RT Journal Article
SR Electronic
T1 HSP and deafness
JF Neurology Genetics
JO Neurol Genet
FD Lippincott Williams & Wilkins
SP e151
DO 10.1212/NXG.0000000000000151
VO 3
IS 3
A1 Donkervoort, Sandra
A1 Bharucha-Goebel, Diana
A1 Yun, Pomi
A1 Hu, Ying
A1 Mohassel, Payam
A1 Hoke, Ahmet
A1 Zein, Wadih M.
A1 Ezzo, Daniel
A1 Atherton, Andrea M.
A1 Modrcin, Ann C.
A1 Dasouki, Majed
A1 Foley, A. Reghan
A1 Bönnemann, Carsten G.
YR 2017
UL http://ng.neurology.org/content/3/3/e151.abstract
AB 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 SOX10 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 SOX10-related neurocristopathy. Mutations in SOX10 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 SOX10 mutations can present in a mosaic state, with a mild clinical manifestation.CV=conduction velocity; HSP=hereditary spastic paraplegia; NCC=neural crest cell; NMD=nonsense-mediated decay; RT=real time; SRY=sex determining region Y; WS4=Waardenburg syndrome type 4; WT=wild type