Mosaic mutations of the FLN1 gene cause a mild phenotype in patients with periventricular heterotopia

X-linked periventricular nodular heterotopia (PNH) (OMIM 300049) is a neuronal migration disorder, associated with mutations of the FLN1 gene (Xq28), accompanied by severe epilepsy and normal to mildly impaired cognitive function in affected women. The recurrence risk has been estimated to be 50% in daughters of affected women, with early post-natal lethality in boys. Mutation analysis [denaturing high-performance liquid chromatography (DHPLC) and sequencing], performed in a woman and a man with PNH, was suggestive of somatic mosaicism. Both patients were investigated using single nucleotide primer extension (SNuPE) and DHPLC. To better characterize mosaicism in the affected man, SNuPE-DHPLC analysis was also performed on a pool of hair roots and single hair roots. The affected woman had features of PNH on magnetic resonance imaging. She had well-controlled epilepsy and normal cognitive function. She was mosaic for a nucleotide insertion (c.568_569ingG). SNuPE-DHPLC findings showed 17% of mutant allele. The affected man had classical PNH and was mosaic for an A>G substitution (intron 11 acceptor splice site). SNuPE-DHPLC on both leukocyte and hair root DNA revealed 42% and 69% of mutant allele. Single hair root analysis confirmed that this patient did not harbor the mutation in all ectodermal derivative cells. His daughter had not inherited the mutation. Phenotypic heterogeneity associated with X-linked PNH may depend on the type of mutation, its location on the protein, as well as on somatic mosaicism. Mosaicism can influence the recurrence risk rates in affected women. Mosaic mutations in men may not be transmitted to their daughters, masking the X-linked nature of the disorder.