RESUMEN
Pregnancy and parturition are intricately regulated to ensure successful reproductive outcomes. However, the factors that control gestational length in humans and other anthropoid primates remain poorly defined. Here, we show the endogenous retroviral long terminal repeat transposon-like human element 1B (THE1B) selectively controls placental expression of corticotropin-releasing hormone (CRH) that, in turn, influences gestational length and birth timing. Placental expression of CRH and subsequently prolonged gestational length were found in two independent strains of transgenic mice carrying a 180-kb human bacterial artificial chromosome (BAC) DNA that contained the full length of CRH and extended flanking regions, including THE1B. Restricted deletion of THE1B silenced placental CRH expression and normalized birth timing in these transgenic lines. Furthermore, we revealed an interaction at the 5' insertion site of THE1B with distal-less homeobox 3 (DLX3), a transcription factor expressed in placenta. Together, these findings suggest that retroviral insertion of THE1B into the anthropoid primate genome may have initiated expression of CRH in placental syncytiotrophoblasts via DLX3 and that this placental CRH is sufficient to alter the timing of birth.
Asunto(s)
Hormona Liberadora de Corticotropina/genética , Placenta/metabolismo , Primates/genética , Retroelementos/genética , Animales , Secuencia de Bases , Sistemas CRISPR-Cas/genética , Cromosomas Artificiales Bacterianos/genética , Hormona Liberadora de Corticotropina/metabolismo , Femenino , Redes Reguladoras de Genes , Proteínas de Homeodominio/metabolismo , Humanos , Masculino , Ratones Transgénicos , Mutagénesis Insercional/genética , Parto , Embarazo , Unión Proteica , Eliminación de Secuencia , Especificidad de la Especie , Secuencias Repetidas Terminales/genética , Factores de Transcripción/metabolismo , Trofoblastos/metabolismoRESUMEN
We describe an infant with a phenotype typical of early onset Marfan syndrome whose genetic evaluation, including Sanger sequencing and deletion/duplication testing of FBN1 and exome sequencing, was negative. Ultimately, genome sequencing revealed a deletion missed on prior testing, demonstrating the unique utility of genome sequencing for molecular genetic diagnosis.
Asunto(s)
Fibrilina-1/genética , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Análisis de Secuencia de ADN , Exoma , Resultado Fatal , Eliminación de Gen , Dosificación de Gen , Variación Genética , Genoma Humano , Humanos , Lactante , Masculino , Fenotipo , Reacción en Cadena de la PolimerasaRESUMEN
OBJECTIVE: To determine the proportion of infant deaths occurring in the setting of a confirmed genetic disorder. STUDY DESIGN: A retrospective analysis of the electronic medical records of infants born from 1 January, 2011 to 1 June, 2017, who died prior to 1 year of age. RESULTS: Five hundred and seventy three deceased infants were identified. One hundred and seventeen were confirmed to have a molecular or cytogenetic diagnosis in a clinical diagnostic laboratory and an additional seven were diagnosed by research testing for a total of 124/573 (22%) diagnosed infants. A total of 67/124 (54%) had chromosomal disorders and 58/124 (47%) had single gene disorders (one infant had both). The proportion of diagnoses made by sequencing technologies, such as exome sequencing, increased over the years. CONCLUSIONS: The prevalence of confirmed genetic disorders within our cohort of infant deaths is higher than that previously reported. Increased efforts are needed to further understand the mortality burden of genetic disorders in infancy.