Hereditary Neuromuscular Disorders in Reproductive Medicine.

Neuromuscular disorders (NMDs) encompass a broad range of hereditary and acquired conditions that affect motor units, significantly impacting patients' quality of life and reproductive health. This narrative review aims to explore in detail the reproductive challenges associated with major hereditary NMDs, including Charcot-Marie-Tooth disease (CMT), dystrophinopathies, Myotonic Dystrophy (DM), Facioscapulohumeral Muscular Dystrophy (FSHD), Spinal Muscular Atrophy (SMA), Limb-Girdle Muscular Dystrophy (LGMD), and Amyotrophic Lateral Sclerosis (ALS). Specifically, it discusses the stages of diagnosis and genetic testing, recurrence risk estimation, options for preimplantation genetic testing (PGT) and prenatal diagnosis (PND), the reciprocal influence between pregnancy and disease, potential obstetric complications, and risks to the newborn.

Challenges of Preimplantation Genetic Counselling in the Context of Cystic Fibrosis and Other CFTR-Related Disorders: A Monocentric Experience in a Cohort of 92 Couples.

Cystic fibrosis is a highly prevalent genetic disorder caused by biallelic pathogenic variants in the gene, causing an altered function of the exocrine glands and a subsequent spectrum of hypofunctional and degenerative manifestations. The increasing availability of carrier screening programmes, the enhanced life expectancy of patients due to improved treatment and care strategies and the development of more precise and affordable molecular diagnostic tools have prompted a rise in demand of prenatal diagnosis procedures for at-risk couples, including Preimplantation Genetic Testing (PGT). However, challenges remain: heterogeneity among screening programmes, nuances of variant interpretation and availability of novel treatments demand a considerate and knowledgeable approach to genetic counselling.

An Unclassified Deletion Involving the Proximal Short Arm of Chromosome 10: A New Syndrome?

To date, only 13 studies have described patients with large overlapping deletions of 10p11.2-p12. These individuals shared a common phenotype characterized by intellectual disability, developmental delay, distinct facial dysmorphic features, abnormal behaviour, visual impairment, cardiac malformation, and cryptorchidism in males.

The impact of a second embryo biopsy for preimplantation genetic testing for monogenic diseases (PGT-M) with inconclusive results on pregnancy potential: results from a matched case-control study.

Purpose: To evaluate whether a second biopsy, following a first diagnostic failure on blastocysts tested for preimplantation genetic testing for monogenic diseases (PGT-M), allows to obtain genetic diagnosis and to what extent this procedure can influence clinical pregnancy and live birth rates compared to the PGT-M process with a successful genetic diagnosis from the first biopsy.

Methods: Embryos from women who underwent PGT-M in an infertility centre and who had been transferred after two biopsies for genetic analysis (n = 27) were matched in a 1:1 ratio accordingly to women's age (± 1 year) and fertility status (fertile vs infertile), as well as with the study period, with embryos who were transferred after receiving a conclusive PGT result straight after the first biopsy (n = 27). The main evaluated outcome was clinical pregnancy rate following embryo transfers in which healthy embryos were transferred after only one biopsy and those in which an embryo was transferred after being re-biopsied.

PGT-M for Premature Ovarian Failure Related to CGG Repeat Expansion of the Gene.

Primary ovarian failure (POF) is caused by follicle exhaustion and is associated with menstrual irregularities and elevated gonadotropin levels, which lead to infertility before the age of 40 years. The etiology of POI is mostly unknown, but a heterogeneous genetic and familial background can be identified in a subset of cases. Abnormalities in the fragile X mental retardation 1 gene () are among the most prevalent monogenic causes of POI.

Preimplantation Genetic Testing for Genetic Diseases: Limits and Review of Current Literature.

Preimplantation genetic testing (PGT) has emerged as a revolutionary technique in the field of reproductive medicine, allowing for the selection and transfer of healthy embryos, thus reducing the risk of transmitting genetic diseases. However, despite remarkable advancements, the implementation of PGT faces a series of limitations and challenges that require careful consideration. This review aims to foster a comprehensive reflection on the constraints of preimplantation genetic diagnosis, encouraging a broader discussion about its utility and implications.

Public Awareness and Acceptability of PGT-M in Cancer Predisposition Syndromes.

Cancer Predisposition Syndromes (CPSs), also known as Hereditary Cancer Syndromes (HCSs), represent a group of genetic disorders associated with an increased lifetime risk of developing cancer. In this article, we provide an overview of the reproductive options for patients diagnosed with CPS, focusing on the emerging role of Preimplantation Genetic Testing for Monogenic disorders (PGT-M). Specifically, we conducted a literature review about the awareness and acceptability of its application to CPSs.

Homozygous Mutations and Severe Early Onset Dilated Cardiomyopathy: Patient Report and Review of the Literature.

The gene encodes for the cardiac isoform of troponin I, a pivotal component of the sarcomeric structure of the myocardium. While heterozygous missense mutations have long been associated with autosomal dominant hypertrophic and restrictive cardiomyopathies, the role of null mutations has been more debated due to the paucity and weak characterization of reported cases and the low penetrance of heterozygous genotypes. In recent years, however, an increasing amount of evidence has validated the hypothesis that biallelic null mutations cause a severe form of neonatal dilated cardiomyopathy.

Epigenetics of pregnancy: looking beyond the DNA code.

Epigenetics is the branch of genetics that studies the different mechanisms that influence gene expression without direct modification of the DNA sequence. An ever-increasing amount of evidence suggests that such regulatory processes may play a pivotal role both in the initiation of pregnancy and in the later processes of embryonic and fetal development, thus determining long-term effects even in adult life. In this narrative review, we summarize the current knowledge on the role of epigenetics in pregnancy, from its most studied and well-known mechanisms to the new frontiers of epigenetic regulation, such as the role of ncRNAs and the effects of the gestational environment on fetal brain development.

Molecular tools for the genomic assessment of oocyte's reproductive competence.

The most important factor associated with oocytes' developmental competence has been widely identified as the presence of chromosomal abnormalities. However, growing application of genome-wide sequencing (GS) in population diagnostics has enabled the identification of multifactorial genetic predispositions to sub-lethal pathologies, including those affecting IVF outcomes and reproductive fitness. Indeed, GS analysis in families with history of isolated infertility has recently led to the discovery of new genes and variants involved in specific human infertility endophenotypes that impact the availability and the functionality of female gametes by altering unique mechanisms necessary for oocyte maturation and early embryo development.

Fertility counseling in women with hereditary cancer syndromes.

Hereditary cancer syndromes are a heterogeneous group of genetic conditions that are associated with an increased risk of developing cancer during lifespan. In affected women, parenthood may be accompanied by concerns for the offspring, considering the common autosomal dominant inheritance. Moreover, fertility preservation to prevent the detrimental effects of cancer treatments differs compared to other clinical contexts.

Chondrodysplasia and growth failure in children after early hematopoietic stem cell transplantation for non-oncologic disorders.

Bone dysplasias (osteochondrodysplasias) are a large group of conditions associated with short stature, skeletal disproportion, and radiographic abnormalities of skeletal elements. Nearly all are genetic in origin. We report a series of seven children with similar findings of chondrodysplasia and growth failure following early hematopoietic stem cell transplantation (HSCT) for pediatric non-oncologic disease: hemophagocytic lymphohistiocytosis or HLH (five children, three with biallelic HLH-associated variants [in PRF1 and UNC13D] and one with HLH secondary to visceral Leishmaniasis), one child with severe combined immunodeficiency and one with Omenn syndrome (both children had biallelic RAG1 pathogenic variants).

When embryology meets genetics: the definition of developmentally incompetent preimplantation embryos (DIPE)-the consensus of two Italian scientific societies.

A clear definition of developmentally incompetent preimplantation embryo (DIPE) in literature is still missing, while several scientific societies are discussing this challenging topic. From both a clinical and scientific perspective, the identification of embryos unfit for reproductive purpose is crucial. This aim should be pursued in light of all diagnostic technologies for embryo evaluation, encompassing also genetic analyses, of recent implementation in IVF.

Biallelic mutations in the gene cause a novel primary ciliopathy.

Background: Dysfunction in non-motile cilia is associated with a broad spectrum of developmental disorders characterised by clinical heterogeneity. While over 100 genes have been associated with primary ciliopathies, with wide phenotypic overlap, some patients still lack a molecular diagnosis.

Objective: To investigate and functionally characterise the molecular cause of a malformation disorder observed in two sibling fetuses characterised by microphthalmia, cleft lip and palate, and brain anomalies.

ESHRE PGT Consortium good practice recommendations for the detection of monogenic disorders.

The field of preimplantation genetic testing (PGT) is evolving fast and best practice advice is essential for regulation and standardisation of diagnostic testing. The previous ESHRE guidelines on best practice for PGD, published in 2005 and 2011, are considered outdated, and the development of new papers outlining recommendations for good practice in PGT was necessary. The current paper provides recommendations on the technical aspects of PGT for monogenic/single-gene defects (PGT-M) and covers recommendations on basic methods for PGT-M and testing strategies.

IUI and uterine lavage of in vivo-produced blastocysts for PGT purposes: is it a technically and ethically reasonable perspective? Is it actually needed?

A recent study by Munné et al. portrayed a protocol to retrieve in vivo produced blastocysts after IUI and uterine lavage for preimplantation genetic testing (PGT) purposes. The authors claimed this protocol might represent a reasonable future perspective for patients who do not want to undergo IVF, but still want to be informed about their embryos' genetic/chromosomal defects.

Testing single/combined clinical categories on 5110 Italian patients with developmental phenotypes to improve array-based detection rate.

Background: Chromosomal microarray analysis (CMA) is nowadays widely used in the diagnostic path of patients with clinical phenotypes. However, there is no ascertained evidence to date on how to assemble single/combined clinical categories of developmental phenotypic findings to improve the array-based detection rate.

Methods: The Italian Society of Human Genetics coordinated a retrospective study which included CMA results of 5,110 Italian patients referred to 17 genetics laboratories for variable combined clinical phenotypes.

Past, Present, and Future Strategies for Enhanced Assessment of Embryo's Genome and Reproductive Competence in Women of Advanced Reproductive Age.

Recent advancements in genomic analysis allow testing of an increasing number of genetic features in human preimplantation embryos. Typical single gene mutation and whole chromosomes testing can now be integrated with assessment of mitochondrial DNA and polygenic conditions. Diagnostic expansion into epigenetic and transcriptomic assessment in the near future are potential technological targets which may improve the prognostic outlook of patients of advanced reproductive age and overall fertilization (IVF) treatment outcomes.

Human teratogens and genetic phenocopies. Understanding pathogenesis through human genes mutation.

Exposure to teratogenic drugs during pregnancy is associated with a wide range of embryo-fetal anomalies and sometimes results in recurrent and recognizable patterns of malformations; however, the comprehension of the mechanisms underlying the pathogenesis of drug-induced birth defects is difficult, since teratogenesis is a multifactorial process which is always the result of a complex interaction between several environmental factors and the genetic background of both the mother and the fetus. Animal models have been extensively used to assess the teratogenic potential of pharmacological agents and to study their teratogenic mechanisms; however, a still open issue concerns how the information gained through animal models can be translated to humans. Instead, significant information can be obtained by the identification and analysis of human genetic syndromes characterized by clinical features overlapping with those observed in drug-induced embryopathies.

Failure mode and effects analysis of witnessing protocols for ensuring traceability during PGD/PGS cycles.

Preimplantation genetic diagnosis and aneuploidy testing (PGD/PGS) use is constantly growing in IVF, and embryo/biopsy traceability during the additional laboratory procedures needed is pivotal. An electronic witnessing system (EWS), which showed a significant value in decreasing mismatch occurrence and increasing detection possibilities during standard care IVF, still does not guarantee the same level of efficiency during PGD/PGS cycles. Specifically, EWS cannot follow single embryos throughout the procedure.

Polymorphism rs2274911 of GPRC6A as a Novel Risk Factor for Testis Failure.

Context: The G protein-coupled receptor GPRC6A is an emerging effector with multiple endocrine roles, including stimulation of T production from the testis. Recently, two men with an inactivating mutation (F464Y) of GPRC6A have been identified, and they showed primary testicular failure and deranged spermatogenesis. Furthermore, one of them also reported cryptorchidism at birth.

Role of familiarity versus interleukin-1 genes cluster polymorphisms in chronic periodontitis.

Periodontitis (PO) is a multifactorial disease affecting about 10% to 20% of the general population. Several studies have suggested that part of the clinical variability in PO might be explained by genetic factors. Among the candidate genes for PO, IL1 gene polymorphisms have been broadly investigated, with variable results, for their relationship with the disease.