Genetic variants underlying developmental arrests in human preimplantation embryos.

Developmental arrest in preimplantation embryos is one of the major causes of assisted reproduction failure. It is briefly defined as a delay or a failure of embryonic development in producing viable embryos during ART cycles. Permanent or partial developmental arrest can be observed in the human embryos from one-cell to blastocyst stages. These arrests mainly arise from different molecular biological defects, including epigenetic disturbances, ART processes, and genetic variants. Embryonic arrests were found to be associated with a number of variants in the genes playing key roles in embryonic genome activation, mitotic divisions, subcortical maternal complex formation, maternal mRNA clearance, repairing DNA damage, transcriptional, and translational controls. In this review, the biological impacts of these variants are comprehensively evaluated in the light of existing studies. The creation of diagnostic gene panels and potential ways of preventing developmental arrests to obtain competent embryos are also discussed.

Translational aspects of novel findings in genetics of male infertility-status quo 2021.

INTRODUCTION: Male factor infertility concerns 7-10% of men and among these 40-60% remain unexplained. SOURCES OF DATA: This review is based on recent published literature regarding the genetic causes of male infertility. AREAS OF AGREEMENT: Screening for karyotype abnormalities, biallelic pathogenic variants in the CFTR gene and Y-chromosomal microdeletions have been routine in andrology practice for >20 years, explaining ~10% of infertility cases. Rare specific conditions, such as congenital hypogonadotropic hypogonadism, disorders of sex development and defects of sperm morphology and motility, are caused by pathogenic variants in recurrently affected genes, which facilitate high diagnostic yield (40-60%) of targeted gene panel-based testing. AREAS OF CONTROVERSY: Progress in mapping monogenic causes of quantitative spermatogenic failure, the major form of male infertility, has been slower. No 'recurrently' mutated key gene has been identified and worldwide, a few hundred patients in total have been assigned a possible monogenic cause. GROWING POINTS: Given the high genetic heterogeneity, an optimal approach to screen for heterogenous genetic causes of spermatogenic failure is sequencing exomes or in perspective, genomes. Clinical guidelines developed by multidisciplinary experts are needed for smooth integration of expanded molecular diagnostics in the routine management of infertile men. AREAS TIMELY FOR DEVELOPING RESEARCH: Di-/oligogenic causes, structural and common variants implicated in multifactorial inheritance may explain the 'hidden' genetic factors. It is also critical to understand how the recently identified diverse genetic factors of infertility link to general male health concerns across lifespan and how the clinical assessment could benefit from this knowledge.

Diagnostics of Hereditary Connective Tissue Disorders by Genetic Next-Generation Sequencing.

Aims: This quality analysis study was designed to review the indications, reports, and clinical consequences of 438 diagnostic next-generation sequencing (NGS) gene panel analyses for hereditary connective tissue disorders (HCTD). Methods: Molecular analyses were retrieved from laboratory databases and patient records, and compared to the clinical information in the requisition and classified according to the Human Phenotype Ontology. Results: In 123 of 438 NGS analyses, 156 sequence variants were reported in 33 of 54 genes analyzed. NGS analyses and, in some cases, postanalytic assessment resulted in identification of pathogenic variants in 40 (9%) of patients, and variants of uncertain significance were identified in 83 (19%) of cases analyzed. While cardiovascular abnormalities were the most common phenotype noted in the requisitions, no specific organ system could be identified in which the reported symptoms provided an actionable indication for the analysis. Certain health issues recorded in the patients' records were found to be frequently left out of requisitions. Conclusions: The interpretation of genetic sequence variants continues to be a significant challenge in HCTD. Although not associated with the highest diagnostic yield, cardiovascular disease and family history may be suitable indications for NGS due to the clinical consequences of the identification of a known or likely causative sequence variant for a vascular HCTD in patients and relatives.