Parental Translocation Research Articles

Non-invasive prenatal diagnosis for translocation carriers-YES please or NO go?

The presence of an unbalanced familial translocation can be reliably assessed in the cytotrophoblast of chorionic villi. However, carriers of a balanced translocation often decline invasive testing. This study aimed to investigate whether an unbalanced translocation can also be diagnosed in cell free DNA by whole-genome non-invasive prenatal screening (NIPS). Pregnant women carrying a fetus with an unbalanced familial translocation, for whom NIPS as well as microarray data were available, were included in this retrospective assessment. NIPS was performed in the course of the TRIDENT study. In 12 cases, both NIPS and microarray data were available. In 10 of 12 cases the unbalanced translocation was correctly identified by NIPS without prior knowledge on parental translocation. One was missed because the fetal fraction was too low. One was missed because of technical restrictions in calling 16p gains. This study supports the hypothesis that routine NIPS may be used for prenatal diagnosis of unbalanced inheritance of familial translocations, especially with prior knowledge of the translocation allowing focused examination of the involved chromosomal regions. Our study showed that routine shallow sequencing designed for aneuploidy detection in cell free DNA may be sufficient for higher resolution NIPS, if specialized copy number software is used and if sufficient fetal fraction is present.

P–540 A feasible diagnostic approach for the cryptic subtelomeric traslocations in early recurrent miscarriage patients by preimplantation genetic testing (PGT)

Abstract Study question Could cryptic subtelomeric traslocations in early recurrent miscarriage patients be diagnosed by preimplantation genetic testing? Summary answer PGT is a powerful tool to detect subtelomeric cryptic traslocations identifying the cause of early recurrent miscarriage and allowing subsequent genetic counselling. What is known already: Chromosome translocations are frequently associated with birth defects, spontaneous early pregnancy losses and infertility. However, submicroscopic traslocations (so-called cryptic traslocations) are too small to be detected by conventional karyotyping.. Due to balanced status, high resolution molecular techniques as arrayCGH are not able to detect it. Thus, cryptic traslocations detection is challenging. PGT is able to detect CNVs at higher resolution than routine karyotyping. Therefore, the recurrent diagnosis of CNV at embryo level could suggest a subchromosomal parental traslocation. The aim of this study is to investigate the feasibility of using PGT as an indicator of parental balanced cryptic traslocations. Study design, size, duration We included three couples who underwent PGT for unexplained repeated pregnancy loss (RPL) in our clinic from February 2020 to November 2020. Common established causes of RPL (uterine anomalies, antiphospholipid syndrome, immunological, hormonal and metabolic disorders) were previously rouled-out. Even couple karyotypes were normal. Twenty-three embryos from those couples were biopsied at blastocyst and analysed for CNVs detection using low coverage whole genome NGS. Participants/materials, setting, methods PGT by NGS was performed by Veriseq-NGS (Illumina), with previous whole genome amplification. Fluorescence in situ hybridization (FISH) using parental blood samples were performed to validate the origin of subchromosomal number variation. Commercially available subtelomeric specific probes were selected according to the CNV identified and the procedures were performed according to the manufacturer’s protocols. Main results and the role of chance Overall, CNVs of terminal duplication and deletion that imply unbalanced traslocation derivatives were detected in the 43.5% of biopsied embryos. For couple 1, 4 out of 5 embryos (80%) carried deletion of telomeric region on chromosomes 5 and 21. Three out of 6 biopsed embyos (50%) were diagnosed with subchromosomal copy variants at telomeric region on chromosomes 6 and 16 for couple 2. In the case of couple 3, three out of 12 embryos (25%) were carriers of CNV at subtelomeric region on chromosomes 2 and 6. The size of CNVs detected ranges from 8Mb to 20Mb. Accurate diagnosis with the parental study was made by FISH. The combination of probes to detect the structural chromosome alteration were: Tel5qter-LSI21q, Tel6pter-CEP16 and Tel6pter-CEP6 for each couple respectively. The FISH studies reveal that CNVs were inherited from one parent carrying the balanced cryptic traslocation. Ultimately, the abnormal karyotype from the carrier parent were 46,XY,t(5;21)(q33.2;q21.2) for couple 1, 46,XY,t(6;16)(p22.3;q22.1) for couple 2 and 46,XY,t(2;6)(p25.1;p24.2) for couple 3. Finally, each couple performed a cryotransfer of a single normal balanced embryo. Two pregnancies are ongoing. Limitations, reasons for caution The main limitation of this approach is the NGS- PGT resolution. CNVs smaller than 5Mb could not be detected. Wider implications of the findings: This study shows the value of PGT for unexplained RPL, followed by parental FISH to better characterize CNVs and identify couples in whom one partner carries a cryptic translocation. Accurate diagnosis of parental chromosome translocation can achieve with FISH only, but FISH would not be performed unless PGT showed CNVs. Trial registration number Not applicable

Parental balanced chromosomal rearrangement leading to major genomic imbalance and an autosomal trisomy resulting in consecutive pregnancy loss: a case report

Chromosomal aberrations such as parental balanced translocation contribute to a significant proportion of recurrent pregnancy losses. These have extreme genetic implications on the foetus which can either cause physical and/or mental retardation or early death. In this study, we report a unique clinical case of a couple with three consecutive pregnancy losses and we aim to determine the genetic abnormalities causing the miscarriages. Conventional cytogenetic and molecular genetic analysis were performed on the products of conception as well as for the parents. Chromosomal analysis was performed based on the ISCN 2016 guidelines. This was followed by Chromosomal microarray analysis carried out using ISCA consortium probe set (8X60K). Genetic testing for the 1st product of conception was not performed. However, the 2nd and 3rd products of conception indicated an autosomal trisomy 22 and a 3.7 Mb deletion of 2p (cytoband p25.3) along with 13.6 Mb duplication of 16p (cytoband p13.3p13.12), respectively. The paternal karyotype was normal but mother showed a balanced translocation 46,XX,t(2;16)(p25.3;p13.3). This was parallel to the products of conception microarray findings, unbalanced chromosomal abnormality in the foetus. Balanced translocation carriers are susceptible for meiotic nondisjunction processes and early detection of genetic anomalies can be informative to parents trying to conceive. Genetic analysis of the abortus after the 1st loss can be helpful to understand the cause of miscarriage. A combined approach with microarray and karyotyping of the products of conception can be important to determine the specific aberrations in the foetal chromosomes leading to abortion.

Inherited unbalanced translocation (4p16.3p15.32 duplication/8p23.3p23.2deletion) in the four generation pedigree with intellectual disability/developmental delay

Chromosomal copy number variants (CNVs) are an important cause of congenital malformations and mental retardation. This study reported a large Chinese pedigree (4-generation, 76 members) with mental retardation caused by chromosome microduplication/microdeletion. There were 10 affected individuals with intellectual disability (ID), developmental delay (DD), and language delay phenotypes. SNP array analysis was performed in the proband and eight patients and found all of them had a microduplication of chromosome 4p16.3p15.2 and a microdeletion of chromosome 8p23.3p23.2. The high-resolution karyotyping analysis of the proband had unbalanced karyotype [46, XY, der(8)t(4;8)(p15.2;p23.1)mat], his mother had balanced karyotype [46, XX, t(4;8) (p15.2;p23.1)], whereas his father had normal karyotype [46,XY]. Fluorescence in situ hybridization (FISH) analysis further confirmed that the proband’s mother had a balanced translocation between the short arm terminal segment of chromosome 4 and the short arm end segment of chromosome 8, ish t(4;8)(8p + ,4q + ;4p + ,8q +). In conclusion, all the patients inherited chromosomes 8 with 4p16.3p15.2 duplication and 8p23.3p23.2 deletion from their parental balanced translocation, which might be the cause of the prevalence of intellectual disability. Meanwhile, 8p23.3p23.2 deletion, rather than 4p16.3p15.2 duplication might cause a more severe clinical syndrome.

Parental status is related to homing motivation in males of the glassfrog Centrolene savagei

The interaction between homing and parental care offers insights about the motivational aspects underlying movement patterns in animals. For species that care for offspring at fixed locations, offspring mortality in the absence of care might impact a parent’s motivation to home after being displaced from young. We tested whether homing motivation is related to parental care in the glassfrog Centrolene savagei (Centrolenidae), a species with extended male care and territoriality. Specifically, we evaluated how parental status (i.e. caring for eggs vs unmated yet territorial males) and translocation distance impacts homing motivation. Along a stream located in the Central Andes of Colombia, we translocated 23 male C. savagei between 5 and 80 m away from their reproductive territories. We found that both parental status and translocation distance impacts homing motivation, as caring males were more likely to return to their initial territories after translocation. Seven of the 16 caring males and one of the seven unmated males returned to the initial capture site. While unmated males might be motivated to home if reproductive territories are a limited resource, our results support that caring males exhibited much higher motivation to home. It is possible that the fitness benefits accrued from caring for vulnerable offspring alters the cost-to-benefits of homing, and thus accounts for a greater frequency of homing among caring males. This study contributes to understanding how aspects of life history (e.g. parental care) relate to homing motivation in vertebrates.

13q deletion syndrome resulting from balanced chromosomal rearrangement in father: the significance of parental karyotyping

BackgroundRetinoblastoma is a malignancy of the eye in children characterized by biallelic inactivation of the retinoblastoma 1 gene (RB1), located at chromosome 13q14.2. Children with interstitial chromosome 13q deletions that include the RB1 gene show a predisposition to develop retinoblastoma and variable other features. Large 13q deletions with severe clinical phenotype are nearly always the result of a de novo mutation, i.e. the pathogenic alteration is not detected in parents. This results in a low risk for siblings to develop 13q deletion syndrome.ResultHere, we describe a patient with profound muscle hypotonia, severe developmental delay and bilateral retinoblastoma carrying a large deletion in 13q13.3q14 with the size of 16 Mb, involving the RB1 gene. Neither parent showed retinoblastoma, muscle hypotonia or developmental delay. Chromosome analysis and Fluorescence in situ hybridization (FISH) showed a balanced complex chromosomal rearrangement (CCR) between chromosome 12 and 13 [ins(12;13)(q21.2;q12.3q14.3)] and an additional balanced translocation of chromosome 7 and 15 [t(7;15)(q31.2;q25.3)] in the healthy father. Malsegregation of the paternal insertional translocation involving chromosome 12 and 13 resulted in a 13q deletion syndrome of the child [46,XY,ins(12;13)(q21.2;q12.3q14.3)].ConclusionBalanced translocations in parents are a rare cause of de novo RB1 deletions in offspring. This case report emphasizes the need for parental chromosomal analysis and FISH in parents of children diagnosed with 13q deletion syndrome or large RB1 gene deletions to precisely determine the recurrence risk in siblings. Guidelines for genetic testing should be revised accordingly.

Non-mosaic partial duplication 12p in a patient with dysmorphic characteristics and developmental delay

Duplication of the short arm of chromosome 12 is a rare chromosomal abnormality that may arise de novo or result from malsegregation of a balanced parental translocation. This study comprises the clinical description, cytogenetic and cytogenomic analyses and genotype-phenotype correlation in a patient with facial dysmorphism, developmental delay and intellectual impairment caused by non-mosaic partial duplication and a paracentric inversion 12p. The patient’s GTG-banded karyotype was 46,XX,invdup(12)(pter → p13.32::p11.1 → p13.31::p13.31 → qter). A genetic gain of approximately 28 Mb was detected in the chromosomal region arr[GRCh37]12p13.31-p11.1(6914072_34756209)x3. The chromosomal alteration seen in our patient is described as “pure” partial duplication 12p. In most cases, duplication 12p phenotype is characterized by dysmorphic features, multiple congenital anomalies and intellectual disability. A small number of cases in literature have described genes associated with neurodevelopmental disease, such as ING4, CHD4, MFAP5, GRIN2B, SOX5, SCN8A and PIANP. In our patient the duplication 12p was de novo. This study should contribute to the genotype-phenotype correlation in partial duplication 12p cases.

Partial Monosomy 4p and Trisomy 12q due to a t(4;12)(p16.3;q24.31) Familial Translocation in Two Cousins

Wolf-Hirschhorn syndrome (WHS) is caused by a distal 4p monosomy usually involving the region of the WHSC1 and WHSC2 genes. About 40-45% of WHS patients show an unbalanced translocation leading to both 4p monosomy and partial trisomy of another chromosome arm. In this case report, we describe 2 female cousins (P1 and P2) with a derivative chromosome leading to a 4p16.3pter deletion and 12q24.31qter duplication. Conventional karyotyping and genomic analyses showed that they both had the same rearrangement derived from a balanced parental translocation involving chromosomes 4 and 12, t(4;12)(p16.3;q24.31). The rearrangements occurred between 4p16.3pter and 12q24.31qter detected by array-CGH analysis, with a 2.7-Mb loss at 4p and a large 12.4-Mb gain at 12q. Both affected patients shared global developmental delay and craniofacial dysmorphisms with some distinct phenotypic findings associated with both WHS and 12qter trisomy. P2 was more severely impaired than P1, and she showed severe intellectual disability, seizures, midface hypoplasia, unilateral microtia, and deafness which were absent in P1. Previous studies of distal 4p monosomies have found phenotypic variability in WHS which does not correlate with haploinsufficiency of specific genes. Features of 12q trisomies are diverse with developmental and growth delay, intellectual disability, behavioral problems, and facial abnormalities. Collectively, our analysis of the literature of 3 similar translocations involving 4p and 12q, together with the clinical features of the affected cousins in this familial translocation, permits an evaluation of genes closely linked to WHSC1 and WHSC2 in the context of WHS and the genes involved in 12q trisomy.

Molecular cytogenetic characterization of partial monosomy 2p and trisomy 16q in a newborn: A case report.

Trisomy 16q is a rare disorder with severe abnormalities, which always leads to early postnatal mortality. It usually results from a parental translocation, exhibiting 16q duplication associated with another chromosomal deletion. The present study reports on the clinical presentation and molecular cytogenetic results of a small-for-gestational-age infant, consisting of partial trisomy 16q21→qter and monosomy 2p25.3→pter. The proband presented with moderately low birthweight, small anterior fontanelles, prominent forehead, low hairline, telecanthus, flat nasal bridge, choanal atresia, clinodactyly of the fifth fingers, urogenital anomalies, congenital muscular torticollis and congenital laryngomalacia. The last two traits have not previously been reported in any trisomy 16q and monosomy 2p cases. The proband was trisomic for the 16q21→qter chromosomal region with the karyotype 46,XY,der(2)t(2;16)(p25;q21)pat. The chromosomal anomaly was the result of unbalanced segregation of a paternal balanced translocation, 46,XY,t(2;16)(p25;q21). In this case, molecular cytogenetic analysis had a critical role in delineating the proband's clinical phenotype. Although this patient had a 16q21→qter duplication and a 2p25.3→pter deletion, the latter may have had mild phenotypic effects when associated with trisomy 16q. The literature was also reviewed, focusing on cases with the same breakpoints, localizations and clinical features reported in recent years.

Correlation between prognostic chromosomal segregation and detected rearrangements in preimplantation embryos in a balanced translocation carrier

Introduction Individuals with balanced translocations are estimated to be around 1 % of the patients with infertility. A reciprocal translocation usually involves breakage of two non-homologous chromosomes with exchange of fragment with different size. The medical history of affected couples includes abortions, stillbirth, congenital anomalies, possible mental retardation and unsuccessful IVF attempts. It is hard to define the exact risk of unbalanced karyotypes in gametes, but it is accepted that it could be more than 80%. Preimplantation genetic screening (PGS) is strongly recommended in cases with chromosome rearrangements allowing the study of female gamete segregation. Material and Methods In the present case we performed two IVF-PGS cycles in a couple with a 34 years old woman with karyotype 46 XX, t(1;16)(q12;q13). Altogether, 14 embryos on day 3 where biopsied and tested using the 24sure (Illumina Inc., USA) protocol for BAC arrays. Results Out of the 14 tested embryos only two were euploid, five embryos had unbalanced genome due to the involvement of the chromosomes with the parental translocation. The other embryos had ‘sporadic'aneuploidy. After the PGS an embryotransfer of two euploid embryos was performed with one healthy baby born. Discussion Commonly more than 60 % of embryos obtained from patients with reciprocal translocations carry abnormal chromosomal constitution and about 1:28/30 are normal. In this case the percentage of unbalanced embryos - 5/14 (∼ 36 %) was significantly lower than the expected according to the published data. However, other independent aneuploidies also co-exist, most of which are age dependent. Conclusions The theoretical percentage of embryos with unbalanced karyotypes and the data from the clinical practice after performing PGS in IVF patients with balanced translocations does not match in every case. The phenomenon reveals the need of additional studies about the molecular mechanisms of chromosomal segregation in human gametes and preimplantation embryos delivered from balanced translocation carriers.

Results of preimplantation genetic testing for aneuploidies as a basis for parental karyotypes correction

Introduction Chromosomal abnormalities are the most common genetic cause of infertility. An information about karyotypes of patients undergoing in vitro fertilization (IVF) is not always known. Therefore, IVF patients can be potential carriers of structural chromosomal rearrangements. We report three cases, in which results of preimplantation genetic testing for aneuploidies (PGT-A) allowed us to suspect the presence of parental reciprocal translocations. In each case, the parental reciprocal translocation was confirmed. Material & Methods PGT-A was performed by microarray comparative genomic hybridization (aCGH) (24sure, Illumina) or by next generation sequencing (NGS) (VeriSeq, Illumina). Indications for preimplantation testing were advanced maternal age (case 1 and 2) and paternal pericentric inversion of chromosome 10 (case 3). Parental karyotypes were not known before PGT-A in cases 1 and 2. In case 3 patients’ karyotypes was known before PGT-A and were 46,XX and 46,XY,inv(10)(p11.2;q22). The trophectoderm biopsy was performed at 5-6 day of embryo development. Analysis of parental karyotypes after obtaining PGT results was performed by standard cytogenetic study or by fluorescence in situ hybridization (FISH) on peripheral blood lymphocyte culture. The choice of method of parental karyotypes analysis was determined by size of the embryo chromosomal imbalance. Results PGT-A results showed a nonrandom pattern of segmental loses and gains in each case (table 1). These facts were the basis for parental karyotypes analysis. It was confirmed, that in each case one of the couple was the carrier of reciprocal translocation. In case 1 a paternal reciprocal translocation between chromosomes 11 and 22 was found – 46,XY,t(11;22)(q23.3;q13). In case 2 a maternal reciprocal translocation between chromosomes 10 and 12 was found – ish t(10;12)(D10S2290-, D12S158+; D10S2290+, D12S158-). In case 3 a maternal reciprocal translocation between chromosomes 2 and 12 was found - ish t(2;12)(D2S2147-,D12S399+; D2S2147+, D12S399-). Table 1 Case № Number of embryos Number of embryos with nonrandom pattern of segmental abnormalities Chromosomes involved in nonrandom segmental abnormalities Case 1 5 3 Chromosomes 11 and 22 Case 2 4 4 Chromosomes 10 and 12 Case 3 4 3 Chromosomes 2 and 12 Conclusions It is very importantto draw attention to pattern of segmental chromosomal abnormalities of embryos. 24-chromosome aneuploidy testing is not only an actual method for detection of embryo chromosomal imbalance, but in some cases also can help to correct parental karyotypes.

Identification of chromosomal rearrangements by next-generation sequencing in blastocysts derived from couples with balanced translocations

Introduction Reciprocal translocations are one of the most common abnormalities in chromosomal structure. Couples with a balanced translocation have an increased risk for infertility and recurrent pregnancy loss. The present study aims to evaluate the ability of next-generation sequencing (NGS) to detect unbalanced chromosomal rearrangements in blastocysts derived from couples with balanced reciprocal translocations. Material & Methods First, the performance of NGS (VeriSeq, Illumina, USA) for unbalanced rearrangement detection was determined. Whole-genome amplification (WGA) products from trophectoderm biopsy samplesof 12 couples with a balanced reciprocal translocation previously analyzed by aCGH (24Sure+array, Illumina, USA) were reanalyzed by NGS. Second, a retrospective study was performed in a private ART clinic in Thailand between January to December 2017. A total of 70 embryos of 10 different couples with a balanced reciprocal translocation were analyzed by NGS and the pregnancy outcomes for couples with normal/balanced embryos available for transfer were followed up. Results NGS was 95.8% concordancefor detecting unbalanced chromosomal rearrangement with aCGH, and 99.7% for overall analyzed chromosomes. We found that NGS can detect segmental aneuploidies as small as 5 Mb in size. Results of 70 embryos revealed 30% normal/balanced embryos. 17.1% of embryos were found to be aneuploid balanced embryos and 2.9% of embryos were mosaic balanced embryos. Imbalanced segmental aneuploidies were detected in 50% of embryos, 47.1% of the imbalances were related to parental translocation while 2.9% of them were not related to parental translocation. Seven couples had normal/balanced embryos available for transfer, 57.1% (4/7) of them had clinical pregnancies as indicated by an intrauterine gestational sac with fetal heartbeat visualized by ultrasound examination at 3 months after embryo transfer. Conclusions Our results demonstrated that NGS hasa high resolution to detect imbalanced segmental rearrangements. The accurate detection of NGS for imbalanced segmental and whole chromosome aneuploidies might improve the IVF success rate and increase thechances of having a healthy child for translocation carriers.

Analysis of chromosomes of embryos derived from translocation carriers during preimplantation genetic diagnosis cycles

To explore the effect of chromosomal translocations on the composition of embryonic chromosomes and its mechanism. For 52 couples with one partner carrying a chromosomal translocation, results of next generation sequencing of all embryos derived from 61 cycles were divided into different groups based on the type of translocations, gender of the carrier, and maternal age. Effect of parental chromosomal translocations on the composition of embryonic chromosomes of each group was analyzed. A significant difference was found between carriers of reciprocal and Robertsonian translocations in terms of proportion of abnormal embryos and structurally normal chromosomes (63.3% vs. 27.5%, and 1.1% vs. 0.3%, respectively). Compared with male carriers, there was an increase in the rate of abnormalities for female carriers (67.2% vs. 58.3% for reciprocal translocations, and 45.5% vs. 13.8% for Robertsonian translocations). The risk for chromosomal abnormality also increased with the maternal age. No significant difference was found in the proportion of abnormal embryos between carriers divided by involvement of acrocentric chromosomes or terminal chromosomal breakpoints. The types of parental translocation, gender of carrier, maternal age, and interchromosomal effect have certain effect on the composition of embryonic chromosomes.

Increased Recurrence Risk in Phelan-McDermid (22q13.3 Deletion) Syndrome: the Importance of FISH Demonstrated by a Case Series of Five Families

Background: Phelan-McDermid syndrome (PMS), or 22q13.3 deletion syndrome, is a neurodevelopmental disorder with an estimated prevalence of 1 in 10,000 to 20,000 newborns. It usually occurs de novo, but an unexpectedly high recurrence risk is observed in some families. Our aim is to provide an overview of the underlying causes of recurrence in families with PMS and to summarize the available detection methods used to assess increased recurrence risk. Methods: We report clinical and (cyto)genetic data for five families with a high recurrence risk for PMS and provide an overview of Dutch families and cases from literature. We also outline a comprehensive work-up of additional cytogenetic testing to follow initial diagnosis in a proband. Results: Using fluorescent in situ hybridization (FISH), we confirmed a paternal translocation in two and a maternal mosaicism in three of our reported families. Of 34 cytogenetically investigated Dutch families, 16 to 20% have a high recurrence risk based on a parental chromosomal rearrangement. We found 18 additional families in the literature. Conclusions: Parental translocations and mosaicisms are not rare events in families with PMS, making follow-up FISH testing necessary. However, existing methods may still miss low-grade parental mosaicisms, and prenatal testing should always be offered.

Detection of fetal subchromosomal aberration with cell-free DNA screening led to diagnosis of parental translocation: Review of 11344 consecutive cases in a university hospital

BackgroundFetal chromosome aberrations and sub-chromosomal copy number variations (CNVs) are not rare. There are several ways to detect duplications and deletions; cell-free DNA screening (cfDNA screening) is nowadays an accurate and safe detection method. The objective of this study is to report the feasibility of cfDNA screening as an indicator of parental balanced chromosome translocation. ResultsFrom February 2015 to March 2016, cfDNA screening was offered to 11344 pregnant women. 137 out of 11344 individuals tested positive for aneuploidies using cfDNA screening were confirmed by karyotyping. 6 additional cases also tested positive for other deletion/duplication were confirmed by chromosomal microarray analysis (CMA). 11201 patients tested negative and 10342 of them were confirmed through interviews after delivery. Among the 137 cases that were screened positive in cfDNA screening, 91 were common trisomies (63 cases of trisomy 21, 25 cases of trisomy 18 and 3 cases of trisomy 13) and 46 cases were positive for sex-chromosomal abnormalities. In addition, 6 cases were positive for other deletion/duplication in which 2 were identified as terminal duplication and deletion on different chromosomes. The cfDNA screening findings were confirmed by CMA or karyotyping, and the origins of CNVs were validated afterward by karyotyping or fluorescence in situ hybridization (FISH) using parental blood samples. ConclusionCfDNA screening may help identify deletions and duplications in fetus, which in some cases may indicate risk of a parent being a balanced rearrangement carrier, and that the diagnostic follow-up testing is necessary.

Cytogenetic Findings on 11,451 Cases of Amniocentesis in Hanoi, Vietnam

Since the 1960s, amniocentesis has become a routine procedure performed in prenatal diagnostic clinics. This study aims to depict the results of amniocentesis, the frequency of chromosomal abnormality and emphasize on amniocentesis indications. A retrospective study was conducted on 11,451 cases who were referred to the Prenatal Diagnosis Center, the National Hospital of Obstetrics and Gynecology, Hanoi, Vietnam from 2012 to 2016. The rate of chromosomal abnormality was 6.7%. The chromosomal aberration in the group with mother or father carrying balanced parental translocations accounted for the highest rate of 22.0%. Triploidy was 1.2%, autosomal chromosome aberration was 59.7%, sex chromosome was 8.3%, and structural rearrangements was 30.8%. Trisomy 21 was the most frequent disorder founded in abnormal ultrasound findings (47.4%), following by the advanced maternal age (44.1%). The large sample size of this study provided reliable evidence to support the development of prenatal counseling and pregnancy management programs.

A child with multiple congenital anomalies due to partial trisomy 7q22.1\u2009\u2192\u2009qter resulting from a maternally inherited balanced translocation: a case report and review of literature

BackgroundParental balanced reciprocal translocations can result in partial aneuploidies in the offspring due to unbalanced meiotic segregation during gametogenesis. Herein, we report the phenotypic and molecular cytogenetic characterization of a 2 years and 4 months old female child with partial trisomy 7q22 → qter. This is the first such reported case resulting from a parental balanced translocation involving the long arms of chromosomes 7 and 14. The phenotype of the proband was compared with that of previously reported cases of trisomy 7q21 → qter or 7q22 → qter resulting from parental balanced translocations.Case presentationThe proband was born pre-term to a 34-year-old mother with a history of two first trimester miscarriages and an early infant death. She was referred at the age of 8 months for genetic evaluation due to prenatal and postnatal growth retardation, developmental delay and multiple congenital anomalies. On clinical evaluation, she had craniofacial dysmorphic features such as scaphocephaly, large anterior fontanelle with open posterior fontanelle, prominent occiput, triangular face, high forehead, hypertelorism, down slanting eyes, flat nasal bridge, small nose, low set ears, micro-retrognathia, high arched palate and short neck. Cranial computerized tomography scan showed lateral ventriculomegaly with features of early cerebral atrophy. Conventional cytogenetic analysis showed the karyotype 46,XX,der(14)t(7;14)(q22;q32)mat in the proband due to an unbalanced segregation of a maternal balanced translocation t(7;14)(q22;q32). Fluorescence in-situ hybridization analysis confirmed the partial trisomy 7q22 → qter in the proband with a minimal loss of genetic material on chromosome 14. Single nucleotide polymorphism array further confirmed the duplication on chromosome 7q22.1 → qter and a small terminal deletion on chromosome 14q32.3 → qter.ConclusionWe report the longest-surviving child with trisomy 7q22 → qter due to a parental balanced translocation between chromosomes 7 and 14. Clinical features observed in the proband were consistent with the consensus phenotype of partial trisomy 7q22 → qter reported in the scientific literature. Early diagnosis of these patients using molecular cytogenetic techniques is important for establishing the precise diagnosis and for making decisions pertaining to the prognostication and management of affected individuals.

A feasible diagnostic approach for the translocation carrier from the indication of products of conception

BackgroundChromosome translocations are rare but frequently associated with infertility. The objective of this study is to investigate the feasibility of using chromosomal microarray analysis (CMA) on products of conception (POC) samples as an indicator of parental balanced translocation. From January 2011 to December 2016, CMA using Affymetrix Cytoscan™750K array was performed on 1294 POC samples in our hospital. Karyotyping and fluorescence in situ hybridization (FISH) using parental blood samples were performed to validate the origin of subchromosomal copy number variations (CNVs).ResultsIn the 1294 cases of POCs, we detected CNVs of terminal duplication and deletion that imply unbalanced translocation derivatives in 16 cases, and accurate diagnosis with the parental study was made in all the cases by karyotyping and/or FISH. In 10/16 (62.5%) of these cases, CNVs were inherited from one carrier parent of balanced translocation (Cases 1 to 10), while 6/16 (37.5%) cases occurred de novo (Cases 11 to 16).ConclusionThis study clearly illustrated the importance of the utilization of CMA on POC, followed by parental karyotyping and FISH to better characterize CNVs. This approach is especially useful for couples in whom one partner carries a cryptic/submicroscopic balanced translocation but has an apparently normal karyotype.

Preliminary analysis of numerical chromosome abnormalities in reciprocal and Robertsonian translocation preimplantation genetic diagnosis cases with 24-chromosomal analysis with an aCGH/SNP microarray.

The aim of this study was to determine whether an interchromosomal effect (ICE) occurred in embryos obtained from reciprocal translocation (rcp) and Robertsonian translocation (RT) carriers who were following a preimplantation genetic diagnosis (PGD) with whole chromosome screening with an aCGH and SNP microarray. We also analyzed the chromosomal numerical abnormalities in embryos with aneuploidy in parental chromosomes that were not involved with a translocation and balanced in involved parental translocation chromosomes. This retrospective study included 832 embryos obtained from rcp carriers and 382 embryos from RT carriers that were biopsied in 139 PGD cycles. The control group involved embryos obtained from age-matched patient karyotypes who were undergoing preimplantation genetic screening (PGS) with non-translocation, and 579 embryos were analyzed in the control group. A single blastomere at the cleavage stage or trophectoderm from a blastocyst was biopsied, and 24-chromosomal analysis with an aCGH/SNP microarray was conducted using the PGD/PGS protocols. Statistical analyses were implemented on the incidences of cumulative aneuploidy rates between the translocation carriers and the control group. Reliable results were obtained from 138 couples, among whom only one patient was a balanced rcp or RT translocation carrier, undergoing PGD testing in our center from January 2012 to June 2014. For day 3 embryos, the aneuploidy rates were 50.7% for rcp carriers and 49.1% for RT carriers, compared with the control group, with 44.8% at a maternal age <36years. When the maternal age was ≥36years, the aneuploidy rates were increased to 61.1% for rcp carriers, 56.7% for RT carriers, and 60.3% for the control group. There were no significant differences. In day 5 embryos, the aneuploidy rates were 24.5% for rcp carriers and 34.9% for RT carriers, compared with the control group with 53.6% at a maternal age <36years. When the maternal age was ≥36years, the aneuploidy rates were 10.7% for rcp carriers, 26.3% for RT carriers, and 57.1% for the control group. The cumulative aneuploidy rates of chromosome translocation carriers were significantly lower than the control group. No ICE was observed in cleavage and blastocyst stage embryos obtained from these carriers. Additionally, the risk of chromosomal numerical abnormalities was observed in each of the 23 pairs of autosomes or sex chromosomes from day 3 and day 5 embryos. There was not enough evidence to prove that ICE was present in embryos derived from both rcp and RT translocation carriers, regardless of the maternal age. However, chromosomal numerical abnormalities were noticed in 23 pairs of autosomes and sex chromosomes in parental structurally normal chromosomes. Thus, 24-chromosomal analysis with an aCGH/SNP microarray PGD protocol is required to decrease the risks of failure to diagnose aneuploidy in structurally normal chromosomes.

Diagnosis of parental balanced reciprocal translocations by trophectoderm biopsy and comprehensive chromosomal screening.

This study investigates a case series of eight couples who underwent trophectoderm (TE) biopsy and comprehensive chromosomal screening (CCS) for routine aneuploidy screening and were found to have CCS results concerning for previously undetected parental balanced reciprocal translocations. In each case, controlled ovarian hyperstimulation and in vitro fertilization (IVF) yielded multiple blastocysts that each underwent CCS with high-density oligonucleotide microarray comparative genomic hybridization (aCGH). Parental translocations were suspected based on the finding of identical break point mutations in multiple embryos from each couple. Confirmation of these suspected translocations within blastocysts was performed with next-generation sequencing (NGS). Subsequent parental karyotypic evaluation resulted in a diagnosis of parental balanced reciprocal translocation in each case. We demonstrated that high-resolution aCGH and NGS on TE biopsies can accurately detect parental reciprocal translocations when previously unrecognized.