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Information × Registration Number 0225U004727, (0121U110054) , R & D reports Title Molecular-genetic mechanisms of human disorders of sexual development popup.stage_title Створення банку ДНК пацієнтів та членів їхніх родин. Виділення та очищення препаратів поліА-РНК та отримання кДНК у пацієнтів з ПРДС. Проведення молекулярно-цитогенетичного аналізу з метою пошуку хромосомних реорганізацій у пацієнтів з ПРДС. Визначення груп для повногеномного дослідження методом array-CGH (пацієнти з хромосомними абераціями) для повноекзомного секвенування (пацієнти без хромосомних аберацій). Head Livshyts Liudmyla A., д.б.н. Registration Date 17-12-2025 Organization Institute of Molecular Biology and Genetics of NAS of Ukraine popup.description1 Identify pathogenic mutations in determinant genes, disorders of which lead to diseases associated with impaired development of sex differentiation. Identify new candidate genes in which mutations are associated with impaired sex differentiation. Develop new effective information tools for the analysis of full-genome sequencing data to effectively assess the pathogenicity of identified genetic variants as a basis for genetic diagnosis and personalized therapy. popup.description2 Results During the study, the nature and origin of new genetic variants (mutations) in known determinant genes that lead to impaired development and differentiation of the genital organs were determined. A clinical and genealogical analysis was conducted among patients from amount different regions of Ukraine with disorders of sexual development and differentiation. All patients were included in the study according to informed consent. The molecular nature of pathogenicity for the c.1437A>G mutation in the WT1 gene, which causes splicing disorders, has been identified and investigated in a patient with a 46XX karyotype, SRY- and a diagnosis of ovotestis. As a result, a WT1 protein is synthesized lacking the 4 zinc finger sequence in the DNA-binding domain and causes an aberrant ratio of alternative +CTS/-CTS transcripts. In a patient with 46XY, SRY+ and a diagnosis of gonadal dysgenesis (complete form), a missense mutation in the GATA4 gene c.34G>C (p.Gly12Arg) was firstly identified. The results of mutant protein in silico modeling established possible molecular mechanisms of the pathogenesis for sexual development disorders. The phenomenon of incomplete penetrance for mutations in the GATA4 gene was also revealed. A new candidate gene – STARD8(DLC3), mutations in which cause gonadogenesis disorders, was identified. Mutations that disrupt the functioning of the C-terminal in protein Start domain, lead to disorders of testicular development in embryogenesis. The genes encoding the partner proteins STARD9 and CDK5RAP2, in which mutant variants were detected in a patient with a karyotype of 46XY, SRY+ and a diagnosis of a gonadal dysgenesis (complete form), were proposed as new genetic factors of oligogenic sex development disorders. It is proposed to include these candidate-genes in a specialized diagnostic panel of genes. An algorithm for bioinformatics analysis of the WES results at the stage of clinical annotation for patients with orphan diseases was developed. Product Description popup.authors Maryna V. Nechyporenko Livshyts Ganna B. Gorodna Oleksandra V. Sirokha Dmytro А. Nataliya Kril Yuliya V. Nazarenko popup.nrat_date 2025-12-17 Close