Rare autosomal recessive hereditary sensory and autonomic neuropathy type VI in a Pakistani family caused by a novel DST variant.

BACKGROUND: Hereditary sensory and autonomic neuropathies (HSANs) are rare inherited disorders characterized by sensory and autonomic nerve dysfunction classified into eight subtypes. HSAN-VI (OMIM: 614653) is an autosomal recessive subtype which manifests severe pain insensitivity, neonatal hypotonia, respiratory and feeding difficulties, lack of psychomotor development and autonomic abnormalities. Pathogenic variants in the DST gene, which encodes dystonin have been identified as the underlying cause of HSAN-VI. Thus far, only 15 HSAN-VI patients associated with 11 DST variants, mostly compound heterozygous, have been identified in the literature.

OBJECTIVES: We aimed clinical and molecular genetic characterization of a Pakistani family presenting a phenotype consistent with HSAN-VI.

METHODS: The proband's DNA was subjected to whole exome sequencing and homozygosity mapping. Sanger sequencing was used to test variant segregation in the available members of the family. Pathogenicity and deleterious effects of the identified variant on the protein function was tested through bioinformatic in silico prediction tools. Further, we collected clinical and molecular information for all 15 patients reported in the literature.

RESULTS: We identified a novel missense DST variant NM_001374736.1:c.21,899 A > G; p.(Asp7300Gly), classified as a VUS, in autosomal recessive pattern of inheritance in the family. We summarized and compared clinical manifestations and mutation data of previously reported HSAN-VI patients along with those presented in the current study.

CONCLUSIONS: Our findings expand the mutation spectrum of DST-associated HSAN-VI potentially adding to its pathophysiology. To our knowledge, this is the second report of a homozygous missense DST variant overall, and first report of HSAN-VI from Pakistan.