HSP and deafness: Neurocristopathy caused by a novel mosaic SOX10 mutation

Abstract

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.

Figure 1. Clinical findings

Cutaneous hypopigmentation is seen in P1 (A) and P2 (E). Photographs demonstrating scissoring-type gait with evidence of proximal lower extremity weakness in P1 (B–D) and P2 (F–H).

Figure 2. Chronic hypomyelinating neuropathy

Plastic-embedded semithin sections (A and B) show a uniform reduction in large and small myelinated fiber density in P1. Several thinly myelinated fibers (arrowheads) and a few primordial onion bulb formations are present (arrows). Multiple empty Schwann cell nuclei are seen (S). Electron microscopy images (C and D) show similar findings. An onion bulb (C, lower right arrow) and an empty onion (C, upper right arrow) are highlighted. D is a higher magnification image of the area of the box in C. There are several empty Schwann cells and Remak bundles (S), suggestive of loss of unmyelinated fibers. Some larger axons appear to have no myelin (*), suggestive of defective myelination. (Scale bars: A: 50 μm, B: 20 μm, C: 10 μm, and D: 2 μm.)

Figure 3. Ophthalmologic findings

(A) Color and red-free fundus photography of the right eye of P1 showing pigmentary changes in a localized area temporal to the macula. Arrows point at the area of patchy hypopigmentation corresponding to the changes noted on optical coherence tomography. (B) Optical coherence tomography of P1 indicating an irregular bowing back of the retina (arrows) with a change in the reflectance of the choroid in the area corresponding to the pigmentary changes noted on examination. There is no interruption of the retinal layers and no loss of retinal cells.

Figure 4. Pedigree and molecular characterization of the family

Family history showing the mosaic father (P3), his unaffected spouse (M), the 2 affected daughters (P1 and P2), and 3 unaffected sons (B1, B2, and B3). Genomic DNA sequence chromatograms show the somatic c.1140C>A; p.Y380X SOX10 mutation in the mosaic father and 2 affected daughters. The mosaic mutation sequence is seen as a lower-height peak in parent (P3) compared to the fully heterozygous mutation in the affected children P1 and P2.