title: Analysis of de novo HOXA13 polyalanine expansions supports replication slippage without repair in their generation.
abstract: Polyalanine repeat expansion diseases are hypothesized to result from unequal chromosomal recombination, yet mechanistic studies are lacking. We identified two de novo cases of hand-foot-genital syndrome (HFGS) associated with polyalanine expansions in HOXA13 that afforded rare opportunities to investigate the mechanism. The first patient with HFGS was heterozygous for a de novo nine codon polyalanine expansion. Haplotype investigation showed that the expansion arose on the maternally inherited chromosome but not through unequal crossing over between homologs, leaving unequal sister chromatid exchange during mitosis or meiosis or slipped mispairing as possible explanations. The asymptomatic father of the second patient with HFGS was mosaic for a six codon polyalanine expansion. Multiple tissue PCR and clonal analysis of paternal fibroblasts showed only expansion/WT and WT/WT clones, and haplotype data showed that two unaffected offspring inherited the same paternal allele without the expansion, supporting a postzygotic origin. Absence of the contracted allele in the mosaic father does not support sister chromatid exchange in the origin of the expansion. Mosaicism for HOXA13 polyalanine expansions may be associated with a normal phenotype, making examination of parental DNA essential in apparently de novo HFGS cases to predict accurate recurrence risks. We could not find an example in the literature where unequal sister chromatid exchange has been proven for any polyalanine expansion, suggesting that the principal mechanism for polyalanine expansions (and contractions) is slipped mispairing without repair or that the true frequency of unequal sister chromatid exchange involving these repeats is low.
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109-5618, USA.
authors.forename: Kailey M
authors.initials: KM
authors.lastname: Owens
authors.forename: Shane C
authors.initials: SC
authors.lastname: Quinonez
authors.forename: Peedikayil E
authors.initials: PE
authors.lastname: Thomas
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Keegan
authors.forename: Nanci
authors.initials: N
authors.lastname: Lefebvre
authors.forename: Diane
authors.initials: D
authors.lastname: Roulston
authors.forename: Christine A
authors.initials: CA
authors.lastname: Larsen
authors.forename: H Scott
authors.initials: HS
authors.lastname: Stadler
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Innis
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D042622:DNA Repeat Expansion / Q000235:genetics*; D005260:Female; D005532:Foot Deformities, Congenital / Q000235:genetics*; D006228:Hand Deformities, Congenital / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010455:Peptides; D010641:Phenotype; D014564:Urogenital Abnormalities / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; D010455:Peptides; C099959:homeobox protein HOXA13; C019529:polyalanine