Linkage Analysis in Familial Angelman Syndrome
J. Wagstaff, Y.Y. Shugart, M. Lalande
American Journal of Human Genetics , 53(1), 105--112 (1993 Jul)
Abstract
Familial Angelman syndrome (AS) can result from mutations in
chromosome 15q11q13 that, when transmitted from father to child,
result in no phenotypic abnormality but, when transmitted from
mother to child, cause AS. These mutations therefore behave neither
as dominant nor as recessive mutations but, rather, show an
imprinted mode of inheritance. We have analyzed two sibling pairs
with AS and a larger family with four AS offspring of three sisters
with several recently described microsatellite polymorphisms in the
AS region. AS siblings inherited the same maternal alleles at the
GABRB3 and GABRA5 loci, and the unaffected siblings of AS
individuals inherited the other maternal alleles at these loci. In
one of the AS sibling pairs, analysis of a recombination event
indicates that the mutation responsible for AS is distal to locus
D15S63. This result is consistent with a previously described
imprinted submicroscopic deletion causing AS, a deletion that
includes loci D15S10, D15S113, and GABRB3, all distal to D15S63. The
analysis of the larger AS family provides the first clear
demonstration of a new mutation in nondeletion AS. Analysis of
linkage of AS to GABRB3 in these three families, on the assumption
of imprinted inheritance (i.e., penetrance of an AS mutation is 1 if
transmitted maternally and is 0 if transmitted paternally),
indicates a maximum lod score of 3.52 at theta = 0.
