Frequency and clinical significance of chromosomal inversions prenatally diagnosed by second trimester amniocentesis.

To compare the frequency and clinical significance of familial and de novo chromosomal inversions during prenatal diagnosis. This was a retrospective study of inversions diagnosed prenatally in an Asian population by applying conventional GTG-banding to amniocyte cultures. Data from 2005 to 2019 were extracted from a single-center laboratory database. The types, frequencies, and inheritance patterns of multiple inversions were analyzed. Pericentric variant inversions of chromosome 9 or Y were excluded. In total, 56 (0.27%) fetuses with inversions were identified in the 15-year database of 21,120 confirmative diagnostic procedures. Pericentric and paracentric inversions accounted for 62.5% (35/56) and 37.5% of the inversions, respectively. Familial inversions accounted for nearly 90% of cases, and de novo mutation was identified in two pericentric and two paracentric cases. Inversions were most frequently identified on chromosomes 1 and 2 (16.1% of all inversions), followed by chromosomes 6, 7, and 10 (8.9% of all cases). The indications for invasive testing were as follows: advanced maternal age (67.3%), abnormal ultrasound findings (2.1%), abnormal serum aneuploidy screening (20.4%), and other indications (10.2%). The mode of inheritance was available for 67.9% of cases (38/56), with 89.5% of inversions being inherited (34/38). A slight preponderance of inheritance in female fetuses was observed. Three patients with inherited inversions opted for termination (two had severe central nervous system lesions and one had thalassemia major). Gestation continued for 53 fetuses, who exhibited no structural defects at birth or significant developmental problems a year after birth. Our study indicates that approximately 90% of prenatally diagnosed inversions involve familial inheritance, are spreading, and behave like founder effect mutations in this isolated population on an island. This finding can help to alleviate anxiety during prenatal counseling, which further underscores the importance of parental chromosomal analysis, further genetic studies, and appropriate counseling in cases where a nonfamilial inversion is diagnosed.

Clinical outcomes of Preimplantation genetic testing (PGT) application in couples with chromosomal inversion, a study in the Chinese Han population.

BACKGROUND: Chromosomal inversion was considered to have adverse effects on pregnancy outcomes through abnormal gametogenesis. The purpose of this retrospective study was to investigate whether preimplantation genetic testing (PGT) improves pregnancy outcomes for couples with chromosomal inversion. METHODS: A total of 188 cycles from 165 couples with one chromosomal inversion carrier were divided into two groups: PGT (136 cycles, 125 couples) and non-PGT (52 cycles, 50 couples). Biochemical pregnancy, clinical pregnancy, ongoing pregnancy, miscarriage and live birth rates of their first transfer cycles, as well as cumulative live birth rates of each cycle and euploidy rates, were analyzed. RESULTS: There were no statistically significant differences in the pregnancy outcomes between the two groups. The euploidy rate of pericentric inversion carriers was not higher than that of paracentric inversion carriers in PGT group (60.71% vs 50.54%, P = 0.073). Similarly, the euploid rate of male carriers was not higher than that of female carriers (61.2% vs 56.1%, P = 0.256). CONCLUSIONS: Due to limitation of retrospective study and small sample size, our current data showed that PGT cannot provide prominent benefits for inversion carriers in the Chinese Han population. Further prospective randomized controlled trials are needed to evaluate the effects of PGT.

Retrospective analysis of meiotic segregation pattern and interchromosomal effects in blastocysts from inversion preimplantation genetic testing cycles.

OBJECTIVE: To determine factors affecting unbalanced chromosomal rearrangement originating from parental inversion and interchromosomal effect occurrence in blastocysts from inversion carriers. DESIGN: Retrospective study. SETTING: University-affiliated center. PATIENT(S): Couples with one partner carrying inversion underwent preimplantation genetic testing for chromosomal structural rearrangement cycles. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Unbalanced rearrangement embryo rate, normal embryo rate, interchromosomal effect. RESULT(S): Preimplantation genetic testing was performed for 576 blastocysts from 57 paracentric (PAI) and 94 pericentric (PEI) inversion carriers. The percentage of normal/balanced blastocysts was significantly higher in PAI than PEI carriers (70.4% vs. 57.5%). Logistic regression indicated the inverted segment size ratio was a statistically significant risk factor for abnormality from parental inversion in both PEI and PAI. The optimal cutoff values to predict unbalanced rearrangement risk were 35.7% and 57%. In PAI, rates of abnormality from parental inversion were 0% and 12.1% in the <35.7% and ≥35.7% groups, respectively, with no gender difference. For PEI, the rates of abnormality from parental inversion were 7.9% and 33.1% in the <57% and ≥57% groups, respectively. In the ≥57% group, the rate of unbalanced rearrangement was significantly higher from paternal than maternal inversion (43.3% vs. 23.6%). In inversion carriers, 21,208 chromosomes were examined, and 187 (0.88%) malsegregations were identified from structurally normal chromosomes. In controls, 56,488 chromosomes were assessed, and 497 (0.88%) aneuploidies were identified, indicating no significant difference. CONCLUSION(S): The risk of unbalanced rearrangement is affected by the ratio of inverted segment size in both PAI and PEI carriers and is associated with gender.

Matrix inversions for chromosomal inversions: a method to construct summary statistics in complex coalescent models.

Chromosomal inversions allow genetic divergence of locally adapted populations by reducing recombination between chromosomes with different arrangements. While patterns of genetic variation within inverted regions are increasingly documented, inferential methods are largely missing to analyze such data. Previous work has provided expectations for coalescence patterns of neutral sites linked to an inversion polymorphism in two locally adapted populations. Here, we define a method to construct summary statistics in such complex population structure models. Under a scenario of selection on the inversion breakpoints, we first construct estimators of the migration rate between the two habitats, and of the recombination rate of a nucleotide site between the two inversion backgrounds. Next, we analyze the disequilibrium between two sites within an inversion and provide an estimator of the distinct recombination rate between these two sites in homokaryotypes and heterokaryotypes. These estimators should be suitable summary statistics for simulation-based methods that can handle the complex dependences in the data.

Cryptic genomic imbalances in de novo and inherited apparently balanced chromosomal rearrangements: array CGH study of 47 unrelated cases.

Investigations of apparently balanced chromosomal rearrangements in patients with abnormal phenotype by molecular cytogenetics tools, especially by array CGH, revealed a proportion of unsuspected imbalances. It was estimated recently that 40% of apparently balanced de novo translocations with abnormal phenotype were associated with cryptic deletion. We explored 47 unrelated mental retardation patients carrying an apparently balanced chromosomal rearrangement with high-resolution oligonucleotides arrays. We included 33 de novo cases (21 translocations, 7 inversions and 5 complex chromosomal rearrangements (CCR)) and 14 inherited cases (7 translocations, 5 inversions and 2 CCR). Twenty of the 47 cases (42.6%) carried a cryptic deletion ranging from 60 kb to 15.37 Mb. It concerned 16/33 de novo rearrangements (8/21 translocations, 4/7 inversions and 4/5 CCR) and 4/14 inherited rearrangements (1/7 translocations, 2/5 inversions and 1/2 CCR). The proportion of imbalances was not statistically different between de novo and inherited cases. Our results support that about 40% apparently balanced chromosomal rearrangements with abnormal phenotype are in fact imbalanced and that these rearrangements should be systematically investigated by array CGH independently of their de novo or inherited character.

[Cytogenetic analysis of the noxious bloodsucker Boophthora erythrocephala (Diptera: Simuliidae) from different geographic zones].

Boophthora erythrocephala is a widely spread species inhabiting both small polluted water-bodies and large rivers. Three populations from Samara region in Russia and from Donetsk and Chernigov regions in the Ukraine have been studied. Five populations of this species in Russia were described earlier (Polyanskaya, Tsapygina, 1968; Petrukhina, 1972). For identification of this species the chromosome map of Adler and Werner (personal communication) was used. Comparison of 8 populations studied was performed. All of them belong to the species B. erythrocephala but everyone has its own individual characteristics. Inversion polymorphism was observed in each population comprising from 88 to 100 %. Mean number of heterozygous inversions per individual is low fluctuating around 3.6. There is one inversion in IIS observed in all populations that proves panmixy among them. Other inversions occur in a part of the individuals.

Frequency of intron 1 and 22 inversions of Factor VIII gene in Mexican patients with severe hemophilia A.

Hemophilia A (HA) is one of the most common inherited bleeding disorders caused by FVIII gene mutations. Inversion of intron 22 (inv22) originates 50% of cases of severe HA and is a major risk factor for inhibitor development. Inversion of intron 1 (inv1) has been reported to occur in 2-3% of severe HA patients. We studied both inversions to determine their frequencies in Mexican patients with severe HA and to compare these data with other HA populations. The inv22 was evaluated as a risk factor for FVIII inhibitor development in severe HA patients. We studied 44 patients from 31 severe HA families for the detection of inv22 and 94 patients from 65 families to detect inv1. We used the subcycling long-distance PCR to detect inv22 and rapid PCR in duplex reactions to detect inv1. We found a frequency of 45% for the inv22 and no inv1-positive patients (0%). These frequencies were not statistically different from other populations, although haplotype analyses of FVIII gene and telomeric regions should be incorporated to explore population-specific variation of inv1 frequencies. Inv22-positive patients showed 1.88X higher risk for developing inhibitors with respect to patients carrying other severe mutations; however, this OR value was not significant. Our findings confirm inv22 as a hot-spot for severe HA and evidence the low frequency of inv1 in a Mexican population. The non-significant risk for developing inhibitors among inv22-positive patients agrees with the variety of genetic and non-genetic factors involved in such a complication.

Prenatally diagnosed balanced chromosome rearrangements: eight years' experience.

OBJECTIVE: To investigate the incidence and pregnancy outcome of prenatally diagnosed balanced chromosome rearrangements from amniocentesis. STUDY DESIGN: Between January 1996 and December 2003, we collected cases with balanced chromosome rearrangements from amniocentesis specimens submitted to our cytogenetics laboratory for fetal karyotyping. Data on maternal age, indication for amniocentesis, detailed anatomic sonographic findings, gestational age at delivery, newborn birth weight and infant anomalies, if any, were obtained by chart review. RESULTS: A total of 66 cases of balanced chromosomal translocations or inversions were identified from the 12,468 amniocentesis specimens. Specifically, 0.256% had a reciprocal translocation, 0.080% had a Robertsonian translocation, and 0.192% had an inversion. The incidences of de novo reciprocal translocations, Robertsonian translocations and inversions were 0.080%, 0.016% and 0.024%, respectively. Abnormal prenatal sonographic findings occurred in 2 cases, 1 in an inherited case and 1 in a de novo case. Abnormal postnatal findings occurred in 5 cases, 3 in inherited cases and 2 in de novo cases. Excluding the cases with minor congenital anomalies, the major congenital anomaly rates of inherited and de novo chromosome rearrangements were 1.96% and 6.66%, respectively. CONCLUSION: The incidences of prenatally diagnosed de novo reciprocal translocations, de novo Robertsonian translocations and de novo inversions were higher than those reported in previous, larger series. The major congenital anomaly rates for inherited and de novo chromosome rearrangements were higher than the 1.4% congenital anomaly rate in our general population. Consequently, detailed ultrasound examination and parental karyotyping should be viewed as essential measures in dealing with prenatally diagnosed balanced chromosome rearrangements.

Accommodating chromosome inversions in linkage analysis.

This work develops a population-genetics model for polymorphic chromosome inversions. The model precisely describes how an inversion changes the nature of and approach to linkage equilibrium. The work also describes algorithms and software for allele-frequency estimation and linkage analysis in the presence of an inversion. The linkage algorithms implemented in the software package Mendel estimate recombination parameters and calculate the posterior probability that each pedigree member carries the inversion. Application of Mendel to eight Centre d'Etude du Polymorphisme Humain pedigrees in a region containing a common inversion on 8p23 illustrates its potential for providing more-precise estimates of the location of an unmapped marker or trait gene. Our expanded cytogenetic analysis of these families further identifies inversion carriers and increases the evidence of linkage.

Embryonic karyotype in recurrent miscarriage with parental karyotypic aberrations.

OBJECTIVE: To assesses chromosomal aberrations in the abortus in recurrent miscarriage, in the presence of parental chromosomal aberrations. DESIGN: Retrospective comparative cohort study. SETTING: Tertiary referral unit in university hospital. PATIENT(S): One thousand one hundred eight patients with 3-16 miscarriages before 20 weeks gestation; 113 patients with and 995 without chromosomal aberrations. INTERVENTION(S): Karyotyping by standard G-banding techniques of both parents, and of 205 abortuses collected at curettage. MAIN OUTCOME MEASURE(S): The incidence of the euploidic and aneuploidic abortuses according to the parental karyotype. RESULT(S): Two hundred three abortuses were successfully karyotyped. In 164 embryos of patients with no parental chromosomal aberrations, 23.2% (38/164) had chromosome aberrations. Of the 39 abortuses karyotyped in patients with chromosomal aberrations, 17 had normal karyotypes, 8 had balanced translocations, 2 had inversions identical to the parents, and 12 (30.8%) had abnormal karyotypes. This difference is not statistically significant (odd ratio 1.47, 95% confidence interval 0.63-3.39). Only 4 of the 39 karyotyped abortuses had an unbalanced translocation. CONCLUSION(S): Parental karyotyping was not particularly predictive of a subsequent miscarriage as a result of chromosomal aberrations as 43.5% of abortuses were euploidic, and the parental aberration was only passed on to the abortus in 10% of cases.

Highly multiplexed molecular inversion probe genotyping: over 10,000 targeted SNPs genotyped in a single tube assay.

Large-scale genetic studies are highly dependent on efficient and scalable multiplex SNP assays. In this study, we report the development of Molecular Inversion Probe technology with four-color, single array detection, applied to large-scale genotyping of up to 12,000 SNPs per reaction. While generating 38,429 SNP assays using this technology in a population of 30 trios from the Centre d'Etude Polymorphisme Humain family panel as part of the International HapMap project, we established SNP conversion rates of approximately 90% with concordance rates >99.6% and completeness levels >98% for assays multiplexed up to 12,000plex levels. Furthermore, these individual metrics can be "traded off" and, by sacrificing a small fraction of the conversion rate, the accuracy can be increased to very high levels. No loss of performance is seen when scaling from 6,000plex to 12,000plex assays, strongly validating the ability of the technology to suppress cross-reactivity at high multiplex levels. The results of this study demonstrate the suitability of this technology for comprehensive association studies that use targeted SNPs in indirect linkage disequilibrium studies or that directly screen for causative mutations.