DST – Hereditary Sensory and Autonomic Neuropathy Type VI

DST encodes dystonin, a giant plakin family cytoskeletal linker with tissue-specific neuronal (a1–a3), muscular (b1–b3), and epithelial (e) isoforms. Hereditary sensory and autonomic neuropathy type VI is a rare autosomal recessive disorder caused by loss-of-function mutations affecting the neuronal a2 isoform, leading to severe pain insensitivity, autonomic dysfunction, and distal muscle wasting.

A homozygous missense variant, c.1118C>T (p.Pro373Leu), was identified by genome sequencing in a male neonate born to consanguineous parents with congenital HSAN-VI, segregating with disease in the kindred (PMID:34897952).

In a multi-family study, a prenatal ultrasound-detected fetus (P1) with musculoskeletal and neurological abnormalities harbored a homozygous nonsense mutation NM_001144769.1:c.3904C>T (p.Arg1302Ter) within the plakin domain, abolishing all DST isoforms and recapitulating HSAN-VI features (PMID:35276021).

Whole-exome sequencing in twin siblings revealed compound heterozygous variants c.3304G>A (p.Val1102Ile) and c.13796G>A (p.Arg4599His), co-segregating with HSAN-VI in a non-consanguineous pedigree and expanding the allelic spectrum (PMID:32528525).

Overall, four unrelated probands across three families demonstrate autosomal recessive inheritance with complete penetrance and consistent sensory and autonomic phenotypes (PMID:34897952, PMID:35276021, PMID:32528525).

Functional data from dystonin knockout and dt mouse models mirror human disease, showing progressive sensory neuron degeneration, neurofilament accumulation, and cytoskeletal disorganization, consistent with a loss-of-function mechanism.

The aggregated genetic and experimental evidence supports a Moderate ClinGen gene-disease association. DST testing permits precise molecular diagnosis, informs recurrence risk, and establishes a foundation for future therapeutic interventions.

References

• American Journal of Medical Genetics Part A • 2022 • A novel variant in the dystonin gene causing hereditary sensory autonomic neuropathy type VI in a male infant: Case report and literature review PMID:34897952
• Experimental Dermatology • 2022 • Pathogenic DST sequence variants result in either epidermolysis bullosa simplex (EBS) or hereditary sensory and autonomic neuropathy type 6 (HSAN-VI) PMID:35276021
• Frontiers in Genetics • 2020 • Novel Compound Heterozygous DST Variants Causing Hereditary Sensory and Autonomic Neuropathies VI in Twins of a Chinese Family PMID:32528525

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