Fei Wang

To report two novel TTN variants associated with fetal recessive titinopathy, thereby broadening the range of TTN variants that can lead to titinopathy. Clinical information on the fetus and parents was gathered, and genomic DNAs were extracted from the fetal tissue and family members' peripheral blood samples. Exome sequencing on fetal DNA was performed and following bioinformatics analysis, the suspected pathogenic variants were confirmed through Sanger sequencing. Prenatal ultrasound performed at 29 weeks of gestation revealed hydrops fetalis, decreased fetal movements, multiple joint contractures and polyhydramnios. Intrauterine fetal death was noted in the third trimester. Exome sequencing revealed compound heterozygous variants in the TTN gene: a paternally inherited allele c.101227C>T (p.Arg33743Ter) and a maternally inherited c.104254C>T (p.Gln34752Ter) allele. These variants have not been previously reported and are evaluated to be likely pathogenic according to the American College of Medical Genetics and Genomics guidelines. We report a fetus with hydrops fetalis and arthrogryposis multiplex congenita associated with a compound heterozygote in the TTN gene. Our report broadens the clinical and genetic spectrum associated with the TTN-related conditions.

Purpose Diminished ovarian reserve (DOR) is associated with compromised fertility that affects approximately 10% of couples. Gene mutations are implicated in the pathogenesis of DOR. Here, we aimed to assess the clinical and genetic characteristics of two sisters with impaired fertility history. The two sisters showed DOR and suffered from recurrent pregnancy loss (RPL) in natural pregnancy and in vitro fertilization-embryo transfer (IVF-ET). Methods Whole exome sequencing (WES) was performed for the proband and pathogenic variants detected were validated by Sanger sequencing in all available family members. Minigene assay was performed to evaluate the impact of sequence variants on splicing effect. Results Two novel heterozygous variants on the HFM1 gene, c.1978-2A > C and c.2680 + 3_2680 + 4delAT, were observed in the two patients. The genotype of their parents was all heterozygous, while the unaffected sister and brother did not carry the variants. Both variants could produce alternative transcripts compared to wild-type counterparts, which might result in protein dysfunction. Conclusion Our results demonstrated that the pathogenic splicing variants in HFM1 are associated with DOR in these two sisters. Mutations in HFM1 may contribute to RPL and poor IVF-ET outcomes because of descending quality and quantity of oocytes. The study enriched the genetic defect spectrum of DOR and understanding of the roles of HFM1 in female reproduction.

Androgenetic complete hydatidiform moles (CHMs) are associated with an increased risk of gestational trophoblastic neoplasia. P57^KIP2 expression in hydatidiform moles is thought to be a powerful marker for differentiating CHMs from partial hydatidiform moles (PHMs). However, since there are so few such families clinically, very few studies have addressed the importance of p57^KIP2-positive in the diagnosis and prognosis of CHM. This study aimed to emphasize the significance of the accurate diagnosis of rare CHM and careful follow-up. The classification of the hydatidiform mole was based on morphologic examination and p57^KIP2 expression was determined by p57^KIP2 immunohistochemical staining. Copy number variation sequencing was used to determine the genetic make-up of the mole tissues. In addition, the short tandem repeat polymorphism analysis was used to establish the parental origin of the moles. Finally, whole-exome sequencing was performed to identify the causal genetic variants associated with this case. In one Chinese family, the proband had numerous miscarriages throughout her two marriages. Morphologic evaluation and molecular genotyping accurately sub-classified two molar specimens as uniparental disomy CHM of androgenetic origin. Furthermore, p57^KIP2 expression was found in cytotrophoblasts and villous stromal cells. In the tissue, there were hyperplasia trophoblastic cells and heteromorphic nuclei. In this family, no deleterious variant genes associated with recurrent CHM were detected. It is important to evaluate the prognostic value of p57^KIP2 expression in androgenetic recurrent CHM. This knowledge may help to minimize erroneous diagnosis of CHMs as PHMs, as well as making us aware of the need to manage potential gestational trophoblastic neoplasia.