ABSTRACT
OBJECTIVE: The aim of the study is to determine the prevalence of RASopathies in a polyhydramnios cohort selected by postnatal medical genetics evaluation. METHODS: In this retrospective study, we reviewed 622 pregnancies with polyhydramnios seen at Lucile Packard Children's Hospital between 2008 and 2017. The findings from 131 cases evaluated by Medical Genetics were included in our final analysis. Genetic testing information was extracted to determine the rate of chromosomal or single gene conditions focusing on the RASopathies. Additional variables collected were: maternal characteristics, ultrasound findings, and the severity and timing of diagnosis of polyhydramnios. RESULTS: Postnatal genetic testing or clinical examination identified a genetic disorder in 63 (48.1%) cases, more than half (n = 33) of which had a single gene condition. Postnatal testing revealed an underlying RASopathy in 15 (11.5%) cases. An underlying RASopathy was significantly associated with the severity and timing of polyhydramnios (p < 0.05). CONCLUSION: Focusing on a selected cohort postnatally evaluated by Medical Genetics, our study identified a chromosomal or genetic disorder in almost half of pregnancies complicated by polyhydramnios. Specifically, an underlying RASopathy was found in 11.5% of cases with 13/15 of these cases having additional ultrasound findings.
Subject(s)
Polyhydramnios/diagnosis , Polyhydramnios/genetics , Adult , Arteriovenous Malformations/diagnosis , Arteriovenous Malformations/epidemiology , Arteriovenous Malformations/genetics , Capillaries/abnormalities , Cohort Studies , Costello Syndrome/diagnosis , Costello Syndrome/epidemiology , Costello Syndrome/genetics , Ectodermal Dysplasia/diagnosis , Ectodermal Dysplasia/epidemiology , Ectodermal Dysplasia/genetics , Facies , Failure to Thrive/diagnosis , Failure to Thrive/epidemiology , Failure to Thrive/genetics , Female , Genetic Testing/methods , Genetic Testing/statistics & numerical data , Heart Defects, Congenital/diagnosis , Heart Defects, Congenital/epidemiology , Heart Defects, Congenital/genetics , Humans , Noonan Syndrome/diagnosis , Noonan Syndrome/epidemiology , Noonan Syndrome/genetics , Polyhydramnios/epidemiology , Port-Wine Stain/diagnosis , Port-Wine Stain/epidemiology , Port-Wine Stain/genetics , Pregnancy , Prevalence , Retrospective Studies , Ultrasonography, Prenatal/methods , Ultrasonography, Prenatal/statistics & numerical dataABSTRACT
The ClinGen Inborn Errors of Metabolism Working Group was tasked with creating a comprehensive, standardized knowledge base of genes and variants for metabolic diseases. Phenylalanine hydroxylase (PAH) deficiency was chosen to pilot development of the Working Group's standards and guidelines. A PAH variant curation expert panel (VCEP) was created to facilitate this process. Following ACMG-AMP variant interpretation guidelines, we present the development of these standards in the context of PAH variant curation and interpretation. Existing ACMG-AMP rules were adjusted based on disease (6) or strength (5) or both (2). Disease adjustments include allele frequency thresholds, functional assay thresholds, and phenotype-specific guidelines. Our validation of PAH-specific variant interpretation guidelines is presented using 85 variants. The PAH VCEP interpretations were concordant with existing interpretations in ClinVar for 69 variants (81%). Development of biocurator tools and standards are also described. Using the PAH-specific ACMG-AMP guidelines, 714 PAH variants have been curated and will be submitted to ClinVar. We also discuss strategies and challenges in applying ACMG-AMP guidelines to autosomal recessive metabolic disease, and the curation of variants in these genes.
Subject(s)
Genome, Human/genetics , Metabolism, Inborn Errors/genetics , Phenylalanine Hydroxylase/genetics , Databases, Genetic , Gene Frequency/genetics , Genetic Testing , Genetic Variation/genetics , HumansABSTRACT
In many animals, male ejaculates coagulate to form what has been termed a copulatory plug, a structure that varies in size and shape but often fills and seals the female's reproductive tract. The first published observation of a copulatory plug in a mammal was made more than 160 years ago, and questions about its formation and role in reproduction continue to endear evolutionary and population geneticists, behavioral ecologists, and molecular, reproductive, and developmental biologists alike. Here, we review the current knowledge of copulatory plugs, focusing on rodents and asking two main questions: how is it formed and what does it do? An evolutionary biology perspective helps us understand the latter, potentially leading to insights into the selective regimes that have shaped the diversity of this structure. Mol. Reprod. Dev. 83: 755-767, 2016 © 2016 Wiley Periodicals, Inc.
Subject(s)
Biological Evolution , Reproduction/physiology , Animals , Female , MaleABSTRACT
Ejaculated proteins play important roles in reproductive fitness. In many species, seminal fluid coagulates and forms what has been referred to as a copulatory plug in the female's reproductive tract. In mice, previous work demonstrated that knockout males missing a key seminal fluid protein were unable to form a plug and less successful at siring litters in noncompetitive matings (one female, one male), probably the result of reduced sperm transport or insufficient stimulation of the female. Here, we extend these previous studies to competitive matings (one female, two males) and make two key insights. First, when first males were unable to form a plug, they lost almost all paternity to second males to mate. Thus, the copulatory plugs of second males could not rescue the reduced fertility of first males. Second, we showed that the copulatory plug of first males effectively blocked fertilization by second males, even if first males were vasectomized. Taken together, our experiments demonstrated that first males lost almost all paternity if they never formed a plug. We discuss our results in the context of natural populations, where in spite of the strong effects seen here, pregnant female mice regularly carry litters fertilized by more than one male.