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The combination of chromosomal reorganization and inherited point mutation has led to the development of a rare clinical phenotype in a patient with disorder of sex differentiation and neuromuscular pathology
SUMMARY. The elucidation of molecular genetic mechanisms in the development of rare inherited diseases is crucial in understanding the processes of pathogenesis, improving the diagnosis and treatment of patients. The aim of our study was to determine the nature of genetic defects in a patient who showed signs of sexual dysfunction in combination with neuromuscular pathology. The study included: clinical and genealogical examination, ultrasonographic examination, electroneuromyography, study of biochemical parameters in serum: hormones and enzymes, molecular cytogenetic study using the FISH method, whole exome sequencing of the patient's DNA analysis, bioinformatiñ analysis. The patient showed signs of primary (hypergonadotropic) hypogonadism and polyneuropathic changes in the lower extremities (axonal-demyelinating). It was found that these clinical characteristics of the patient's phenotype do not agree with any description of the clinical phenotype registered in the OMIM International Database. According to the results of molecular cytogenetic study in the patient's karyotype, an unbalanced translocation of the Yp11.3 region containing the SRY gene to the short arm region of the X chromosome Xp22.33 with the formation of a derivative X chromosome was detected. On another side, the results of whole exome sequencing of the patient's genomic DNA revealed the presence of a homozygous mutation chr5: 131165096 C> G (c.110G> C, p.Arg37Pro) in the HINT1 gene. Thus, it can be concluded that the phenotype with signs of disorders of sex differentiation in combination with axonal neuropathy with myotonia is due to two independent pathogenetic factors - unbalanced translocation of the SRY gene sequence on the X chromosome, resulting in paternal spermatogenesis and inheritance of the HINT1 gene homozygous missence mutation (c.110G>C, p.Arg37Pro). These results support the effectiveness of a combination of molecular cytogenetic research methods and the results of high-performance WES to elucidate the molecular mechanisms of pathogenesis in patients with rare clinical phenotypes.
Key words: disorder of sex differentiation, neuromuscular disorder, chromosomal unbalanced translocation, missense mutation, SRY, HINT1, Õ chromosome
Tsitologiya i Genetika 2022, vol. 56, no. 5, pp. 25-31
E-mail: livshits edu.imbg.org.ua
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