The FMR1 premutation and reproduction.
OBJECTIVE
To update clinicians on the reproductive implications of premutations in FMR1 (fragile X mental retardation 1). Fragile X syndrome, a cause of mental retardation and autism, is due to a full mutation (>200 CGG repeats). Initially, individuals who carried the premutation (defined as more than 55 but less than 200 CGG repeats) were not considered at risk for any clinical disorders. It is now recognized that this was incorrect, specifically with respect to female reproduction.


METHODS
Literature review and consensus building at two multidisciplinary scientific workshops.


CONCLUSIONS
Convincing evidence now relates the FMR1 premutation to altered ovarian function and loss of fertility. An FMR1 mRNA gain-of-function toxicity may underlie this altered ovarian function. There are major gaps in knowledge regarding the natural history of the altered ovarian function in women who carry the FMR1 premutation, making counseling about reproductive plans a challenge. Women with premature ovarian failure are at increased risk of having an FMR1 premutation and should be informed of the availability of fragile X testing. Specialists in reproductive medicine can provide a supportive environment in which to explain the implications of FMR1 premutation testing, facilitate access to testing, and make appropriate referral to genetic counselors.
Wittenberger
Michael D
MD
Intramural Research Program, Section on Women's Health Research, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1103, USA.
Hagerman
Randi J
RJ
Sherman
Stephanie L
SL
McConkie-Rosell
Allyn
A
Welt
Corrine K
CK
Rebar
Robert W
RW
Corrigan
Emily C
EC
Simpson
Joe Leigh
JL
Nelson
Lawrence M
LM
D000293:Adolescent; D000328:Adult; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics* / Q000503:physiopathology* / Q000628:therapy; D005817:Genetic Counseling; D005820:Genetic Testing; D006801:Humans; D008297:Male; D009154:Mutation; D011247:Pregnancy; D019836:Preimplantation Diagnosis; D016649:Primary Ovarian Insufficiency / Q000209:etiology / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion
D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human