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Genetics in Medicine : Official Journal... Jul 2022Noninvasive prenatal screening (NIPS) using cell-free DNA has been assimilated into prenatal care. Prior studies examined clinical validity and technical performance in... (Review)
Review
PURPOSE
Noninvasive prenatal screening (NIPS) using cell-free DNA has been assimilated into prenatal care. Prior studies examined clinical validity and technical performance in high-risk populations. This systematic evidence review evaluates NIPS performance in a general-risk population.
METHODS
Medline (PubMed) and Embase were used to identify studies examining detection of Down syndrome (T21), trisomy 18 (T18), trisomy 13 (T13), sex chromosome aneuploidies, rare autosomal trisomies, copy number variants, and maternal conditions, as well as studies assessing the psychological impact of NIPS and the rate of subsequent diagnostic testing. Random-effects meta-analyses were used to calculate pooled estimates of NIPS performance (P < .05). Heterogeneity was investigated through subgroup analyses. Risk of bias was assessed.
RESULTS
A total of 87 studies met inclusion criteria. Diagnostic odds ratios were significant (P < .0001) for T21, T18, and T13 for singleton and twin pregnancies. NIPS was accurate (≥99.78%) in detecting sex chromosome aneuploidies. Performance for rare autosomal trisomies and copy number variants was variable. Use of NIPS reduced diagnostic tests by 31% to 79%. Conclusions regarding psychosocial outcomes could not be drawn owing to lack of data. Identification of maternal conditions was rare.
CONCLUSION
NIPS is a highly accurate screening method for T21, T18, and T13 in both singleton and twin pregnancies.
Topics: Cell-Free Nucleic Acids; Down Syndrome; Female; Humans; Noninvasive Prenatal Testing; Pregnancy; Prenatal Diagnosis; Sex Chromosome Aberrations; Trisomy; Trisomy 13 Syndrome; Trisomy 18 Syndrome
PubMed: 35608568
DOI: 10.1016/j.gim.2022.03.019 -
American Journal of Medical Genetics.... Aug 2022Crossed pulmonary arteries (CPAs) represent an uncommon anatomic variant, usually associated with some specific syndromes and conotruncal defects. This finding has been... (Review)
Review
Crossed pulmonary arteries: An underestimated cardiovascular variant with a strong association with genetic syndromes-A report of 74 cases with systematic review of the literature.
Crossed pulmonary arteries (CPAs) represent an uncommon anatomic variant, usually associated with some specific syndromes and conotruncal defects. This finding has been described in 22q11.2 Deletion Syndrome (22q11.2DS). We evaluated the correlation between CPAs and genetic diseases, in order to better define the characteristics of this variant, considered a rare anatomic pattern. An in-depth analysis of CPAs genotype-phenotype correlations was performed via a literature review. We detected 74 CPAs patients through echocardiography. Of these 74 patients, 35.1% of patients showed additional intracardiac malformations, while 29.7% showed extracardiac vascular anomalies, of which 16.2% were associated with intracardiac defects and 13.5% were not. In all, 62.2% of patients were diagnosed with genetic diseases and 52.2% of them were 22q11.2DS patients. In conclusions, CPAs represent a cardiovascular variant, which is detectable in nonsyndromic individuals, but especially in various genetic syndromes and in particular in 22q11.2DS patients. Data on the real prevalence of this morphology is lacking in literature. Knowledge of this anatomic variant is useful to interpret the unusual course of the pulmonary branches and is helpful information before cardiovascular surgical correction. Moreover, due to the strong association of CPAs with some genetic syndromes, the identification of this anatomic pattern can indicate the utility of a genetic assessment of these patients.
Topics: Chromosome Deletion; Chromosomes, Human, Pair 22; DiGeorge Syndrome; Heart Defects, Congenital; Humans; Lung; Pulmonary Artery
PubMed: 35491976
DOI: 10.1002/ajmg.a.62763 -
Genetics in Medicine : Official Journal... Jun 2022Recently, preimplantation genetic testing (PGT) for polygenic conditions (PGT-P) has been introduced commercially. In view of the lack of specific guidance on this... (Review)
Review
PURPOSE
Recently, preimplantation genetic testing (PGT) for polygenic conditions (PGT-P) has been introduced commercially. In view of the lack of specific guidance on this development, we analyzed normative documents on PGT for monogenic conditions (PGT-M) to understand what we can learn from these documents for recommendations for PGT-P.
METHODS
We conducted a systematic review of normative guidelines and recommendations on PGT-M. The aim was to understand what the current consensus and disagreements are on ethical acceptability of PGT-M and how this compares with PGT-P.
RESULTS
We analyzed 38 documents by advisory committees at the national, European, and global level. In total, 2 themes were identified, which included the following: (1) what PGT is considered appropriate for and (2) who can make decisions regarding the use of PGT. Many aspects of PGT-M documents apply to PGT-P as well. Additional factors such as the fact that PGT-P screens for risk indications of multiple polygenic conditions increase ethical difficulties regarding severity, risk, autonomy, and informed decision-making.
CONCLUSION
On the basis of PGT-M normative documents, we conclude that ethical acceptability for PGT-P is limited. Our findings present various factors that have to be considered for the development of guidelines and the appropriateness of PGT.
Topics: Aneuploidy; Female; Genetic Testing; Humans; Morals; Multifactorial Inheritance; Pregnancy; Preimplantation Diagnosis
PubMed: 35341652
DOI: 10.1016/j.gim.2022.03.001 -
Biomedicines Mar 2022Artificial intelligence (AI) has been gaining support in the field of in vitro fertilization (IVF). Despite the promising existing data, AI cannot yet claim... (Review)
Review
Artificial intelligence (AI) has been gaining support in the field of in vitro fertilization (IVF). Despite the promising existing data, AI cannot yet claim gold-standard status, which serves as the rationale for this study. This systematic review and data synthesis aims to evaluate and report on the predictive capabilities of AI-based prediction models regarding IVF outcome. The study has been registered in PROSPERO (CRD42021242097). Following a systematic search of the literature in Pubmed/Medline, Embase, and Cochrane Central Library, 18 studies were identified as eligible for inclusion. Regarding live-birth, the Area Under the Curve (AUC) of the Summary Receiver Operating Characteristics (SROC) was 0.905, while the partial AUC (pAUC) was 0.755. The Observed: Expected ratio was 1.12 (95%CI: 0.26-2.37; 95%PI: 0.02-6.54). Regarding clinical pregnancy with fetal heartbeat, the AUC of the SROC was 0.722, while the pAUC was 0.774. The O:E ratio was 0.77 (95%CI: 0.54-1.05; 95%PI: 0.21-1.62). According to this data synthesis, the majority of the AI-based prediction models are successful in accurately predicting the IVF outcome regarding live birth, clinical pregnancy, clinical pregnancy with fetal heartbeat, and ploidy status. This review attempted to compare between AI and human prediction capabilities, and although studies do not allow for a meta-analysis, this systematic review indicates that the AI-based prediction models perform rather similarly to the embryologists' evaluations. While AI models appear marginally more effective, they still have some way to go before they can claim to significantly surpass the clinical embryologists' predictive competence.
PubMed: 35327499
DOI: 10.3390/biomedicines10030697 -
Human Vaccines & Immunotherapeutics Dec 2022This study comprehensively evaluated and compared three human rabies vaccines. Seven electronic databases were systematically searched. The Cochrane Handbook v5.1.0 was... (Meta-Analysis)
Meta-Analysis
Immunogenicity and safety of human diploid cell vaccine (HDCV) vs. purified Vero cell vaccine (PVRV) vs. purified chick embryo cell vaccine (PCECV) used in post-exposure prophylaxis: a systematic review and meta-analysis.
This study comprehensively evaluated and compared three human rabies vaccines. Seven electronic databases were systematically searched. The Cochrane Handbook v5.1.0 was used to assess the risk of bias. A random-effects model was used to combine individual rates, and network meta-analysis was used for pairwise comparisons. Twenty-seven articles were included, with a total of 18,630 participants. The pooled incidence of the total adverse reaction to HDCV was significantly lower than that of PCECV. HDCV administration resulted in a lower incidence of local pain, fever, and weakness than purified Vero cell vaccine. HDCV caused a lower incidence of local pain and fever than PCECV. No significant difference was observed in terms of the seroconversion rate on day 7 or the rabies virus-neutralizing antibody titer on day 14. HDCV demonstrated superiority in terms of safety compared with the other two rabies vaccines, while the same was not observed in terms of immunogenicity.
Topics: Animals; Antibodies, Viral; Chick Embryo; Chickens; Chlorocebus aethiops; Diploidy; Fever; Humans; Pain; Post-Exposure Prophylaxis; Rabies; Rabies Vaccines; Rabies virus; Vero Cells
PubMed: 35192787
DOI: 10.1080/21645515.2022.2027714 -
Zhonghua Nan Ke Xue = National Journal... Jun 2021During the spermatogenesis of fertile men, an incidental meiosis mistake could induce the generation of aneuploid sperm, which may further cause the aneuploidy of... (Review)
Review
During the spermatogenesis of fertile men, an incidental meiosis mistake could induce the generation of aneuploid sperm, which may further cause the aneuploidy of embryos, miscarriage and chromosome abnormality of the offspring. Sex chromosomes of sperm have a higher tendency to be aneuploid than autosomes, though the mechanisms of sperm sex chromosome aneuploidy are not yet thoroughly understood. It may be attributed to the fact that the synapsis of sex chromosomes is confined to the pseudoautosomal region and that only one subsequent crossover is formed there. In addition, gene mutation, advanced age, lifestyle and environmental pollution may induce the segregation errors of sex chromosomes or failure of the meiosis checkpoint, and thus increase the incidence of sperm sex chromosome aneuploidy. With a systematic review of the relevant literature, this paper illustrated the generation mechanisms of sperm sex chromosome aneuploidy in men with normal and abnormal karyotypes, aiming to shed some new light on the studies of sperm sex chromosome aneuploidy.
Topics: Aneuploidy; Chromosome Aberrations; Humans; Male; Meiosis; Sex Chromosomes; Spermatozoa
PubMed: 34914297
DOI: No ID Found -
Journal of Pediatric Ophthalmology and... 2021Tetrasomy 18p is often the result of an additional isochromosome for the short arm of chromosome 18. Although many organ systems are affected phenotypically, the ocular...
Tetrasomy 18p is often the result of an additional isochromosome for the short arm of chromosome 18. Although many organ systems are affected phenotypically, the ocular manifestations associated with tetrasomy 18p have not been well characterized in the literature. This case report presents the ocular and facial features associated with tetrasomy 18p in a 4-year-old Black girl, along with a review of clinical presentations previously reported in the literature. A systematic review of the literature in PubMed was conducted to summarize the reported eye, ocular adnexa, and distinctive facial features in individuals with confirmed tetrasomy 18p. Searching "Tetrasomy 18p" generated 65 article results, of which 28 articles had sufficient eye and facial descriptions. Including the patient in this report, 90 patients had confirmed tetrasomy 18p. The most common features noted in these 90 patients, with a roughly equal male-to-female ratio of impact (7:8), were as follows: microcephaly (57%), triangular facies (18%), anomalous palpebral fissures (31%), strabismus (48%), low-set ears (52%), hearing loss to some extent (16%), depressed or flat nasal bridge (18%), smooth philtrum (41%), thin upper lip (27%), and highly arched palate (21%). Additionally, many were noted to have feeding difficulties (28%), developmental delay (58%), and abnormal brain findings on imaging (20%). Muscle tone was abnormal in 23% of the patients. This report elucidates the reoccurring eye, ocular adnexa, and distinctive facial features associated with tetrasomy 18p. This knowledge may assist in timely diagnosis and encourage providers to use a multidisciplinary approach for the treatment of affected individuals. .
Topics: Aneuploidy; Child, Preschool; Chromosomes, Human, Pair 18; Eye; Female; Humans; Male
PubMed: 34851787
DOI: 10.3928/01913913-20210826-01 -
JBRA Assisted Reproduction Apr 2022The impact of gonadotropins used for COS on the rate of embryo aneuploidy in patients without the negative effects of age as a confounding factor, is still a subject of...
The impact of gonadotropins used for COS on the rate of embryo aneuploidy in patients without the negative effects of age as a confounding factor, is still a subject of lively debate. We ran a systematic search for studies in MEDLINE, PubMed, Google Scholar and the Cochrane Library. A librarian coordinated the search in December of 2020. We included all original peer-reviewed papers in English, irrespective of study-design. There were no restrictions concerning method of amplification or platform used to analyze the amplified DNA. We used the PICO model to select the study population. We included women/couples submitted to COS for IVF with the intention to genetically analyze her/their embryos through PGT. The primary outcome was the rate of aneuploidy. We used the Newcastle-Ottawa scale (NOS) score to evaluate the quality of the studies included. The search yielded 73 citations, and 14 were eligible for analysis, which included data on 4805 cycles. Media quality NOS score was 8. Although it has been demonstrated that natural cycles are associated with aneuploidy, it does seem that more robust stimulations are indeed associated with a higher proportion of aneuploidy. Nevertheless, a higher response is associated with an increased number of euploid embryos available for transfer, which translates into more embryo-transfer cycles with a prospective higher cumulative live birth rate. Further evidence is needed to ascertain if there is a negative impact of COS, especially at the cellular level.
Topics: Aneuploidy; Female; Fertilization in Vitro; Genetic Testing; Humans; Live Birth; Ovulation Induction; Pregnancy; Pregnancy Rate; Prospective Studies; Retrospective Studies
PubMed: 34751016
DOI: 10.5935/1518-0557.20210069 -
Human Reproduction Update Dec 2021Human male infertility has a notable genetic component, including well-established diagnoses such as Klinefelter syndrome, Y-chromosome microdeletions and monogenic...
BACKGROUND
Human male infertility has a notable genetic component, including well-established diagnoses such as Klinefelter syndrome, Y-chromosome microdeletions and monogenic causes. Approximately 4% of all infertile men are now diagnosed with a genetic cause, but a majority (60-70%) remain without a clear diagnosis and are classified as unexplained. This is likely in large part due to a delay in the field adopting next-generation sequencing (NGS) technologies, and the absence of clear statements from field leaders as to what constitutes a validated cause of human male infertility (the current paper aims to address this). Fortunately, there has been a significant increase in the number of male infertility NGS studies. These have revealed a considerable number of novel gene-disease relationships (GDRs), which each require stringent assessment to validate the strength of genotype-phenotype associations. To definitively assess which of these GDRs are clinically relevant, the International Male Infertility Genomics Consortium (IMIGC) has identified the need for a systematic review and a comprehensive overview of known male infertility genes and an assessment of the evidence for reported GDRs.
OBJECTIVE AND RATIONALE
In 2019, the first standardised clinical validity assessment of monogenic causes of male infertility was published. Here, we provide a comprehensive update of the subsequent 1.5 years, employing the joint expertise of the IMIGC to systematically evaluate all available evidence (as of 1 July 2020) for monogenic causes of isolated or syndromic male infertility, endocrine disorders or reproductive system abnormalities affecting the male sex organs. In addition, we systematically assessed the evidence for all previously reported possible monogenic causes of male infertility, using a framework designed for a more appropriate clinical interpretation of disease genes.
SEARCH METHODS
We performed a literature search according to the PRISMA guidelines up until 1 July 2020 for publications in English, using search terms related to 'male infertility' in combination with the word 'genetics' in PubMed. Next, the quality and the extent of all evidence supporting selected genes were assessed using an established and standardised scoring method. We assessed the experimental quality, patient phenotype assessment and functional evidence based on gene expression, mutant in-vitro cell and in-vivo animal model phenotypes. A final score was used to determine the clinical validity of each GDR, across the following five categories: no evidence, limited, moderate, strong or definitive. Variants were also reclassified according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines and were recorded in spreadsheets for each GDR, which are available at imigc.org.
OUTCOMES
The primary outcome of this review was an overview of all known GDRs for monogenic causes of human male infertility and their clinical validity. We identified a total of 120 genes that were moderately, strongly or definitively linked to 104 infertility phenotypes.
WIDER IMPLICATIONS
Our systematic review curates all currently available evidence to reveal the strength of GDRs in male infertility. The existing guidelines for genetic testing in male infertility cases are based on studies published 25 years ago, and an update is far overdue. The identification of 104 high-probability 'human male infertility genes' is a 33% increase from the number identified in 2019. The insights generated in the current review will provide the impetus for an update of existing guidelines, will inform novel evidence-based genetic testing strategies used in clinics, and will identify gaps in our knowledge of male infertility genetics. We discuss the relevant international guidelines regarding research related to gene discovery and provide specific recommendations to the field of male infertility. Based on our findings, the IMIGC consortium recommend several updates to the genetic testing standards currently employed in the field of human male infertility, most important being the adoption of exome sequencing, or at least sequencing of the genes validated in this study, and expanding the patient groups for which genetic testing is recommended.
Topics: Animals; Chromosome Deletion; Genetic Testing; Genomics; High-Throughput Nucleotide Sequencing; Humans; Infertility, Male; Male
PubMed: 34498060
DOI: 10.1093/humupd/dmab030 -
American Journal of Medical Genetics.... Dec 2021MEF2C-related disorders (aka MEF2C-haploinsufficiency) are caused by variations in or involving the MEF2C gene and are characterized by intellectual disability,... (Review)
Review
MEF2C-related disorders (aka MEF2C-haploinsufficiency) are caused by variations in or involving the MEF2C gene and are characterized by intellectual disability, developmental delay, lack of speech, limited walking, and seizures. Despite these findings, the disorder is not easily recognized clinically. We performed a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to assemble the most comprehensive list of patients and their phenotypes. Through searching PubMed, Web of Science, and MEDLINE, 43 articles met the inclusion criteria and were fully reviewed. One hundred and seventeen patients were identified from these publications with most having a phenotype of intellectual disability, developmental delay, seizures, hypotonia, absent speech, inability to walk, stereotypic movements, and MRI abnormalities. Nonclassical findings included one patient with a question mark ear, two patients with a jugular pit, one patient with a unique neuroendocrine finding, and nine patients that did not have MEF2C deletions or disruptions but may be affected due to a positional effect on MEF2C. This systematic review characterizes the phenotype of MEF2C-related disorders, documents the severity of this condition, and will help providers to better diagnose and care for patients and their families. Additionally, this compiled information provides a comprehensive resource for investigators interested in pursuing specific genotype-phenotype correlations.
Topics: Chromosome Deletion; Epilepsy; Genetic Predisposition to Disease; Haploinsufficiency; Humans; Intellectual Disability; MEF2 Transcription Factors; Muscle Hypotonia
PubMed: 34184825
DOI: 10.1002/ajmg.a.62412