Showing papers on "Chromosome 22 published in 2020"

The Genetics and Epigenetics of 22q11.2 Deletion Syndrome.

Abstract: Chromosome 22q11.2 deletion syndrome (22q11.2del) is a complex, multi-organ disorder noted for its varying severity and penetrance among those affected. The clinical problems comprise congenital malformations; cardiac problems including outflow tract defects, hypoplasia of the thymus, hypoparathyroidism, and/or dysmorphic facial features. Additional clinical issues that can appear over time are autoimmunity, renal insufficiency, developmental delay, malignancy and neurological manifestations such as schizophrenia. The majority of individuals with 22q11.2del have a 3 Mb deletion of DNA on chromosome 22, leading to a haploinsufficiency of ~106 genes, which comprise coding RNAs, noncoding RNAs, and pseudogenes. The consequent haploinsufficiency of many of the coding genes are well described, including the key roles of T-box Transcription Factor 1 (TBX1) and DiGeorge Critical Region 8 (DGCR8) in the clinical phenotypes. However, the haploinsufficiency of these genes alone cannot account for the tremendous variation in the severity and penetrance of the clinical complications among those affected. Recent RNA and DNA sequencing approaches are uncovering novel genetic and epigenetic differences among 22q11.2del patients that can influence disease severity. In this review, the role of coding and non-coding genes, including microRNAs (miRNA) and long noncoding RNAs (lncRNAs), will be discussed in relation to their bearing on 22q11.2del with an emphasis on TBX1.

Variations in chromosomal aneuploidy rates in IVF blastocysts and early spontaneous abortion chorionic villi.

Abstract: To compare chromosomal aberrations and aneuploidy features in (i) blastocysts following intracytoplasmic sperm injection (ICSI) and trophectoderm (TE) biopsy using preimplantation genetic screening (PGS) and (ii) early spontaneous abortion chorionic villus biopsies (SA-CVB) using single-nucleotide polymorphism (SNP) array detection. We retrospectively reviewed the data for 1014 TEs from 220 PGS cycles and 1724 SA-CVBs originating from naturally pregnant couples and patients undergoing assisted reproductive technology (ART) during 2017 to 2018. SNP array was applied in both PGS and SA-CVBs detection. Aberrations were defined, and the frequency and ratio of each chromosome aberration were compared between the two groups. There were more abnormalities in TEs in the form of complex chromosome aneuploidies and monosomies, while SA-CVBs had more trisomies, sex chromosome abnormalities, and polyploidies. In both groups, chromosomal aneuploidies (including monosomies and trisomies) were confined to chromosomes 14, 15, 16, 18, 21, and 22, but showed varying distributions across the groups. Aneuploidy of chromosome 22 was most frequent in TEs, whereas that of chromosome 16 predominated in SA-CVBs. Among the sex chromosome abnormalities, X monosomies were significantly more prevalent in SA-CVBs. Chromosomal aberrations and aneuploidy manifested specific characteristics that differed between TEs and SA-CVBs, which indicates that distinct chromosomal abnormalities can affect certain developmental stages of embryos. Further analysis is needed to explore the chromosomal mechanisms affecting embryo development and implantation. Such information will help clinical assessments in prenatal diagnosis and reduce the incidence of genetically abnormal fetuses.

Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage-Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities.

Abstract: Philadelphia chromosome (Ph) results from a translocation between the breakpoint cluster region (BCR) gene on chromosome 9 and ABL proto-oncogene 1 (ABL1) gene on chromosome 22. The fusion gene, BCR-ABL1, is a constitutively active tyrosine kinase which promotes development of leukemia. Depending on the breakpoint site within the BCR gene, different isoforms of BCR-ABL1 exist, with p210 and p190 being the most prevalent. P210 isoform is the hallmark of chronic myeloid leukemia (CML), while p190 isoform is expressed in majority of Ph-positive B cell acute lymphoblastic leukemia (Ph+ B-ALL) cases. The crucial component of treatment protocols of CML and Ph+ B-ALL patients are tyrosine kinase inhibitors (TKIs), drugs which target both BCR-ABL1 isoforms. While TKIs therapy is successful in great majority of CML patients, Ph+ B-ALL often relapses as a drug-resistant disease. Recently, the high-throughput genomic and proteomic analyses revealed significant differences between CML and Ph+ B-ALL. In this review we summarize recent discoveries related to differential signaling pathways mediated by different BCR-ABL1 isoforms, lineage-specific genetic lesions, and metabolic reprogramming. In particular, we emphasize the features distinguishing Ph+ B-ALL from CML and focus on potential therapeutic approaches exploiting those characteristics, which could improve the treatment of Ph+ B-ALL.

Consequences of 22q11.2 Microdeletion on the Genome, Individual and Population Levels.

Abstract: Chromosomal 22q11.2 deletion syndrome (22q11.2DS) (ORPHA: 567) caused by microdeletion in chromosome 22 is the most common chromosomal microdeletion disorder in humans. Despite the same change on the genome level, like in the case of monozygotic twins, phenotypes are expressed differently in 22q11.2 deletion individuals. The rest of the genome, as well as epigenome and environmental factors, are not without influence on the variability of phenotypes. The penetrance seems to be more genotype specific than deleted locus specific. The transcript levels of deleted genes are not usually reduced by 50% as assumed due to haploinsufficiency. 22q11.2DS is often an undiagnosed condition, as each patient may have a different set out of 180 possible clinical manifestations. Diverse dysmorphic traits are present in patients from different ethnicities, which makes diagnosis even more difficult. 22q11.2 deletion syndrome serves as an example of a genetic syndrome that is not easy to manage at all stages: diagnosis, consulting and dealing with.

22q13 Microduplication Syndrome in Siblings with Mild Clinical Phenotype: Broadening the Clinical and Behavioral Spectrum

Abstract: Distal duplication 22q (22q13.3qter) is a rare condition with only 24 cases described so far. Parental balanced reciprocal translocations and pericentric inversions involving chromosome 22 predispose to the conception of an unbalanced offspring and are more frequently reported than de novo events. The clinical phenotype of patients is highly variable and does not necessarily correlate with the extent of the duplicated segment. Short stature, microcephaly, hypertelorism, cleft lip or palate, low-set ears, and intellectual disability seem to be the most consistent features. Familial reoccurrence is extremely rarely reported. Here, we report 2 siblings with a 22q13.3qter duplication detected by array CGH; their mother is a carrier of a pericentric inversion in chromosome 22. Their relatively mild phenotype and identical chromosomal breakpoints as well as duplication size are unique. This is the first case described so far.

Could PGT-A pick up true abnormalities that have clinical relevance? Retrospective analysis of 1043 embryos.

Abstract: Objective To determine whether preimplantation genetic testing for aneuploidy (PGT-A) could pick up true abnormalities that have clinical relevance. Materials and methods This was a retrospective cohort study of patients who underwent in vitro fertilization with PGT-A from 2015 to 2017. We evaluated the associations of aneuploidy and mosaicism with maternal age, the chromosome abnormalities present in individual chromosomes, and the effect of embryo sex on the proportion of each type of error in the four chromosomes most frequently affected. Result(s) A total of 1043 embryos from 255 patients (mean maternal age = 39 ± 4 years) were included in the initial analysis. Of these, 36% (377/1043) were euploid, 47% (487/1043) were aneuploid, 13% (140/1043) contained mosaicism, and 4% (39/1043) gave no result. We excluded the 39 embryos with no result; thus, 1004 embryos were included in the analysis. Increased aneuploidy was associated with increased maternal age, but the rate of embryo mosaicism was not. A combined analysis of aneuploidy with noncomplex abnormalities and mosaicism showed that chromosomes 22, 21, 16, and 15 were the most frequently involved. Chromosome 22 showed the highest proportion of mosaicism and chromosome 15 showed the highest proportion of aneuploidy. When we included embryo sex in the analysis, embryo sex was associated with these chromosome errors in the most susceptible chromosome, 22. Conclusion(s) PGT-A showed that chromosomes 22, 21, 16, and 15 were the most frequently involved among common chromosome abnormalities, comparable with those of published data analyzed from spontaneous abortion. This result suggested that PGT-A could pick up abnormalities that have clinical relevance to spontaneous abortion. Moreover, we identified a role of embryo sex in these chromosomal errors on chromosome 22.

Cytogenetic and Molecular Study of an Adult Sclerosing Rhabdomyosarcoma of the Extremity: MYOD1-mutation and Clonal Evolution

Abstract: Background Spindle cell/sclerosing rhabdomyosarcoma is a genomically heterogeneous, uncommon subtype of rhabdomyosarcoma, particularly rare in adults. Its MYOD1-mutant variant is aggressive irrespective of age. Cytogenetic data on spindle cell/sclerosing rhabdomyosarcoma are sparse and disparate. Materials and methods Cytogenetic and molecular analyses were performed on an adult sclerosing rhabdomyosarcoma. Results The karyotype of the sclerosing rhabdomyosarcoma displayed clonal evolution corresponding to two hyperdiploid clones: 48,XY,+i(19)(p10),+22/48,idem,der(9)t(2;9)(q21~22;p21). The changes were gain of chromosome 19 with the overrepresentation of 19p arm, gain of chromosome 22, gain of the 2q arm, and loss of 9p21. Mutation analysis revealed a homozygous c.T365G (p.L122R) mutation of the MYOD1 gene, but none of PIK3CA. Conclusion To our knowledge, this is the first adult MYOD1-mutant sclerosing rhabdomyosarcoma studied cytogenetically. The only other reported sclerosing rhabdomyosarcoma with MYOD1 mutation and abnormal karyotype was pediatric. Since these tumors are highly aggressive, further studies unravelling their cytogenetic and molecular characteristics are warranted.

Loss of Integrase Interactor 1 (INI1) Expression in a Subset of Differentiated Thyroid Cancer

Abstract: Alterations in the switching defective/sucrose non-fermenting (SWI/SNF) chromatin-remodeling complex are enriched in advanced thyroid cancer. Integrase interactor 1 (INI1), encoded by the SMARCB1 gene on the long arm of chromosome 22, is one of the core subunits of the SWI/SNF complex. INI1 immunohistochemistry is frequently used for the diagnosis of malignant rhabdoid neoplasms. In the present study, we found normal and benign thyroid tissues generally had diffusely intense nuclear immunostaining. Loss of INI1 immunohistochemical expression was observed in 8% of papillary thyroid cancer and 30% of follicular thyroid cancer. Furthermore, loss of INI1 expression was associated with extrathyroidal extension (p < 0.001) and lymph node metastasis (p = 0.038). Analysis of The Cancer Genome Atlas database revealed that SMARCB1 underexpression was associated with the follicular variant subtype and aneuploidy in papillary thyroid cancer. We speculate that SMARCB1 is an important effector in addition to NF2 and CHEK2 inactivation among thyroid cancers with chromosome 22q loss.

Detecting Philadelphia Chromosome on Metaphase Images using a Convolutional Neural Network

Abstract: Philadelphia chromosome is a specific genetic abnormality, a reciprocal translocation between chromosome 9 and chromosome 22. This abnormality can cause Chronic Myelogenous Leukemia (CML). Although there are many techniques to diagnose Philadelphia chromosome such as karyotyping, Fluorescence in Situ Hybridizations (FISH), and chromosome painting, etc., these techniques are expensiye and can lead to patients’ financial problem. In addition, the number of expert medical technicians who can diagnose chromosomes abnormality is yery low. Thus, it takes many days to inform the result to the patients and increases medical technicians’ workloads. This paper proposes a Philadelphia chromosome detection framework using image processing and deep learning techniques. It will help medical technicians to screen the patients who haye the Philadelphia chromosome, so it can reduce the workloads of medical technicians and the time that patients haye to wait for the result. Additionally, this framework can improye the diagnosis of Philadelphia chromosome with less cost.

Multiple Whole Chromosomal Gains Define Angiomatous Meningiomas and Are Absent From the Tumor Vasculature.

Abstract: Angiomatous meningioma is a variant with prominent vascularity that can mimic other highly vascularized tumors and present diagnostic challenges. Unlike most meningioma variants, where NF2 gene loss on chromosome 22 is the most common genetic abnormality, angiomatous meningiomas are unique in having multiple whole chromosome gains (polysomies). We analyzed 38 meningiomas, 9 angiomatous (including 2 atypical and 1 anaplastic), and 29 nonangiomatous meningiomas, using array comparative genomic hybridization (aCGH). Angiomatous meningiomas showed multiple chromosomal alterations including polysomies and copy neutral loss of heterozygosity in comparison to nonangiomatous variants. The most frequent gains were of chromosomes 5 and 20 (100% and 89% of cases, respectively); none showed chromosome 22 loss. Furthermore, using fluorescence in situ hybridization we show that the vasculature lacked chromosomal polysomy. While generally benign, we present 2 grade II and the first cytogenetically confirmed grade III angiomatous meningioma, demonstrating their potentially aggressive behavior. Thus, multiple polysomies define angiomatous meningioma and aCGH can distinguish this variant from nonangiomatous meningiomas and other histological mimics in diagnostically challenging cases. Furthermore, the prominent vasculature is not neoplastic and likely induced by angiogenic factors. Together, these findings suggest a distinct tumorigenic pathway in angiomatous meningiomas.

METHOD TO DETECT DUPLICATIONS AND/OR DELETIONS IN THE 22q11.2 CHROMOSOME REGION (Machine-translation by Google Translate, not legally binding)

Abstract: Method to detect duplications and/or deletions in the chromosomal region 22q11.2. The present invention relates to a method for detecting duplications and/or deletions in chromosome 22, particularly in chromosomal region 22q11.2, which comprises determining the number of alleles that have a set of genetic markers present among the low-repeat regions of copies (Low Copy Repeats, LCR22, in its acronym in English), this method being applied in the diagnosis of diseases associated with said genetic abnormalities, such as congenital heart disease and DiGeorge syndrome among others. Likewise, the present invention also relates to capable primers useful in detecting the number of alleles, the kit comprising said primers and the use of them for the diagnosis of diseases associated with said genetic abnormalities. (Machine-translation by Google Translate, not legally binding)