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Gene discovery informatics toolkit defines candidate genes for unexplained infertility and prenatal or infantile mortality.

ABSTRACT: Despite a recent surge in novel gene discovery, genetic causes of prenatal-lethal phenotypes remain poorly defined. To advance gene discovery in prenatal-lethal disorders, we created an easy-to-mine database integrating known human phenotypes with inheritance pattern, scores of genetic constraint, and murine and cellular knockout phenotypes-then critically assessed defining features of known prenatal-lethal genes, among 3187 OMIM genes, and relative to 16,009 non-disease genes. While around one-third (39%) of protein-coding genes are essential for murine development, we curate only 3% (624) of human protein-coding genes linked currently to prenatal/infantile lethal disorders. 75% prenatal-lethal genes are linked to developmental lethality in knockout mice, compared to 54% for all OMIM genes and 34% among non-disease genes. Genetic constraint correlates with inheritance pattern (autosomal recessive <90% of recessive genes show neither missense nor loss-of-function constraint, even for prenatal-lethal genes. Detailed ontology mapping for 624 prenatal-lethal genes shows marked enrichment among dominant genes for nuclear proteins with roles in RNA/DNA biology, with recessive genes enriched in cytoplasmic (mitochondrial) metabolic proteins. We conclude that genes without genetic constraint should not be excluded as potential novel disease genes, and especially for recessive conditions (<10% constrained). Prenatal lethal genes are 5.9-fold more likely to be associated with a lethal murine phenotype than non-disease genes. Cell essential genes are largely a subset of mouse-lethal genes, notably under-represented among known OMIM genes, and strong candidates for gamete/embryo non-viability. We therefore curate 3435 'candidate developmental lethal' human genes: essential for murine development or cellular viability, not yet linked to human disorders, presenting strong candidates for unexplained infertility and prenatal/infantile mortality.

SUBMITTER: Dawes R

PROVIDER: S-EPMC6465277 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Gene discovery informatics toolkit defines candidate genes for unexplained infertility and prenatal or infantile mortality.

Dawes Ruebena R Lek Monkol M Cooper Sandra T ST

NPJ genomic medicine 20190415

Despite a recent surge in novel gene discovery, genetic causes of prenatal-lethal phenotypes remain poorly defined. To advance gene discovery in prenatal-lethal disorders, we created an easy-to-mine database integrating known human phenotypes with inheritance pattern, scores of genetic constraint, and murine and cellular knockout phenotypes-then critically assessed defining features of known prenatal-lethal genes, among 3187 OMIM genes, and relative to 16,009 non-disease genes. While around one- ...[more]

PMID: 30993004

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Project description:BackgroundThe standard therapy for women with unexplained infertility is gonadotropin or clomiphene citrate. Ovarian stimulation with letrozole has been proposed to reduce multiple gestations while maintaining live birth rates.MethodsWe enrolled couples with unexplained infertility in a multicenter, randomized trial. Ovulatory women 18 to 40 years of age with at least one patent fallopian tube were randomly assigned to ovarian stimulation (up to four cycles) with gonadotropin (301 women), clomiphene (300), or letrozole (299). The primary outcome was the rate of multiple gestations among women with clinical pregnancies.ResultsAfter treatment with gonadotropin, clomiphene, or letrozole, clinical pregnancies occurred in 35.5%, 28.3%, and 22.4% of cycles, and live birth in 32.2%, 23.3%, and 18.7%, respectively; pregnancy rates with letrozole were significantly lower than the rates with standard therapy (gonadotropin or clomiphene) (P=0.003) or gonadotropin alone (P<0.001) but not with clomiphene alone (P=0.10). Among ongoing pregnancies with fetal heart activity, the multiple gestation rate with letrozole (9 of 67 pregnancies, 13%) did not differ significantly from the rate with gonadotropin or clomiphene (42 of 192, 22%; P=0.15) or clomiphene alone (8 of 85, 9%; P=0.44) but was lower than the rate with gonadotropin alone (34 of 107, 32%; P=0.006). All multiple gestations in the clomiphene and letrozole groups were twins, whereas gonadotropin treatment resulted in 24 twin and 10 triplet gestations. There were no significant differences among groups in the frequencies of congenital anomalies or major fetal and neonatal complications.ConclusionsIn women with unexplained infertility, ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation but also a lower frequency of live birth, as compared with gonadotropin but not as compared with clomiphene. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01044862.).

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Gene discovery informatics toolkit defines candidate genes for unexplained infertility and prenatal or infantile mortality.

Publications

Gene discovery informatics toolkit defines candidate genes for unexplained infertility and prenatal or infantile mortality.

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