Meiotic Silencing in Pigs: A Case Study in a Translocated Azoospermic Boar

Carriers of balanced constitutional reciprocal translocations usually present a normal phenotype, but often show reproductive disorders. For the first time in pigs, we analyzed the meiotic process of an autosome–autosome translocation associated with azoospermia. Meiotic process analysis revealed the presence of unpaired autosomal segments with histone γH2AX accumulation sometimes associated with the XY body. Additionally, γH2AX signals were observed on apparently synapsed autosomes other than the SSC1 or SSC15, as previously observed in Ataxia with oculomotor apraxia type 2 patients or knock-out mice for the Senataxin gene. Gene expression showed a downregulation of genes selected on chromosomes 1 and 15, but no upregulation of SSCX genes. We hypothesized that the total meiotic arrest observed in this boar might be due to the silencing of crucial autosomal genes by the mechanism referred to as meiotic silencing of unsynapsed chromatin (MSUC).

P–554 Reproductive risks and preimplantation genetic testing intervention for X-autosome translocation carriers

Study question For X-autosome translocation [t(X-A)] carriers, is it a more applicable preimplantation genetic testing (PGT) strategy, that distinguishing noncarrier from euploid/ balanced embryos and prioritized transfer? Summary answer Noncarrier and carrier embryos discrimination in PGT is an applicable strategy to avoid transferring genetic and reproductive risks to the offspring of t(X-A) carriers. What is known already Balanced t(X-A) is a specific reciprocal translocation, with a higher risk of detrimental phenotype and fertility issues compared to individuals with autosomal translocation. Alternative X-chromosome inactivation (XCI) is a specific pathogenic mechanism in this population. For carrier offspring of couples with t(X-A), the genetic counseling is challenged in both the prenatal and postpartum stages, because of the complexity and severity of phenotype outcomes that are unpredictable and associated with the complex XCI mechanism. Therefore, caution is necessary when designing a PGT strategy for couples with t(X-A). Study design, size, duration A retrospective study. We collected a 3-year-old girl with maternal translocation 46,X,t(X;1)(q28;p31.1) presenting with multiple congenital disabilities. Three couples with female t(X-A) carrier requesting for PGT. Participants/materials, setting, methods Karyotype analysis, whole-exome sequencing (WES), and X inactivation analysis were performed for the girl with congenital cardiac anomaly, language defect, and mild neurodevelopmental delay. PGT based on next-generation sequencing following the microdissecting junction region to distinguish noncarrier and carrier embryos were used in three couples with female t(X-A) carrier (Cases 1–3). Main results and the role of chance The girl carried a maternal balanced translocation 46,X,t(X;1)(q28;p31.1). WES revealed none monogenic mutation related to her phenotype, but she carried a rare skewed inactivation of the translocation X chromosome and spread to the adjacent interstitial 1p segment, contrary to her mother. All translocation breakpoints of Cases 1–3 were successfully identified and each couple underwent one PGT cycle. Thirty oocytes were retrieved, and 13 blastocysts were eligible for biopsy, of which 6 (46.15%) embryos were balanced and only 4 were noncarriers. Three frozen embryo transfers with noncarrier embryos resulted in the birth of two healthy children (one girl and one boy), who were subsequently confirmed to have normal karyotypes. We reported a girl with multiple congenital disabilities resulting from maternally balanced t(X-A) and validated that noncarrier and carrier embryo discrimination is an effective and applicable strategy for avoiding transferring genetic and reproductive risks to the offspring from t(X-A) carriers. Limitations, reasons for caution Here, we reported a girl with multiple congenital disabilities resulting from maternally balanced t(X-A) found different XCI patterns, while we did not further determine the mechanism causing the different XCI patterns between the girl and her mother. Wider implications of the findings: We demonstrated passing on a balanced t(X-A) may result in clinical manifestations associated with the X-inactivation, and verified the PGT strategy, that distinguishing normal and carrier embryos in can widely applied in t(X-A) carrier couples to avoid the genetic and reproductive risk of transferring t(X-A) to the next generation. Trial registration number the National Key Research & Developmental Program of China (2018YFC1004900), the National Natural Science Foundation of China (81771645 and 81971447), the Key Grant of Prevention and Treatment of Birth Defect from Hunan Province (2019SK1012), Hunan Provincial Grant for Innovative Province Construction (2019SK4012) and the Research Grant of CITIC-Xiangya (YNXM–201916).

Duchenne muscular dystrophy in a female with x-autosome translocation

Duchenne’s muscular dystrophy is the most common hereditary neuromuscular disease, which affects all races. Its classical characteristic clinical features being progressive muscular weakness, intellectual impairment and hypertrophy of the calves with proliferation of connective tissue and progressive fibrosis in muscles. As the disease is inherited as an X-linked recessive trait, thus females not manifesting the disease and acting as carriers only, as second X chromosome prevents the manifestation of disease. We report a case of classical Duchenne muscular dystrophy in 10 year old female with no intellectual deficit and no family history of similar type of muscular dystrophy.

Unbalanced Y;7 Translocation between Two Low-Similarity Sequences Leading to SRY-Positive 45,X Testicular Disorders of Sex Development

Unbalanced translocations of Y-chromosomal fragments harboring the sex-determining region Y gene (SRY) to the X chromosome or an autosome result in 46,XX and 45,X testicular disorders of sex development (DSD), respectively. Of these, Y;autosome translocation is an extremely rare condition. Here, we identified a 20-year-old man with a 45,X,t(Y;7)(q11.21;q35) karyotype, who exhibited unilateral cryptorchidism, small testis, intellectual disability, and various congenital anomalies. The fusion junction of the translocation was blunt, and the breakpoint-flanking regions shared only 50% similarity. These results indicate that Y;autosome translocations can occur between 2 low-similarity sequences, probably via nonhomologous end joining. Furthermore, translocations of a Ypterq11.21 fragment to 7q35 likely result in normal or only mildly impaired male-type sexual development, along with various clinical features of 7q deletion syndrome, although their effects on adult testicular function remain to be studied.