title: BRCA1/2 mutations appear embryo-lethal unless rescued by low (CGG n<26) FMR1 sub-genotypes: explanation for the "BRCA paradox"?
abstract: BRCA1/2 mutations and recently described constitutional FMR1 genotypes have, independently, been associated with prematurely diminished ovarian reserve. Whether they interrelate in distribution, and whether observed effects of BRCA1/2 and FMR1 on ovaries are independent of each other, is unknown. In a prospective comparative cohort study, we, therefore, investigated the distribution of constitutional FMR1 genotypes, normal (norm), heterozygous (het) and homozygous (hom), and of their respective sub-genotypes (high/low), in 99 BRCA1/2 mutation-positive women and 410 female controls to determine whether distribution patterns differed between study and control patients. In contrast to controls, BRCA1/2 carriers demonstrated almost complete absence of all constitutional FMR1 genotypes except for sub-genotypes with low (CGG (n<26)) alleles. Cross tabulation between BRCA1/2-positive patients and controls confirmed significant group membership, related to FMR1 distribution (P<0.0001). These results offer as most likely explanation the conclusion that BRCA1/2 mutations are embryo-lethal, unless rescued by low (CGG (n<26)) FMR1 sub-genotypes, present in approximately one quarter of all women. Women with low FMR1 sub-genotypes, therefore, should reflect increased BRCA1/2-associated cancer risks, while the remaining approximately 75 percent should face almost no such risks. If confirmed, this observation offers opportunities for more efficient and less costly BRCA1/2 cancer screening. The study also suggests that previously reported risk towards prematurely diminished ovarian reserve in association with BRCA mutations is FMR1-mediated, and offers a possible explanation for the so-called "BRCA paradox" by raising the possibility that the widely perceived BRCA1/2-associated tumor risk is actually FMR1-mediated.
authors.affiliation: The Center for Human Reproduction, New York, New York, United States of America.
authors.forename: Andrea
authors.initials: A
authors.lastname: Weghofer
authors.forename: Muy-Kheng
authors.initials: MK
authors.lastname: Tea
authors.forename: David H
authors.initials: DH
authors.lastname: Barad
authors.forename: Ann
authors.initials: A
authors.lastname: Kim
authors.forename: Christian F
authors.initials: CF
authors.lastname: Singer
authors.forename: Klaus
authors.initials: K
authors.lastname: Wagner
authors.forename: Norbert
authors.initials: N
authors.lastname: Gleicher
mesh_terms: D020121:5' Untranslated Regions; D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005786:Gene Expression Regulation; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D012306:Risk
chemical_list: D020121:5' Untranslated Regions; D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human