Familial interstitial 570 kbp deletion of the UBE3A gene region causing Angelman syndrome but not Prader-Willi syndrome.
Angelman syndrome (AS) is a disorder of psychomotor development caused by loss of function of the imprinted UBE3A gene. Since the paternal UBE3A copy is regularly silent, only mutations inactivating the maternal copy cause AS. Among 1,272 patients suspected of AS, we found one with an isolated deletion of the UBE3A gene on the maternally inherited chromosome. Initial DNA methylation testing at the SNURF-SNRPN locus in the patient revealed a normal pattern. The deletion was only detected through allelic loss at microsatellite loci D15S1506, D15S122, and D15S210, and confirmed with fluorescence in situ hybridization (FISH) using bacterial artificial chromosome (BAC) probes derived from the loci. It extends approximately 570 kilobase pairs (kbp), encompassing the UBE3A locus, and is flanked by loci PAR/SN and D15S986. The deletion is familial, and haplotype studies suggest that a great grandfather of the index patient already carried this deletion, and that it causes AS when inherited through the female germline but not Prader-Willi syndrome (PWS) when paternally inherited. Our findings support the hypothesis that the functional loss of maternal UBE3A gene activity is sufficient to cause AS and that the deleted region does not contain genes or other structures that are involved in PWS. Finally, this case highlights that methylation tests can fail to detect some familial AS cases with a recurrence risk of 50%.
Bürger
Joachim
J
Institute of Human Genetics, Charité, Humboldt-Universität, Berlin, Germany.
Horn
Denise
D
Tönnies
Holger
H
Neitzel
Heidemarie
H
Reis
André
A
D017204:Angelman Syndrome / Q000209:etiology / Q000235:genetics*; D001483:Base Sequence; D002675:Child, Preschool; D002884:Chromosomes, Human, Pair 15; D019175:DNA Methylation; D005260:Female; D006239:Haplotypes; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008025:Ligases / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats; D010375:Pedigree; D011218:Prader-Willi Syndrome / Q000209:etiology / Q000235:genetics*; D017384:Sequence Deletion; D044767:Ubiquitin-Protein Ligases
C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases; D008025:Ligases