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 are 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.
SUMMARYIn 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: 755À767,
Across a diversity of animals, male seminal fluid coagulates upon ejaculation to form a hardened structure known as a copulatory plug. Previous studies suggest that copulatory plugs evolved as a mechanism for males to impede remating by females, but detailed investigations into the time course over which plugs survive in the female's reproductive tract are lacking. Here, we cross males from eight inbred strains to females from two inbred strains of house mice (Mus musculus domesticus). Plug survival was significantly affected by male genotype. Against intuition, plug survival time was negatively correlated with plug size: long-lasting plugs were small and relatively more susceptible to proteolysis. Plug size was associated with divergence in major protein composition of seminal vesicle fluid, suggesting that changes in gene expression may play an important role in plug dynamics. In contrast, we found no correlation to genetic variation in the protein-coding regions of five genes thought to be important in copulatory plug formation (Tgm4, Svs1, Svs2, Svs4 and Svs5). Our study demonstrates a complex relationship between copulatory plug characteristics and survival. We discuss several models to explain unexpected variation in plug phenotypes.
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.
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 non-competitive 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 blocks fertilization by second males, even if first males are vasectomized. Taken together, our experiments demonstrate that first males lose almost all paternity if they never form 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.
On the Cover: This cover image is based on the Special Article Unique aspects of sequence variant interpretation for inborn errors of metabolism (IEM): The ClinGen IEM Working Group and the Phenylalanine Hydroxylase Gene by Diane B. Zastrow et al., Pages 1569–1580. DOI: https://doi.org/10.1002/humu.23649.
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