Tyrosinemia type 1 and Angelman syndrome due to paternal uniparental isodisomy 15.
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.
Ferrer-Bolufer
Irene
I
Unidad de Genética y Diagnóstico Prenatal, Hospital Universitario La Fe, Avda. Campanar, 21, 46009, Valencia, Spain.
Dalmau
Jaime
J
Quiroga
Ramiro
R
Oltra
Silvestre
S
Orellana
Carmen
C
Monfort
Sandra
S
Roselló
Mónica
M
De La Osa
Alberto
A
Martinez
Francisco
F
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