scholarly journals Characterization of a Rare Mosaic Unbalanced Translocation of t(3;12) in a Patient With Neurodevelopmental Disorders

2021 ◽  
Author(s):  
Xiaolin Hu ◽  
Elizabeth K Baker ◽  
Jodie Johnson ◽  
Stephanie Balow ◽  
Loren D.M. Pena ◽  
...  
Keyword(s):  
De Novo ◽  
Chromosomal Abnormalities ◽  
Snp Array ◽  
Chromosome Analysis ◽  
Chromosome 12 ◽  
Derivative Chromosome ◽  
Unbalanced Translocation ◽  
Balanced Translocation ◽  
Chromosomal Disorders ◽  
History Of

Abstract Background Unbalanced translocations may be de novo or inherited from one parent carrying the balanced form and are usually present in all cells. Mosaic unbalanced translocations are extremely rare with a highly variable phenotype depending on the tissue distribution and level of mosaicism. Mosaicism for structural chromosomal abnormalities is clinically challenging for diagnosis and counseling due to the limitation of technical platforms and complex mechanisms, respectively. Here we report a case with a tremendously rare maternally-derived mosaic unbalanced translocation of t(3;12), and we illustrate the unreported complicated mechanism using single nucleotide polymorphism (SNP) array, fluorescence in situ hybridization (FISH), and chromosome analyses. Case Presentation: An 18-year-old female with a history of microcephaly, pervasive developmental disorder, intellectual disability, sensory integration disorder, gastroparesis, and hypotonia presented to our genetics clinic. She had negative karyotype by parental report but no other genetic testing performed previously. SNP microarray analysis revealed a complex genotype including 8.4 Mb terminal mosaic duplication on chromosome 3 (3p26.3->3p26.1) with the distal 5.7 Mb involving two parental haplotypes and the proximal 2.7 Mb involving three parental haplotypes, and a 6.1 Mb terminal mosaic deletion on chromosome 12 (12p13.33->12p13.31) with no evidence for a second haplotype. Adjacent to the mosaic deletion is an interstitial mosaic copy-neutral region of homozygosity (1.9 Mb, 12p13.31). The mother of this individual was confirmed by chromosome analysis and FISH that she carries a balanced translocation, t(3;12)(p26.1;p13.31). Conclusion Taken together, the proband, when at the stage of a zygote, likely carried the derivative chromosome 12 from this translocation, and a postzygotic mitotic recombination event occurred between the normal paternal chromosome 12 and maternal derivative chromosome 12 to “correct” the partial 3p trisomy and partial deletion of 12p. To the best of our knowledge, it is the first time that a mechanism utilizing a combined cytogenetic and cytogenomic approach, and we believe it expands our knowledge of mosaic structural chromosomal disorders and provides new insight into clinical management and genetic counseling.

A Novel SETBP1 Gene Disruption by a De Novo Balanced Translocation in a Patient with Speech Impairment, Intellectual, and Behavioral Disorder

2020 ◽  
Author(s):  
Ivona Vrkić Boban ◽  
Futoshi Sekiguchi ◽  
Mirela Lozić ◽  
Noriko Miyake ◽  
Naomichi Matsumoto ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Autosomal Dominant ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Chromosome Translocation ◽  
Behavioral Disorder ◽  
Behavioral Difficulties ◽  
Speech Impairment ◽  
Balanced Translocation ◽  
Severe Intellectual Disability

AbstractBalanced chromosomal abnormalities (BCAs) can disrupt gene function resulting in disease. To date, BCA disrupting the SET binding protein 1 (SETBP1) gene has not been reported. On the other hand, de novo heterozygous variants in the highly conserved 11-bp region in SETBP1 can result in the Schinzel–Giedion syndrome. This condition is characterized by severe intellectual disability, a characteristic face, and multiple-system anomalies. Further other types of mutations involving SETBP1 are associated with a different phenotype, mental retardation, autosomal dominant 29 (MRD29), which has mild dysmorphic features, developmental delay, and behavioral disorders. Here we report a male patient who has moderate intellectual disability, mild behavioral difficulties, and severe expressive speech impairment resulting from a de novo balanced chromosome translocation, t(12;18)(q22;q12.3). By whole genome sequencing, we determined the breakpoints at the nucleotide level. The 18q12.3 breakpoint was located between exons 2 and 3 of SETBP1. Phenotypic features of our patient are compatible with those with MRD29. This is the first reported BCA disrupting SETBP1.

Angelman Syndrome Caused by Chromosomal Rearrangements: A Case Report of 46,XX,+der(13)t(13;15)(q14.1;q12)mat,-15 with an Atypical Phenotype and Review of the Literature

2016 ◽  
Vol 149 (4) ◽  
pp. 247-257
Author(s):  
Yo Niida ◽  
Hitoshi Sato ◽  
Mamoru Ozaki ◽  
Masatsune Itoh ◽  
Kanju Ikeno ◽  
...  
Keyword(s):  
Angelman Syndrome ◽  
De Novo ◽  
Chromosomal Rearrangements ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Parental Origin ◽  
Review Of The Literature ◽  
Balanced Translocation ◽  
Multicolor Fish ◽  
Partial Monosomy

Less than 1% of the cases with Angelman syndrome (AS) are caused by chromosomal rearrangements. This category of AS is not well defined and may manifest atypical phenotypes. Here, we report a girl with AS due to der(13)t(13;15)(q14.1;q12)mat. SNP array detected the precise deletion/duplication points and the parental origin of the 15q deletion. Multicolor FISH confirmed a balanced translocation t(13;15)(q14.1;q12) in her mother. Her facial appearance showed some features of dup(13)(pter→q14). Also, she lacked the most characteristic and unique behavioral symptoms of AS, i.e., frequent laughter, happy demeanor, and easy excitability. A review of the literature indicated that AS cases caused by chromosomal rearrangements can be classified into 2 major categories and 4 groups. The first category is paternal uniparental disomy 15, which is subdivided into isodisomy by de novo rob(15;15) and heterodisomy caused by paternal translocation. The second category is the deletion of the AS locus due to maternal reciprocal translocation, which is subdivided into 2 groups associated with partial monosomy by 3:1 segregation and partial trisomy by adjacent-2 segregation. Classification into these categories facilitates the understanding of the mechanisms of chromosomal rearrangements and helps in accurate diagnosis and genetic counseling of these rare forms of AS.

scholarly journals A Novel De Novo Chromosomal Insertion, 46 XX, ins(7:13)(p14; q14.2q21.1) is Related to the Embryo Development Arrest Following Assisted Reproductive Technique

2020 ◽  
Author(s):  
Azam Azargoon ◽  
Nahid Azad
Keyword(s):  
Embryo Development ◽  
De Novo ◽  
Chromosomal Rearrangements ◽  
Chromosome 7 ◽  
Infertile Woman ◽  
Normal Male ◽  
Derivative Chromosome ◽  
Assisted Reproductive Technique ◽  
History Of ◽  
Reproductive Technique

Background: Infertility is a problem affecting a large number of couples in the world. One of the causes of infertility can be chromosomal rearrangements such as insertions. In this case report study, the outcome of two intra-cytoplasmic sperm injection (ICSI) cycles of an infertile woman with de novo chromosomal insertion is explained. Case Presentation: A couple with a 10-year history of infertility referred to our infertility clinic. The husband had a daughter in his first previous marriage. The wife had a 7 and a 10 year history of infertility in the first and second marriages, respectively. In the first marriage, she reported a history of 2 failed intra-uterine insemination (IUI) cycles. In the second marriage, she had a history of 1 spontaneous abortion at 12 weeks of pregnancy, 4 failed IUI cycles, and 1 failed ICSI cycle. The couple was subjected to ICSI cycles twice and failed due to embryo development arrest. The couple referred for karyotyping. The husband showed a normal male karyotype. In comparison, the wife revealed an abnormal female karyotype with two rearrangements: chromosome 13 with an interstitial deletion between bands q14.2 and q21.1, and a derivative chromosome 7 containing this segment of chromosome 7 as an insertion onto short arm at the p14 position. Conclusion: To the best of our knowledge, this is the first report of insertion 46 XX, ins(7:13)(p14; q14.2q21.1) which is associated with the embryo development arrest following assisted reproductive technique.

scholarly journals Chromosomal Concordance between the Baby Produced by Preimplantation Genetic Testing Embryo and the Trophectoderm Biopsy: a Retrospective Study

2021 ◽  
Author(s):  
Zhongyuan Yao ◽  
Xiaoxia Wang ◽  
Jun Zeng ◽  
Jing Zhao ◽  
Qiuping Xia ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Diagnostic Accuracy ◽  
Peripheral Blood ◽  
Chromosomal Abnormalities ◽  
Snp Array ◽  
Chromosome Analysis ◽  
Clinical Trial Registry ◽  
Preimplantation Genetic Testing ◽  
Developmental Potential ◽  
Low Sensitivity

Abstract BackgroundChromosomal mosaicism and aneuploidies are routine phenomena throughout human pre- and post-implantation development. The benefit of implanting mosaicism or aneuploidies is still controversial. The purposes of the study are to investigate the developmental potential of embryos with chromosomally segmental or mosaic abnormalities, and whether precise Next Generation Sequencing (NGS) resolution would reduce the development of an abnormal embryo in preimplantation genetic testing (PGT) cycles.MethodsThe peripheral blood of 17 PGT babies were collected for single nucleotide polymorphism (SNP) array and were compared with trophectoderm (TE) biopsy results at different NGS resolutions.Results76.5% (13/17) of babies’ peripheral blood chromosome analysis was consistent with 10Mb TE biopsies and 58.8% (10/17) of babies’ analysis was consistent with 4Mb TE biopsies. 2 babies who had euploid TE showed abnormal peripheral blood chromosome analysis. 17.6% (3/17) embryos with aberrant TE biopsies produced healthy babies. Although the sensitivity of 10Mb was lower than 4Mb (25% vs. 50%), the specificity (100% vs. 76.9%), PPV (100% vs. 40%) and diagnostic accuracy (82.4% vs. 70.6%) of 10Mb showed better results than 4Mb.Conclusion(s)The chromosomal results between peripheral blood samples and TE biopsies of born babies are not completely congruent. Aneuploid and mosaic embryos have potential to produce healthy babies, whereas normal embryos also have chance to produce babies with chromosomal abnormalities. In spite of low sensitivity of both resolutions, 10Mb has higher specificity, PPV and diagnostic accuracy than 4Mb. It is suggested that TE biopsy be analyzed in both 10Mb and 4Mb resolutions to uncover severely adverse chromosomal aberrations but use 10Mb resolution to guide transfer.Trial registrationThe study was retrospectively registered in the Chinese Clinical Trial Registry (ChiCTR2100042522).

scholarly journals SAT-289 Evidence That Combined Pituitary Hormone Deficiency Frequently Has a Digenic/Oligogenic Etiology

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Youn Hee Jee ◽  
Mariam Gangat ◽  
Olga Yeliosof ◽  
Adrian Temnycky ◽  
Selena Vanapruks ◽  
...  
Keyword(s):  
Family History ◽  
De Novo ◽  
Snp Array ◽  
De Novo Mutation ◽  
Control Group ◽  
Pituitary Hormone ◽  
Monogenic Inheritance ◽  
Pituitary Disease ◽  
History Of ◽  
Congenital Hypopituitarism

Abstract Congenital hypopituitarism usually occurs in a child without a family history of pituitary disease. Explanations for such sporadic occurrence include: 1) monogenic inheritance (recessive or de novo), 2) digenic/oligogenic inheritance, and/or 3) nongenetic factors. To help distinguish these possibilities, we studied 9 children with hypopituitarism (HP)(small anterior pituitary gland, ectopic posterior pituitary, and either isolated GH deficiency (n=1) or combined with other pituitary hormone deficiencies(n=8)), with non-consanguineous parents and no family history of pituitary disease. SNP array analyses confirmed paternity and non-consanguinity and excluded significant copy-number variation. Exome sequencing was performed in probands and parents. Candidate variants (coverage >10, confirmed by examining BAM files, population frequency <1%, <2 homozygous subjects in gnomAD, and pathogenic prediction by at least 2 out of 3 prediction algorithms (SIFT, MutationTaster, PolyPhen2)) were identified. Children with non-familial non-endocrine idiopathic short stature (ISS) (n=19, sequenced at the same laboratory followed by simultaneous data processing with HP patients), served as a control group. To assess the frequency of genetic (mono-, di-, or oligogenic) HP cases, we identified heterozygous variants (regardless of inheritance) in 42 genes previously reported to be associated with pituitary development. The average number of variants per proband was greater in HP than in ISS (1.1 vs 0.26, P = 0.04). Similarly, the number of probands with at least 1 variant in a pituitary-associated gene was greater in HP than in ISS (67% vs 21%, P = 0.035). These data suggest that sporadic hypopituitarism is frequently genetic. To assess the number of monogenic cases, we counted the number of candidate variants (in any gene in the genome, to capture undiscovered causes) that were inherited in a fashion that could explain the sporadic occurrence with a monogenic etiology (de novo mutation, autosomal recessive, X-linked recessive). There were fewer monogenic candidates in subjects with HP than ISS (1.6 vs 2.6 candidates/proband, P = 0.03). These data are consistent with approximately 1.6 non-causative variants/proband in both groups plus approximately 1 causative monogenic variant in ISS vs approximately 0 causative monogenic variants in HP. Candidate variants in genes previously reported to explain the phenotype were identified in 0 out of 9 trios with HP and in 8 of 19 trios with ISS (42%). These findings suggest that a monogenic inheritance is less common in HP than in ISS. In conclusion, the findings suggest that sporadic congenital hypopituitarism is frequently genetic but infrequently monogenic, implying a likely digenic/oligogenic etiology.

scholarly journals Characterisation of two unusual cases of haemoglobin Bart’s hydrops foetalis caused by –SEA and large novel α-globin gene cluster deletions

2021 ◽  
Vol 49 (2) ◽  
pp. 030006052199364
Author(s):  
Yunan Wang ◽  
Ying Xiong ◽  
Chang Liu ◽  
Jian Lu ◽  
Jicheng Wang ◽  
...  
Keyword(s):  
De Novo ◽  
Southern China ◽  
Globin Gene ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Maternal Cell ◽  
Suspension Array ◽  
Frequent Mutations ◽  
History Of ◽  
Hb Bart's

Background We describe 2 unusual haemoglobin (Hb) Bart’s hydrops cases that could not be explained by traditional factors. Case presentation: Two families with a diagnosis or history of foetal hydrops were enrolled. A suspension-array system was used to detect the 23 most frequent mutations in southern China. Multiplex ligation-dependent probe amplification (MLPA) was used to screen for possible deletions. Precise characterisation of the breakpoints of the novel variants and uniparental disomy analysis were performed using a single nucleotide polymorphism (SNP) array. Quantitative fluorescence PCR was used to eliminate maternal cell contamination and nonpaternity. In case 1, the suspension-array system indicated a maternal heterozygous (–SEA/) deletion, and the paternal sample was negative. The foetal hydrops was caused by the maternal (–SEA/) deletion and a de novo α-globin gene deletion (–193). In case 2, the paternal sample had a heterozygous (–SEA/) deletion, and MLPA and SNP array analysis revealed a large maternal deletion (–227) that encompassed the α-globin gene, which explained the history of Hb Bart’s foetal hydrops. Conclusions Our cases describe 2 new α0-thalassaemia deletions and illustrate the importance of using a combination of methods to detect rare types of α-thalassaemia.

scholarly journals Nonrandom chromosomal aberrations in chronic lymphocytic leukemia revealed by polyclonal B-cell-mitogen stimulation

Blood ◽  
1980 ◽  
Vol 56 (4) ◽  
pp. 640-647 ◽  
Author(s):  
G Gahrton ◽  
KH Robert ◽  
K Friberg ◽  
L Zech ◽  
AG Bird
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Chromosomal Abnormalities ◽  
Extra Chromosome ◽  
Normal Karyotype ◽  
Chromosome Analysis ◽  
Peripheral Blood Lymphocytes ◽  
Lymphocytic Leukemia ◽  
Chromosome 12 ◽  
Banding Technique ◽  
Chromosome 11

Peripheral blood lymphocytes from 11 patients with chronic lymphocytic leukemia were stimulated by Epstein-Barr virus (EBV), lipopolysaccharide from Escherichia (LPS), and phytohemagglutinin (PHA). Chromosome analysis with the Q-banding technique after 5 days incubation revealed an extra chromosome 12 in 5 of the patients and a translocation between chromosome 11 and chromosome 14 in 1. Two patients had a deletion of chromosome 6, and only 3 patients had a normal karyotype. In most patients, the abnormalities were found in the majority of metaphases after stimulation with EBV, LPS, or both mitogens, while PHA revealed a normal karyotype, with the exception of a total of 4 metaphases in 3 patients. An extra chromosome 12 appears to be specifically associated with chronic lymphocytic leukemia. The frequency of chromosomal abnormalities in this disease appears to be much higher than has previously been thought.

A Novel Variant Rearrangement of the Rare Aberration dic(17;20)(p11.2;q11.2) Characterized by Array-CGH as an Insertion in a Patient with Myelodysplastic Syndrome of Multilineage Dysplasia (MDS-MLD)

2020 ◽  
Vol 160 (1) ◽  
pp. 22-28
Author(s):  
Maryna A. Vazmitsel ◽  
Vasiliki Grammatopoulou ◽  
Jianhui Yao ◽  
Jacqueline R. Batanian
Keyword(s):  
Myelodysplastic Syndrome ◽  
Array Cgh ◽  
De Novo ◽  
Chromosome Analysis ◽  
Chromosome 17 ◽  
Flat Band ◽  
Derivative Chromosome ◽  
Novel Variant ◽  
Unknown Gene ◽  
First Time

We report on a novel variant of the dicentric chromosome 17;20 (dic (17;20)(p11.2;q11.2) in a patient with de novo myelodysplastic syndrome (MDS). Based on FISH and array-CGH, the variant turns out to be an insertion of chromosome 17 (17p11.2-telomere 17) into chromosome 20 with breakpoints at 20q11.22 and 20q13.33. Based on conventional chromosome analysis and G-banding patterns, the region 17p11.2-17q25 was directly inserted between 20q11.22 and 20q13.33. The breakpoint junctions occurred within KCNJ12 (17p11.2), UQCC1 (20q11.2), and CDH4 (20q13.3), leading to 5′ deletions of all the genes and positioning the 3′ of UQCC1 next to KCNJ12 at 17p11.2 and CDH4 next to an unknown gene at 17q25-20q13.3. In addition, the centromere of chromosome 17 was not active, transforming the primary constriction to a flat band. Therefore, the novel insertion variant is a pseudo dicentric derivative chromosome with one functional centromere: 45,XX,der(17;20)del(20)(q11.22q13.33)ins(20;17)(q11.2;p11.2q25). A review of the literature of all dic(17;20) cases is presented. For the first time, we report an array-CGH characterization of such rare variant that revealed to be an insertion.

scholarly journals Nonrandom chromosomal aberrations in chronic lymphocytic leukemia revealed by polyclonal B-cell-mitogen stimulation

Blood ◽  
1980 ◽  
Vol 56 (4) ◽  
pp. 640-647 ◽  
Author(s):  
G Gahrton ◽  
KH Robert ◽  
K Friberg ◽  
L Zech ◽  
AG Bird
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Chromosomal Abnormalities ◽  
Extra Chromosome ◽  
Normal Karyotype ◽  
Chromosome Analysis ◽  
Peripheral Blood Lymphocytes ◽  
Lymphocytic Leukemia ◽  
Chromosome 12 ◽  
Banding Technique ◽  
Chromosome 11

Abstract Peripheral blood lymphocytes from 11 patients with chronic lymphocytic leukemia were stimulated by Epstein-Barr virus (EBV), lipopolysaccharide from Escherichia (LPS), and phytohemagglutinin (PHA). Chromosome analysis with the Q-banding technique after 5 days incubation revealed an extra chromosome 12 in 5 of the patients and a translocation between chromosome 11 and chromosome 14 in 1. Two patients had a deletion of chromosome 6, and only 3 patients had a normal karyotype. In most patients, the abnormalities were found in the majority of metaphases after stimulation with EBV, LPS, or both mitogens, while PHA revealed a normal karyotype, with the exception of a total of 4 metaphases in 3 patients. An extra chromosome 12 appears to be specifically associated with chronic lymphocytic leukemia. The frequency of chromosomal abnormalities in this disease appears to be much higher than has previously been thought.

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