Genetic heterogeneity in familial acute myelogenous leukemia: evidence for a second locus at chromosome 16q21-23.2.
The identification of genes responsible for the rare cases of familial leukemia may afford insight into the mechanism underlying the more common sporadic occurrences. Here we test a single family with 11 relevant meioses transmitting autosomal dominant acute myelogenous leukemia (AML) and myelodysplasia for linkage to three potential candidate loci. In a different family with inherited AML, linkage to chromosome 21q22.1-22.2 was recently reported; we exclude linkage to 21q22.1-22.2, demonstrating that familial AML is a heterogeneous disease. After reviewing familial leukemia and observing anticipation in the form of a declining age of onset with each generation, we had proposed 9p21-22 and 16q22 as additional candidate loci. Whereas linkage to 9p21-22 can be excluded, the finding of a maximum two-point LOD score of 2.82 with the microsatellite marker D16S522 at a recombination fraction theta = 0 provides evidence supporting linkage to 16q22. Haplotype analysis reveals a 23.5-cM (17.9-Mb) commonly inherited region among all affected family members extending from D16S451 to D16S289. In order to extract maximum linkage information with missing individuals, incomplete informativeness with individual markers in this interval, and possible deviance from strict autosomal dominant inheritance, we performed nonparametric linkage analysis (NPL) and found a maximum NPL statistic corresponding to a P-value of .00098, close to the maximum conditional probability of linkage expected for a pedigree with this structure. Mutational analysis in this region specifically excludes expansion of the AT-rich minisatellite repeat FRA16B fragile site and the CAG trinucleotide repeat in the E2F-4 transcription factor. The "repeat expansion detection" method, capable of detecting dynamic mutation associated with anticipation, more generally excludes large CAG repeat expansion as a cause of leukemia in this family.
Horwitz
M
M
Markey Molecular Medicine Center, and Department of Medicine, School of Medicine, University of Washington, Seattle 98195, USA. horwitz@u.washington.edu
Benson
K F
KF
Li
F Q
FQ
Wolff
J
J
Leppert
M F
MF
Hobson
L
L
Mangelsdorf
M
M
Yu
S
S
Hewett
D
D
Richards
R I
RI
Raskind
W H
WH
D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16; D005190:Family; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D005819:Genetic Markers; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008126:Lod Score; D008297:Male; D018598:Minisatellite Repeats; D009190:Myelodysplastic Syndromes / Q000235:genetics; D010375:Pedigree; D016133:Polymerase Chain Reaction / Q000379:methods; D018709:Statistics, Nonparametric; D018911:Trinucleotide Repeats
D005819:Genetic Markers