Faulty Epigenetics Germline Mutations

Germline mutations in genes that encode parts of the methylation machinery have been associated with two human diseases, the immunodeficiency centromeric instability facial anomalies (ICF) syndrome and Rett syndrome (Table 6.2). The salient features of ICF syndrome are immunodeficiency, centromere instability, and facial anomalies. This recessive disorder of childhood is associated with mutations in the DNA methyltransferase gene, DNMT3B. The mutations are largely confined to satellite DNA at the centromeric regions of chromosomes 1, 9,

Table 6.2 Epigenetics in Human Disease

Human disorder

Salient clinical features

Molecular pathology


ICF syndrome

Rett syndrome '

Fragile X syndrome

Benign dermoid ovarian teratomas

Hydatidform moles

Wilms' tumors

Recessive disorder of children with immunodeficiency, centromere instability and mild facial anomalies causing most ICF patients to succumb to infectious disease before adulthood Postnatal neurodevelopmental disorder of infant girls with a variable clinical phenotype characterized by loss of motor and language skills, microcephaly, autistic features, and stereotypic hand movements Mental retardation affecting males primarily; other diagnostic criteria: long face, large everted ears, autism, hand biting, hyperactivity and macroorchidism (large testicles)

Tumors contain many tissue types but no placental trophoblast

Placental-derived extraembryonic tumors

Nephroblastoma of childhood

Almost completely unmethylated satellite DNA in centromeric regions of chromosomes 1, 9, and 16 attributed to mutations in DMNT3B Various germline MECP2 mutations may affect the role of MECP2 in higher order chromatin organization and imprinting

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