Paternal transmission of a FMR1 full mutation allele

Abstract

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID) and autism. In most of cases, the molecular basis of this syndrome is a CGG repeat expansion in the 5' untranslated region of the FMR1 gene. It is inherited as an X linked dominant trait, with a reduced penetrance (80% for males and 30% for females). Full mutation (FM) expansion from premutated alleles (PM) is only acquired via maternal meiosis, while paternal transmission always remains in the PM range. We present a 16-year-old girl with a mild fragile X syndrome phenotype. FMR1 gene study showed that the patient inherited a mosaic premutation-full mutation with an unmethylated uninterrupted allele (175, >200 CGG) from her father. The father showed an 88 CGG uninterrupted unmethylated allele in blood and sperm cells. To our knowledge, this is the first case of a FMR1 mosaic premutation-full mutation allele inherited from a PM father. In our opinion, the most likely explanation could be a postzygotic somatic expansion. We can conclude that in rare cases of a child with a full mutation whose mother does not carry a premutation, the possibility of paternal transmission should be considered.

Repeat Instability in the Fragile X-Related Disorders: Lessons from a Mouse Model

“…Thus, it is possible that any evidence of expansion in human blood, reflects the presence of even more extensive expansion in organs like brain or gonads. Different allele profiles in different tissues have been reported in some PM carriers [32,33,34,35,36,37,38,39] and 2 different studies support the idea that some men have larger expansions with broader σs in sperm relative to blood [40,41]. Differences between allele sizes in blood and in brain or gonads in expansion-prone individuals could lead to an underestimation of the intergenerational expansion risk.…”

DNA Methylation at Birth Predicts Intellectual Functioning and Autism Features in Children with Fragile X Syndrome

“…Expansion from a PM to FM has been considered to occur exclusively through vertical transmission from females. Nonetheless, two case reports of PM/FM females with paternal inheritance have been described [ 35 , 36 ]. Unfortunately, due to a lack of sufficient DNA quantity, no further CGG sizing analyses could be performed to investigate the possibility of mosaic FM alleles in the two females in this study, that were not detected by standard of care FXS testing.…”

Educational Case: Fragile X Syndrome with Size Mosaicism

“…A repeat length of 50-59 is associated with 3.7% risk of expansion to a full mutation in offspring, while a repeat length of 90-99 is associated with 80.1% risk of expansion to a full mutation in offspring. 14,16…”