Compound Heterozygosity at the FMR1 Gene

Abstract

Individuals affected with Fragile X syndrome are usually characterized at the DNA level by the presence of at least 200 CGG repeats in the 5' untranslated region of the FMR1 gene; this number of repeats is defined as a full mutation. Repeats that number 50-200 usually define those with premutations and are termed unaffected carriers. We report here a compound heterozygous female who carried CGG repeats in the FMR1 gene that fall within the premutation and full mutation ranges. The former appears to have been inherited from the father, whereas the latter is an expansion of the premutation carried by the proband's mother. Therefore, the offspring of the proband will carry a significant risk of being affected with Fragile X syndrome, and the paternal uncle and any cousins should be counselled for being at risk for this syndrome.

Four sisters compound heterozygotes for the pre- and full mutation in fragile X syndrome and a complete inactivation of X-functional chromosome: implications for genetic counseling

“…6 Up to date, several cases of compound heterozygotes for FXS have been reported; three sisters with both chromosomes in the premutation range, 7,8 two sisters with one gray-zone allele and one full mutation allele, 9 four of them are unrelated female carriers of a premutation and a full mutation. [10][11][12][13] In the present study we describe an exceptional consanguineous Moroccan family, who has been living in Spain for 4 years, in which the four sisters show a compound heterozygote genotype for full and pre-mutation, and the index case has complete inactivation of functional X chromosome.…”

A fragile X sibship from a consanguineous family with a compound heterozygous female and partially methylated full mutation male

“…There are several reports of females with compound heterozygous mutations [Hegde et al, 2001; Heine-Suner et al, 2003; Linden et al, 1999; Martorell et al, 2011; Mila et al, 1996; Russo et al, 1998]. The female sibling reported here differs from the previously reported females because she is more severely affected, having a lower FSIQ than the reported females carrying premutation and full mutation alleles [Linden et al, 1999; Martorell et al, 2011; Russo et al, 1998].…”

Unexpected finding of a paternal premutation of the fragile X FMR1 gene in a female fetus of a premutation carrier mother

“…The possible finding of compound heterozygosity in a female fetus, either pre‐/full mutation or pre‐/premutation, would pose an unusual counseling dilemma. A few cases of compound heterozygote females with a paternal premutation and a maternal full mutation have been reported [Milà et al, 1996; Russo et al, 1998; Linden et al, 1999; Hegde et al, 2001], some of whom present mental impairment. However, predicting prenatally the postnatal phenotype of such an individual would be challenging if not impossible.…”