Balanced Autosomal Translocation Research Articles

Repeated pregnancy losses with multiple aneuploidies and major genomic imbalance: A case report

Rationale: If one of the partners is having balanced autosomal translocation, it is usually observed that the offspring inherit either normal chromosomes, balanced translocation identical to one of the parent or unbalanced chromosomal rearrangements of the same parental chromosome having translocation. Concern: A unique case presented with history of 8 miscarriages for genetic counseling. The last abortus material evaluation showed monosomy of chromosome X (Turner syndrome) in all the analyzed cells. There was a history of infertility and also repeated second trimester abortions on the paternal side. On the maternal side, there was a history of intellectual disability. Diagnose: History of repeated abnormal pregnancy outcomes. Wife’s karyotype is normal; however, husband shows translocation between chromosome 4 and 22. Intervention: Peripheral blood sample around 3 mL was collected for karyotype. Embryo biopsy was done and DNA was extracted and processed for whole exome sequencing. Outcomes: Wife’s karyotype is normal and husband has translocation between chromosome 4 and 22. Surprisingly, the entire pregnancy outcome including embryo screening has different, complete or partial aneuploidies of chromosomes other than chromosome 4 and 22. Main lesson: Though the translocation in one of the parent is balanced, we have to think beyond traditional ways for evaluating a couple with repeated pregnancy loss as we cannot predict the errors at cell division. Option of in vitro fertilization and preimplantation genetic diagnosis in couples having balanced translocations should be discussed so that early intervention can prevent the agony of pregnancy loss.

The Boy in the Borstal: Gene Hunting, Dopaminergic Dogma, and the Science of Schizophrenia

The Boy in the Borstal: Gene Hunting, Dopaminergic Dogma, and the Science of Schizophrenia

Are ovarian responses and the number of transferable embryos different in females and partners of male balanced translocation carriers?

To compare ovarian response and the number of transferable embryos between women with balanced autosomal translocations and women whose partners carry the translocation (control group). To investigate the predictive value of metaphase II (MII) oocyte number and biopsied embryo number for gaining at lowest one transferable embryo. We retrospectively analyzed 1942 preimplantation genetic testing for structural rearrangements (PGT-SR) cycles of 1505 balanced autosomal translocation couples over 8years. All cycles were divided into two subgroups: Robertsonian and reciprocal translocations (ROBT and ReBT). Receiver operator characteristic (ROC) curves were plotted to ascertain a cutoff of MII oocytes and biopsied embryos as predictors of gaining at lowest one transferable embryo. There were no statistical differences in baseline features or ovarian response indicators regarding the number of retrieved/MII oocytes, E2 level on the day of HCG, and ovarian sensitivity index (OSI) between women with balanced autosomal translocations and control group (P > 0.05). A decreased number of transferable embryos were found in women with balanced autosomal translocations regardless of the type of translocation. The cutoff values for gaining at lowest one transferable embryo are 12.5 MII oocytes and 4.5 biopsied embryos, respectively. Women with balanced autosomal translocations have a normal ovarian response, but fewer transferable embryos, meaning that higher gonadotropin (Gn) doses may be required to increase transferable embryos. When fewer than 12.5 MII oocytes or 4.5 blastocysts are obtained in a PGT-SR cycle, couples should be notified that the likelihood of gaining a transferable embryo is low.

Evaluation of Risk Factors for the Birth of Children with Chromosomal Imbalance in Carriers of Autosomal Reciprocal Translocations

An important problem of genetic counseling is to determine the personalized risk of the birth of a child with an unbalanced karyotype in families with reciprocal translocation carriers. The risks of the formation of zygotes with chromosomal imbalance among carriers of balanced autosomal translocations vary significantly. These risks will depend on the most probable type of malsegregation for each specific translocation, leading to the formation of unbalanced gametes, and the probable viability of zygotes, embryos, fetuses, or newborns with unbalanced karyotype. In turn, these probabilities depend on many factors, including cytogenetic and quantitative characteristics of the translocation. During regression analysis of several independent factors and characteristics affecting the segregation behavior of the quadrivalent in meiosis I from 49 autosomal reciprocal translocations, it was found that the terminal location of breakpoints on the chromosomes involved in the translocation is statistically significant, i.e., independently associated with the risk of the birth of a viable child with chromosomal imbalance.

An Inherited Balanced Translocation Between Chromosomes 4 and 6 in Recurrent Pregnancy Loss: A Case Report

Recurrent pregnancy loss is an important reproductive issue with a heterogeneous etiology where two or more consecutive abortions occur before 20 weeks of gestation. Approximately 15% of all clinically recognized pregnancies result in miscarriage with an incidence of 1 in 300 cases. Couples, who experience repeated pregnancy loss before three months of gestation, mostly have fetuses with chromosomal aneuploids. A non-consanguineous couple with a married life of 4 years was referred to the Institute with a clinical history of three first trimester abortions. Karyotype analysis revealed a balanced autosomal translocation between chromosomes 4 and 6 with 46, XX, t (4;6)(q35; q22) karyotype in the female and normal 46, XY in the male partner. Therefore, the siblings and the couple were suggested for extended genetic counseling. Interestingly, similar translocation was seen in her father and three sisters, whereas her mother and elder sister showed a normal chromosomal constitution, indicating the paternal inheritance.

A new balanced autosomal translocation as a cause of premature ovarian insufficiency

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Two cases of complex balanced autosomal translocations associated with severe oligozoospermia

Complex balanced autosomal translocation is rare and can lead to impaired spermatogenesis in males; however, its effects on oligozoospermia have rarely been reported. We report here two cases of rare complex balanced translocation in men with infertility. The karyotype of the first case was 46,XY,der(1)t(1;12)(p22;p11.2)ins(9;1)(p24;q25q23),der(9)ins(9;1),der(12)t(1;12)·ish der(1)t(1;12)(RP11-636B1+;RP11-659D23+)ins(9;1)(RP11-118P13+),der(9)ins(9;1),der(12)t(1;12). And the patient showed severe oligozoospermia with adult schizophrenia without other abnormalities. The karyotype of the second patient was 46,XY,der(5)t(5;11)(q14;p11.2),der(11)t(11;18)(p11.2;q11.2),der(18)t(5,18)(q14;p11.3)add(18)(q11.2?)·ish der(5)t(5;11)(RP11-846K3+,RP11-89B9+),der(11)t(11;18)(RP11-89B9-,RP11-170L12+,RP11-469N6+),der(18)t(5;18)(RP11-125L2+,RP11-29M13+)add(18)(q11.2?), and the patient displayed severe oligozoospermia without other abnormalities. The two cases were verified by fluorescent in situ hybridization, and no abnormalities were found by genome-wide copy number variation analysis. To our knowledge, these two cases of complex autosomal karyotypes have not been reported previously. Although rare, these cases suggest that complex balanced translocations may be important causes of oligozoospermia. We speculate that the balanced translocation hinders germ cell meiosis and causes impaired spermatogenesis. Accordingly, the two reported patients have very low probabilities of giving birth to a normal child; therefore, we suggest choosing donor semen or adopting a child.

A Non‐Reciprocal Autosomal Translocation 64,XX, t(4;10)(q21;p15) in an Arabian Mare with Repeated Early Embryonic Loss

Balanced autosomal translocations are a known cause for repeated early embryonic loss (REEL) in horses. In most cases, carriers of such translocations are phenotypically normal, but the chromosomal aberration negatively affects gametogenesis giving rise to both genetically balanced and unbalanced gametes. The latter, if involved in fertilization, result in REEL, whereas gametes with the balanced form of translocation will pass the defect into next generation. Therefore, in order to reduce the incidence of REEL, identification of translocation carriers is critical. Here, we report about a phenotypically normal 3-year-old Arabian mare that had repeated resorption of conceptuses prior to day 45 of gestation and was diagnosed with REEL. Conventional and molecular cytogenetic analyses revealed that the mare had normal chromosome number 64,XX but carried a non-mosaic and non-reciprocal autosomal translocation t(4;10)(q21;p15). This is a novel translocation described in horses with REEL and the first such report in Arabians. Previous cases of REEL due to autosomal translocations have exclusively involved Thoroughbreds. The findings underscore the importance of routine cytogenetic screening of breeding animals.

Cytogenetic analysis of 531 Chinese women with premature ovarian failure

This retrospective cohort study was to determine the frequency and types of chromosomal abnormalities in Han Chinese women with well-documented premature ovarian failure (POF). Karyotype analysis and correlation to phenotypes were performed on 531 Chinese patients with proven POF (FSH > 40 mIU/ml) attending four reproductive centers in China. G-banded metaphase chromosomes were prepared and analyzed, with mosaicism excluded by counting up to 100 cells from lymphocytes. Chromosomal abnormalities were present in 64 of 531 (12.1%) POF cases, of which 32 were X-structural aberrations (7 mosaic): 15 del(Xq), 2 del(Xp), 11 isochromosomes [6 i(Xp); 5 i(Xq)], 1 ring chromosome (mosaic), 1 inversion (mosaic), 1 isodicentric chromosome and 1 complex arrangement. Nine non-mosaic X-autosome translocations were detected, all but 1 involving Xq. Aneuploidy without a structurally abnormal X was found in 19 cases: 7 non-mosaic 45,X, 9 45,X mosaicisms and 3 47,XXX (1 mosaic with 46,XX line). Karyotypic abnormalities were more frequent in patients with primary amenorrhea (15/70, 21.4%) than those with secondary amenorrhea (49/461, 10.6%; P = 0.01). 45,X and 45,X/46,XX mosaicism were the complements most frequently associated with primary amenorrhea (46.7%). Two of the three cases with 46,XY or 45,X/46,XY karyotype presented with 'secondary amenorrhea'. One balanced autosomal Robertsonian translocation was also detected. The overall prevalence of chromosomal abnormalities was 12.1% in this first large scale report of chromosomal aberrations in Chinese women with POF. In one of the largest samples of women with POF reported from any population, the prevalence of X-structural abnormalities, X-autosome translocations and X aneuploidy confirms the essential role X chromosomal abnormalities play in POF.

Balanced autosomal translocation and double Robertsonian translocation in cases of primary amenorrhea in an Indian population

ObjectiveTo assess the frequency of balanced autosomal translocations in patients with primary amenorrhea in an Indian population. MethodsCytogenetic analysis was carried out among women referred from all parts of India for primary amenorrhea between 2002 and 2010. Clinical history and laboratory findings were taken into consideration to determine the diagnosis. G-banding with trypsin–Giemsa was performed to detect chromosome abnormalities. ResultsThere were 15 balanced autosomal translocations in 1100 patients. Two novel translocations were identified: 1 with mosaic pattern of X chromosome monosomy and male karyotype, together with balanced autosomal translocation of chromosomes 11 and 20 in both cell lines; and 1 with double Robertsonian translocation of chromosomes 14 and 21. ConclusionAutosomal genes have a crucial role in reproductive development. More candidate genes need to be recognized for appropriate genetic counseling and clinical management.

Premature ovarian failure in a woman with a balanced 15;21 translocation: a case report

IntroductionA case of premature ovarian failure with concomitant findings of Robertsonian translocation between 15 and 21 chromosomes is reported here. The aforementioned karyotypic aberration has not been reported in the context of premature ovarian failure to date.Case presentationWe present a case of premature ovarian failure in a 27-year-old infertile Kurdish Iranian woman with a Robertsonian 15;21 translocation.ConclusionsThe diagnosis of premature ovarian failure of unknown etiology, but with karyotypic evidence of a balanced autosomal translocation, suggests the possible role of autosomal genes in the pathogenesis of ovarian follicular attrition.

Hormonal and ultrasound markers of ovarian function in a woman with a balanced 1;11 translocation

To present a case of a poor responder woman with a rare balanced autosomal translocation. Case report. Infertility center in a university teaching hospital. A 34-year-old white woman with primary infertility. Laboratory and ultrasound evaluation, karyotype analysis, ovarian stimulation with gonadotropins. Markers of ovarian reserve and ovarian response to gonadotropin stimulation. The patient was a carrier of a balanced translocation (1;11) (q23;p11.2). The hormone ovarian reserve markers (FSH, anti-Mullerian hormone, inhibin B) were within the normal range. The antral follicle count (AFC) was measured twice and only in one occasion did it reach the lower limit of the normal range. Furthermore, the patient had regular menstrual cycles. However, ovarian response to the administration of a maximal dose FSH was extremely poor. Patients with balanced autosomal translocations should be counseled regarding their increased risk for poor response even if markers of ovarian reserve are in the range of normality.

High Incidence of Minor Chromosomal Variants in Teratozoospermic Males

Chromosomal analysis was performed on 109 males with teratozoospermia. Four cases of anomaly were found, including three cases of mosaic Klinefelter's syndrome and one balanced autosomal translocation. Among chromosomal heteromorphisms, 9qh+ was found in 25% of the patients. The fraction of malformed spermatozoa in the semen of the 9qh+ group is significantly higher than in the chromosomally normal group. It is speculated that heterochromatic variants like 9qh+ could be one of several unknown factors disturbing normal gametogenesis.

Fine Mapping on Chromosome 10q22-q23 Implicates Neuregulin 3 in Schizophrenia

Linkage studies have implicated 10q22-q23 as a schizophrenia (SZ) susceptibility locus in Ashkenazi Jewish (AJ) and Han Chinese from Taiwan populations. To further explore our previous linkage signal in the AJ population (NPL score: 4.27, empirical p = 2 x 10(-5)), we performed a peakwide association fine mapping study by using 1414 SNPs across approximately 12.5 Mb in 10q22-q23. We genotyped 1515 AJ individuals, including 285 parent-child trios, 173 unrelated cases, and 487 unrelated controls. We analyzed the binary diagnostic phenotype of SZ and 9 heritable quantitative traits derived from a principal components factor analysis of 73 items from our consensus diagnostic ratings and direct assessment interviews. Although no marker withstood multiple test correction for association with the binary SZ phenotype, we found strong evidence of association by using the "delusion" factor as the quantitative trait at three SNPs (rs10883866, rs10748842, and rs6584400) located in a 13 kb interval in intron 1 of Neuregulin 3 (NRG3). Our best p value from family-based association analysis was 7.26 x 10(-7). We replicated this association in the collection of 173 unrelated AJ cases (p = 1.55 x 10(-2)), with a combined p value of 2.30 x 10(-7). After performing 10,000 permutations of each of the phenotypes, we estimated the empirical study-wide significance across all 9 factors (90,000 permutations) to be p = 2.7 x 10(-3). NRG3 is primarily expressed in the central nervous system and is one of three paralogs of NRG1, a gene strongly implicated in SZ. These biological properties together with our linkage and association results strongly support NRG3 as a gene involved in SZ.

Recurrent CNVs Disrupt Three Candidate Genes in Schizophrenia Patients

Schizophrenia is a severe psychiatric disease with complex etiology, affecting approximately 1% of the general population. Most genetics studies so far have focused on disease association with common genetic variation, such as single-nucleotide polymorphisms (SNPs), but it has recently become apparent that large-scale genomic copy-number variants (CNVs) are involved in disease development as well. To assess the role of rare CNVs in schizophrenia, we screened 54 patients with deficit schizophrenia using Affymetrix's GeneChip 250K SNP arrays. We identified 90 CNVs in total, 77 of which have been reported previously in unaffected control cohorts. Among the genes disrupted by the remaining rare CNVs are MYT1L, CTNND2, NRXN1, and ASTN2, genes that play an important role in neuronal functioning but--except for NRXN1--have not been associated with schizophrenia before. We studied the occurrence of CNVs at these four loci in an additional cohort of 752 patients and 706 normal controls from The Netherlands. We identified eight additional CNVs, of which the four that affect coding sequences were found only in the patient cohort. Our study supports a role for rare CNVs in schizophrenia susceptibility and identifies at least three candidate genes for this complex disorder.

Diminished ovarian reserve in a woman with a balanced 13;21 translocation

To present the a case of decreased ovarian reserve in a patient with a balanced 13;21 translocation. Case report. Reproductive endocrinology and infertility practice in a university teaching hospital. A 33-year-old caucasian woman with primary infertility. Laboratory evaluation, hysterosalpingogram, karyotype analysis, semen analysis. Endocrinologic evaluation and genetic analysis. A diagnosis of decreased ovarian reserve based upon laboratory evaluation with concomitant findings of a balanced translocation between the long arms of chromosomes 13 and 21. A diagnosis of primary infertility secondary to decreased ovarian reserve of unknown etiology, but with karyotype evidence of a balanced autosomal translocation and a familial history of early menopause, suggested possible roles of autosomal genes in mechanisms of ovarian follicular attrition.

First reported convergence of premature ovarian failure and cutis marmorata telangiectatica congenita

Objective To describe the convergence of five rare phenotypic features in a woman with premature ovarian failure referred for reproductive endocrinology evaluation. Design Case report and literature review. Setting Major urban infertility referral center. Patient(s) A 24-year-old nulligravida with cutis marmorata telangiectatica congenita (CMTC), premature ovarian failure, unilateral ovarian agenesis, septate uterus, and de novo balanced autosomal translocation. Intervention(s) High-resolution chromosomal evaluation, radiographic study of reproductive organs, and assessment of endogenous estrogen production. Main outcome measure(s) Patient counseling regarding future reproductive options (i.e., donor oocyte in vitro fertilization/embryo transfer), and satisfactory management of hypoestrogenism using oral contraceptives. Result(s) We identified a balanced reciprocal translocation 46,XX t(8;9)(q22.1;p24.1), and confirmed unilateral ovarian agenesis with midline intrauterine septum. Conclusion(s) Although genetic factors considered contributory to premature ovarian failure usually involve the X chromosome, in our patient a previously undescribed autosomal translocation was identified in association with CMTC, a rare vascular disorder. The fundamental role of follicular oxygenation in oocyte competence and subsequent ovarian function is discussed. From the clinical and laboratory findings evident in this unusual case, a developmental hypothesis connecting the vascular abnormalities of CMTC and premature ovarian failure is offered.

A new balanced autosomal reciprocal translocation in cattle revealed by banding techniques and human-painting probes

Three hundred and twenty-two (264 males and 58 females), randomly sampled Grey Alpine cattle individuals from Northeastern Italy, were investigated cytogenetically by both conventional chromosome staining and R-banding. Two hundred and eighty-one (87%) individuals had a normal karyotype and 41 (13%) carried chromosomal aberrations such as (a) rob(1;29) in two individuals, (b) rob(26;29) in 36 individuals, (c) XX/XY-chimerism in two individuals, and (d) an abnormally long chromosome in one individual. All these aberrations except (d) have been described before. GBG-, RBG-, CBA-banding and sequential GBG/CBA- and RBG/CBA-banding techniques revealed that the abnormally long chromosome was the result of a reciprocal translocation between chromosomes 1 (q21→qter) and 5 (q11→q33), as confirmed also by chromosome painting with human chromosome 3 and 12 probes. The dam of the carrier bull carried the same translocation, while the grandam showed a normal karyotype. Since the sire of the dam was not available for study, no conclusion about the origin of the chromosome translocation could be drawn. The carrier bull was eliminated because of poor fertility. The dam had three other calves, which all were chromosomally normal. On average the dam had to be served 2.5 times (breed average was 1.2) to be in calf.

Two de-novo balanced autosomal translocations after intracytoplasmic sperm injection

Intracytoplasmic sperm injection (ICSI) pregnancies have an increased risk of sex chromosome abnormalities, but not of de-novo autosomal rearrangements.1,2 Only one case of trisomy 21 has been reported in a woman aged 41 years.1

Recombination patterns around the breakpoints of a balanced 1;11 autosomal translocation associated with major mental illness.

The frequency and extent of pairing failure around human translocations are unknown. We have examined the pattern of recombination around the breakpoints of a balanced autosomal translocation t(1;11) (q43;q21) associated with major mental illness. DNA was available from 17 carriers and 10 non-translocation carriers with meioses involving four generations. The derivative 1 and 11 chromosomes were also isolated in somatic cell hybrids and used to confirm phase. We have genotyped pedigree members using 20 polymorphic markers within 10 cM on either side of both chromosome 1 and 11 breakpoints. We find no significant reduction of recombination in the vicinity of either breakpoint. However we estimate that there are insufficient meioses even in this large family to make a meaningful interpretation and suggest that sperm typing alone can answer these interesting questions.