 gains on survival, and to significantly improve the survival of these patients. Conclusion Our data demonstrated that copy numbers of 1q21 increased with progression of myeloma and predicted a poor prognosis in MM patients treated with bortezomib-based therapy. Our results also indicate that three copies of 1q21 gains and 20% of plasma cells with this abnormality were enough to confer bortezomib resistance. Chromosome 1q21 gains should be considered a high-risk feature in MM, and 1q21 analysis should be added to the diagnostic panel of FISH probes used in routine assessment of prognosis in patients with MM, especially those receiving bortezomib-based regimens. Disclosures: No relevant conflicts of interest to declare.

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