A novel mutation in DST gene cause HSAN-VI and mental retardation

Background and Aim: Hereditary and sensory autonomic neuropathies (HSANs) are classified as a genetically and clinically heterogenous disorders. Various pathways play roles in pathogenesis of the disease and cytoskeletal involvement was elucidated recently. Investigations revealed that DST gene loss of function cause lethal movement disorder in mice. The human equivalent is HSAN-VI which is the most severe one in HSAN group and characterized by infant hypotonia, progressive disability, respiratory and feeding problems, lack of psychomotor development, autonomic abnormalities and lack of corneal reflexes. DST gene encodes a cytoskeletal linker large protein, dystonin, which has several isoforms result from various promoters and several alternative splicing procedures. Alternative transcription of the first exons lead to ۳ neuronal isoforms (dystonin-a) and their mutations result in HSAN-VI. The first report of HSAN-VI was frameshift mutation in Glu ۴۹۹۵ that leads to neuronal isoforms loss of function. The object of this study was to investigate the genetic cause of disease in sibling of consanguineous marriage.Methods: A ۹ year-old girl with hypotonia, developmental delay and mental retardation was evaluated. The younger brother has also the same symptoms. The missense mutation in DST gene was identified by NGS method and the confirmation was performed by sanger sequencing. Some bioinformatics tools were used to prove the disease causing mutation.Results: A novel homozygous and heterozygous missense mutation of DST gene was identified (NM_۰۱۵۵۴۸: c.۱۵۳۸۶A>C, p.E۵۱۲۹A) in patients and their parents, respectively.Conclusion: This autosomal recessive mutation has not been reported previously. Such studies may help to conduct genetic counseling and prenatal diagnosis more accurately for individuals at the high risk of these disorders.