Transmission of a Fragile X full mutation from a premutation male to his two daughters

Abstract

A 10 year old female patient with developmental delay was tested for Fragile X syndrome. When she was found to have a mutation, we requested a blood specimen from her mother and recommended specific genetic counselling. When the mother was shown to be a non-carrier of Fragile X (19 and 23 repeats), we pursued the rest of the family and found another mutation in her older sister, a normal allele in her brother and a premutation in her mentally normal father. Mutations have been tested by a complementary combination of Southern blot, radiolabelled triplet repeat sizing when possible, and complete mutation analysis using a newly developed Applied Biosystems Inc. kit. The premutation in the father has 114 repeats. Fibroblasts and sperm from the father confirm the presence of only a premutation. The mutations in both daughters are mosaic smears extending from the top end of the premutation range well into the full mutation range. Both daughters have a further unusual feature in that approximately half of the mutant alleles are unmethylated. This leads to the rare appearance of a mitotically-unstable smear below the inactive X chromosome band (5.1 kb on Southern blot) as well as the smear in the usual position above this 5.1 kb band.

We believe that this is the first case of a Fragile X premutation expanding to a mutation when transmitted from a male to his daughter. This case obviously has important repercussions for the counselling of families with Fragile X syndrome.