RESUMEN
BACKGROUND: Genomic imprinting results from the resistance of germline epigenetic marks to reprogramming in the early embryo for a small number of mammalian genes. Genetic, epigenetic or environmental insults that prevent imprints from evading reprogramming may result in imprinting disorders, which impact growth, development, behaviour and metabolism. We aimed to identify genetic defects causing imprinting disorders by whole-exome sequencing in families with one or more members affected by multilocus imprinting disturbance. METHODS: Whole-exome sequencing was performed in 38 pedigrees where probands had multilocus imprinting disturbance, in five of whom maternal variants in NLRP5 have previously been found. RESULTS: We now report 15 further pedigrees in which offspring had disturbance of imprinting, while their mothers had rare, predicted-deleterious variants in maternal effect genes, including NLRP2, NLRP7 and PADI6. As well as clinical features of well-recognised imprinting disorders, some offspring had additional features including developmental delay, behavioural problems and discordant monozygotic twinning, while some mothers had reproductive problems including pregnancy loss. CONCLUSION: The identification of 20 putative maternal effect variants in 38 families affected by multilocus imprinting disorders adds to the evidence that maternal genetic factors affect oocyte fitness and thus offspring development. Testing for maternal-effect genetic variants should be considered in families affected by atypical imprinting disorders.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Síndrome de Beckwith-Wiedemann/genética , Desiminasas de la Arginina Proteica/genética , Síndrome de Silver-Russell/genética , Proteínas Reguladoras de la Apoptosis , Síndrome de Beckwith-Wiedemann/patología , Cromosomas Humanos Par 11/genética , Metilación de ADN/genética , Femenino , Impresión Genómica/genética , Mutación de Línea Germinal/genética , Humanos , Recién Nacido , Enfermedades del Recién Nacido/genética , Enfermedades del Recién Nacido/fisiopatología , Herencia Materna , Linaje , Embarazo , Arginina Deiminasa Proteína-Tipo 6 , Síndrome de Silver-Russell/fisiopatologíaRESUMEN
Permanent neonatal diabetes mellitus (PNDM) is caused by reduced ß-cell number or impaired ß-cell function. Understanding of the genetic basis of this disorder highlights fundamental ß-cell mechanisms. We performed trio genome sequencing for 44 patients with PNDM and their unaffected parents to identify causative de novo variants. Replication studies were performed in 188 patients diagnosed with diabetes before 2 years of age without a genetic diagnosis. EIF2B1 (encoding the eIF2B complex α subunit) was the only gene with novel de novo variants (all missense) in at least three patients. Replication studies identified two further patients with de novo EIF2B1 variants. In addition to having diabetes, four of five patients had hepatitis-like episodes in childhood. The EIF2B1 de novo mutations were found to map to the same protein surface. We propose that these variants render the eIF2B complex insensitive to eIF2 phosphorylation, which occurs under stress conditions and triggers expression of stress response genes. Failure of eIF2B to sense eIF2 phosphorylation likely leads to unregulated unfolded protein response and cell death. Our results establish de novo EIF2B1 mutations as a novel cause of permanent diabetes and liver dysfunction. These findings confirm the importance of cell stress regulation for ß-cells and highlight EIF2B1's fundamental role within this pathway.