HSP and deafness: Neurocristopathy caused by a novel mosaic mutation.

OBJECTIVE

To identify the underlying genetic cause in 2 sisters affected with progressive lower extremity spasticity, neuropathy, and early-onset deafness.

METHODS

Whole-exome sequencing was performed, and segregation testing of variants was investigated using targeted Sanger sequencing. An inherited paternal mosaic mutation was further evaluated through quantitative analysis of the ratio of mutant vs wild-type allele in genomic DNA from various tissues, including blood, dermal fibroblasts, and saliva.

RESULTS

A novel heterozygous nonsense mutation (c.1140C>A; p.Y380X) in was identified in the affected sisters. Paternal mosaicism was suspected based on a small chromatogram peak, which was less than the heterozygous peak of the mutated allele. Consistent with mosaicism, the mosaic paternal samples had notable variability in the ratio of mutant vs wild-type allele in various tissues (compared with the fully heterozygous daughter), with the highest paternal mutant levels in saliva (32.7%) and lowest in dermal fibroblasts (13.9%). Targeted clinical re-examination of the father revealed a sensorimotor neuropathy that was previously clinically unrecognized.

CONCLUSIONS

These findings expand the phenotypic spectrum of -related neurocristopathy. Mutations in should be considered in patients presenting with a complicated form of hereditary spastic paraplegia that includes neuropathy and deafness. Diagnostic workup may be complicated, as mutations can present in a mosaic state, with a mild clinical manifestation.