title: Tyrosinemia type 1 and Angelman syndrome due to paternal uniparental isodisomy 15.
abstract: Uniparental isodisomy arises when an individual inherits two copies of a specific chromosome from a single parent, which can unmask a recessive mutation or cause a problem of genetic imprinting. Here we describe an exceptional case in which the patient simultaneously presents tyrosinemia type 1 and Angelman syndrome. The genetic studies showed that the patient presents paternal uniparental isodisomy of chromosome 15, with absence of the maternal homolog. As a consequence of this isodisomy, the patient is homozygous for the mutation IVS12+5G>A in the FAH gene, located in the chromosomal region 15q23-25, causing tyrosinemia type 1. The mutation was inherited from his father in double dosage, whereas the mother is not a carrier, which implies that the recurrence risk in the family is negligible. On the other hand, the lack of maternal contribution causes Angelman syndrome, a neurodevelopmental disorder associated with a loss of maternal gene expression in chromosome region 15q11-q13, and more specifically, of the UBE3A gene. This gene shows a tissue-specific imprinting, and only the maternally derived allele is expressed in certain areas of the brain. We observed through a literature review that uniparental disomy probably occurs more frequently than suspected, although it is more usually detected when the uniparental disomy implies the appearance of a disease because of the gene imprinting or by reduction to homozygosity of a recessive mutation. The conclusion is that uniparental disomy should always be considered when more than one genetic disease mapping to the same chromosome is present in a patient.
authors.affiliation: Unidad de Genética y Diagnóstico Prenatal, Hospital Universitario La Fe, Avda. Campanar, 21, 46009, Valencia, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Ferrer-Bolufer
authors.forename: Jaime
authors.initials: J
authors.lastname: Dalmau
authors.forename: Ramiro
authors.initials: R
authors.lastname: Quiroga
authors.forename: Silvestre
authors.initials: S
authors.lastname: Oltra
authors.forename: Carmen
authors.initials: C
authors.lastname: Orellana
authors.forename: Sandra
authors.initials: S
authors.lastname: Monfort
authors.forename: Mónica
authors.initials: M
authors.lastname: Roselló
authors.forename: Alberto
authors.initials: A
authors.lastname: De La Osa
authors.forename: Francisco
authors.initials: F
authors.lastname: Martinez
mesh_terms: D000328:Adult; D017204:Angelman Syndrome / Q000150:complications* / Q000235:genetics*; D001483:Base Sequence; D002675:Child, Preschool; D002884:Chromosomes, Human, Pair 15; D004252:DNA Mutational Analysis; D005220:Fathers; D005260:Female; D018392:Genomic Imprinting; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010375:Pedigree; D020176:Tyrosinemias / Q000150:complications* / Q000235:genetics*; D024182:Uniparental Disomy