A systematic review and standardized clinical validity assessment of genes involved in female reproductive failure

Genetic testing is becoming increasingly required at almost every stage of failed female reproduction/infertility. Nonetheless, clinical evidence for the majority of identified gene-disease relationships is ill-defined, thus leading to difficult gene variant interpretation and poor translation of existing knowledge into clinics. We aimed to identify the genes that have ever been implicated in monogenic female reproductive failure in humans and to classify the identified gene-disease relationship pairs using a standardized clinical validity assessment. A PubMed search following PRISMA guidelines was conducted on 20 September 2021 aiming to identify studies pertaining to genetic causes of phenotypes of female reproductive failure. The clinical validity of identified gene-disease pairs was assessed using standardized criteria, counting whether sufficient genetic and experimental evidence has been accumulated to consider a single gene 'characterized' for a single Mendelian disease. In total, 1256 articles were selected for the data extraction; 183 unique gene-disease pairs were classified spanning the following phenotypes: hypogonadotropic hypogonadism, ovarian dysgenesis, premature ovarian failure/insufficiency, ovarian hyperstimulation syndrome, empty follicle syndrome, oocyte maturation defect, fertilization failure, early embryonic arrest, recurrent hydatidiform mole, adrenal disfunction and Mullerian aplasia. Twenty-four gene-disease pairs showed definitive evidence, 36 - strong, 19 - moderate, 81 - limited and 23 - showed no evidence. Here, we provide comprehensive, systematic and timely information on the genetic causes of female infertility. Our classification of genetic causes of female reproductive failure will facilitate the composition of up-to-date guidelines on genetic testing in female reproduction, the development of diagnostic gene panels and the advancement of reproductive decision-making.publishersversionPeer reviewe

The outcomes after transfers of embryos with chromosomal mosaicism : a single reproductive medicine center experience at iVF Riga clinic

Publisher Copyright: © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of the UR MED GRUPP (LLC). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Aim: The aim of this study is to summarize the outcomes of transfers of mosaic embryos, which were classified according to guidelines and in strong collaboration of reproductologists, clinical geneticists and patients approved as suitable for transfer. Material and Methods: Retrospective data were collected from 70 patients from a private IVF center to whom embryos with mosaic changes in chromosomal material were transferred from 2015 to 2019. Results and Conclusion: Implantation outcomes and continuing pregnancies showed slight differences, when compared to fully normal embryos. Artifacts have to be differentiated from undeniable aberrations, and correct interpretation of results must be done with following patient counselling and prenatal testing if necessary.publishersversionPeer reviewe

Overview of Neuromuscular Disorder Molecular Diagnostic Experience for the Population of Latvia

Funding Information: The Article Processing Charge was funded by the authors. Publisher Copyright: © American Academy of Neurology.Background and ObjectivesGenetic testing has become an integral part of health care, allowing the confirmation of thousands of hereditary diseases, including neuromuscular disorders (NMDs). The reported average prevalence of individual inherited NMDs is 3.7-4.99 per 10,000. This number varies greatly in the selected populations after applying population-wide studies. The aim of this study was to evaluate the effect of genetic analysis as the first-tier test in patients with NMD and to calculate the disease prevalence and allelic frequencies for reoccurring genetic variants.MethodsPatients with NMD from Latvia with molecular tests confirming their diagnosis in 2008-2020 were included in this retrospective study.ResultsDiagnosis was confirmed in 153 unique cases of all persons tested. Next-generation sequencing resulted in a detection rate of 37%. Two of the most common childhood-onset NMDs in our population were spinal muscular atrophy and dystrophinopathies, with a birth prevalence of 1.01 per 10,000 newborns and 2.08 per 10,000 (male newborn population), respectively. The calculated point prevalence was 0.079 per 10,000 for facioscapulohumeral muscular dystrophy type 1, 0.078 per 10,000 for limb-girdle muscular dystrophy, 0.073 per 10,000 for nondystrophic congenital myotonia, 0.052 per 10,000 for spinobulbar muscular atrophy, and 0.047 per 10,000 for type 1 myotonic dystrophy.DiscussionDNA diagnostics is a successful approach. The carrier frequencies of the common CAPN3, FKRP, SPG11, and HINT1 gene variants as well as that of the SMN1 gene exon 7 deletion in the population of Latvia are comparable with data from Europe. The carrier frequency of the CLCN1 gene variant c.2680C>T p.(Arg894Ter) is 2.11%, and consequently, congenital myotonia is the most frequent NMD in our population.publishersversionPeer reviewe

A novel EDA variant causing X-linked hypohidrotic ectodermal dysplasia : Case report

Publisher Copyright: © 2021 The AuthorsHereditary ectodermal dysplasias are a complex group of inherited disorders characterised by abnormalities in two or more ectodermal derivatives (skin, nails, sweat glands, etc.). There are two main types of these disorders – hidrotic and hypohidrotic/anhidrotic ectodermal dysplasias. Hypohidrotic ectodermal dysplasia (HED) or Christ-Siemens-Touraine syndrome (OMIM: 305100) occurs in 1 out of 5000–10,000 births [19] and has an X-linked recessive inheritance pattern (X-linked hypohydrotic ectodermal dysplasia – XLHED) [2]. The main cause of XLHED is a broad range of pathogenic variants in the EDA gene (HGNC:3157, Xq12-13) which encodes the transmembrane protein ectodysplasin-A [4]. We report here the case of a patient with a novel inherited allelic variant in the EDA gene – NM_001399.5:c.337C>T (p.Gln113*) – in the heterozygous state. Targeted family member screening was conducted and other carriers of this EDA gene pathogenic variant were identified and phenotypically characterised. The patient subsequently underwent in vitro fertilisation with preimplantation genetic testing for monogenic diseases (PGT-M).publishersversionPeer reviewe

Heterozygous <i>De Novo</i> and Inherited Mutations in the Smooth Muscle Actin (<i>ACTG2</i>) Gene Underlie Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome

<div><p>Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare disorder of enteric smooth muscle function affecting the intestine and bladder. Patients with this severe phenotype are dependent on total parenteral nutrition and urinary catheterization. The cause of this syndrome has remained a mystery since Berdon's initial description in 1976. No genes have been clearly linked to MMIHS. We used whole-exome sequencing for gene discovery followed by targeted Sanger sequencing in a cohort of patients with MMIHS and intestinal pseudo-obstruction. We identified heterozygous <i>ACTG2</i> missense variants in 15 unrelated subjects, ten being apparent <i>de novo</i> mutations. Ten unique variants were detected, of which six affected CpG dinucleotides and resulted in missense mutations at arginine residues, perhaps related to biased usage of CpG containing codons within actin genes. We also found some of the same heterozygous mutations that we observed as apparent <i>de novo</i> mutations in MMIHS segregating in families with intestinal pseudo-obstruction, suggesting that <i>ACTG2</i> is responsible for a spectrum of smooth muscle disease. <i>ACTG2</i> encodes γ2 enteric actin and is the first gene to be clearly associated with MMIHS, suggesting an important role for contractile proteins in enteric smooth muscle disease.</p></div

Characteristics of the <i>ACTG2</i> mutations in the MMIHS cohort.

a<p>Deduced cDNA change in transcript NM_001615 unless otherwise indicated.</p>b<p>Transcript Uc010fex.1.</p>c<p>Deduced amino acid substitution.</p>d<p>Presence of the observed mutation in other exomes from the Baylor Center for Mendelian Genomics cohort.</p

CpG dinucleotides within arginine codons are targets of <i>de novo</i> events in MMIHS.

<p>A.) The coding exons are shown with translation for the <i>ACTG2</i> gene. CpG dinucleotides are highlighted in red. Arginine residues in the protein are highlighted in green, and the mutations associated with <i>ACTG2</i> smooth muscle disease are aligned above the sequence. B.) The frequency of codon usage per 1000 codons for 6 arginine codons is shown. The human genome as a whole (bottom bar) is compared to all human actin genes including <i>ACTG2</i>.</p

Clinical characteristics of the patients with MMIHS due to <i>ACTG2 de novo</i> mutations.

<p>+ Feature present, − Feature absent,</p><p>*M- Metaclopramide, Cis- Cisapride, E-Erythromycin, (+) responsive, (−) non-responsive.</p

Exome analysis summary for six probands with MMIHS due to <i>ACTG2</i> mutations.

<p>Exome analysis summary for six probands with MMIHS due to <i>ACTG2</i> mutations.</p

<i>ACTG2</i> mutations affect conserved residues that are also targets for Mendelian disease.

<p>A.) Depiction of the mutations on the exons of the gene. Introns are not shown to scale. The mutations associated with MMIHS and intestinal pseudo-obstruction (orange) and those associated with intestinal pseudo-obstruction (green), including the previously reported mutation in one Finnish family are shown. A nonsense allele at position R63 was identified in our exome database associated with no clinical phenotype. The black, red, and blue lines under specific mutations highlight areas of multi-sequence alignment in boxes of corresponding colors in B. B.) Comparison of the mutations in MMIHS/intestinal pseudo-obstruction with disease causing mutations in other actin genes.</p