Evidence of mosaicism in SPAST variant carriers in four French families

Abstract

Hereditary spastic paraplegias (HSP) are heterogeneous disorders, with more than 70 causative genes. Variants in SPAST are the most frequent genetic etiology and are responsible for spastic paraplegia type 4 (SPG4). Age at onset can vary, even between patients from the same family, and incomplete penetrance is described. Somatic mosaicism is extremely rare with only three patients reported in the literature. We report here SPAST mosaic variants in four unrelated patients. We confirm that mosaicism in SPAST is a very rare event with only four identified cases on more than 300 patients with a SPAST variant previously described by our clinical diagnostic laboratory.

Fig. 1. Family pedigrees and schematic representation of identified variants in SPAST.

A Pedigrees of the four families. Mosaic mosaic variant, homogeneous homogeneous variant, WT wild type; *sampled individual. Black: patients presenting spasticity. B schematic view of SPAST with its main domains and the variants found in the series.

Fig. 2. Array-CGH profiles of patient 3.II.1, and his father 3.I.1. Probes are plotted as dots corresponding to the log2 ratio of fluorescence intensities Cy5/Cy3.

Observe the deletion in the proband 3.II.1, partially including SPAST (log₂ ratio is equal to −0.948). In the father’s proband (3.I.1), log₂ ratio is around −0.31, indicating a deletion with a mosaic pattern (mosaic rate estimated around 45% and allelic frequency around 23%).