Project Title: „The determination of rare inherited diseases’ causative mechanisms using whole genome sequencing approach”
Funding: European Regional Development Fund (ERDF), Measure 1.1.1.1 “Support for applied research”
Project No.: 1.1.1.1/18/A/096
Period: 1 April 2019 – 31 March 2022
Project costs: 648 648 EUR
Principle Investigator: Dr. biol. Inna Iņaškina
Cooperation partner: SIA Latvia MGI Tech
Project summary:
The general aim of the project is to improve public health through the expansion of our knowledge about rare inherited diseases and diagnostics of patients with such disorders. Specific aim of the project is to identify novel causative genetic elements in rare inherited disease patients in whom pathogenic variants have not been identified so far by conventional genetic analysis approaches.
To reach the specific aim of the project we have tailored the following activities:
- Establishing criteria for selection and recruitment of patients suffering from rare diseases. The patients included in the study will represent a challenging group for testing as they have been previously extensively investigated using gene panel or whole exome sequencing approaches and remain without a genetic diagnosis for their disease.
- Whole genome sequencing of trio samples (patients plus parents), bioinformatic analysis of data
- Validation and interpretation of genetic variants identified by WGS. Analysis of candidate genes or other genetic elements selected on the basis of WGS, using available sources of scientific information (publications, genetic variant and medical databases, as well as databases on available animal models).
Information published 01.04.2019.
Progress of the project:
1 April 2019 – 30 June 2019
As part of the ERDF 096 project, the involvement of patients suffering from rare inherited diseases and their relatives in the Genome Database of Latvian Population, including the collection of clinical and phenotypical data, DNA and tissue samples, was initiated.
Joint meetings between the project’s executors and envolved clinical specialists are held on a regular basis (monthly). During these meetings, selected family cases are discussed and decisions are made whether to move them to the next phase of the project (whole genome sequencing). In parallel, available row data from patients’ previous genetic tests, for example, whole exome or gene panel sequencing, are re-analyzed.
Information published 28.06.2019.
Progress of the project:
1 July 2019 – 30 September 2019
As part of the ERDF 096 project, the enrolment of patients suffering from rare inherited diseases and their relatives in the Genome Database of Latvian Population, including the collection of clinical and phenotypical data, DNA and tissue samples, was continued. The experimental part of the project was started – the whole genome sequencing analysis was performed for several patients. The data analysis algorithm is currently being developed and the data obtained is being analysed. Joint meetings between the project’s executors and envolved clinical specialists are held on a regular basis (monthly). During these meetings, selected family cases are discussed and decisions are made whether to move them to the next phase of the project (whole genome sequencing).
Information published 30.09.2019.
Progress of the project:
1 October 2019 – 31 December 2019
As part of the ERDF 096 project, the enrolment of patients suffering from rare inherited diseases and their relatives in the Genome Database of Latvian Population was continued. It is including the collection of clinical and phenotypical data, DNA and tissue samples. Joint meetings between the project’s executors and envolved clinical specialists are held on a regular basis (monthly). During these meetings, selected family cases are discussed. The whole genome sequencing analysis was performed for selected patients and their relatives. The data analysis algorithm is currently being developed and the data obtained is being analysed. In parallel, available row data from patients’ previous genetic tests, for example, whole exome or gene panel sequencing, are re-analyzed.
Information published 30.12.2019.
Project progress
1 January 2020 – 31 March 2020
As part of the ERDF 096 project, the enrolment of patients suffering from rare inherited diseases and their relatives in the Genome Database of Latvian Population was continued. It is including the collection of clinical and phenotypical data, DNA and tissue samples. Joint meetings between the project’s executors and involved clinical specialists are held on a regular basis (monthly). During these meetings, selected family cases are discussed. The whole genome sequencing analysis was performed for selected patients and their relatives. The data analysis algorithm is currently being developed and the data obtained is being analysed. In parallel, available row data from patients’ previous genetic tests, for example, whole exome or gene panel sequencing, are re-analysed.
Information published 31.03.2020.
Progress of the project:
1 April 2020 – 30 June 2020
As part of the ERDF 096 project, the enrolment of patients, suffering from rare inherited diseases, and their relatives, as well as the paediatric oncological patients with suspected genetic changes, in the Genome Database of Latvian Population was continued. It is including the collection of clinical and phenotypical data, DNA and tissue samples.
Due to the emergency caused by the COVID-19 epidemic, work in the laboratory was suspended in March and resumed in June.
Joint meetings between the project’s executors and involved clinical specialists are held on a regular basis (in person and on-line). During these meetings, selected family cases are discussed.
The data analysis algorithm is currently being developed and the data obtained is being analysed. In parallel, available raw data from patients’ previous genetic tests, for example, whole exome or gene panel sequencing, are being re-analysed.
Information published 30.06.2020.
Progress of the project:
1 July 2020 – 30 September 2020
As part of the ERDF 096 project, the enrolment of patients suffering from rare inherited diseases and their relatives in the Genome Database of Latvian Population was continued. It is including the collection of clinical and phenotypical data, DNA and tissue samples. Joint meetings between the project’s executors and involved clinical specialists are held on a regular basis (monthly). During these meetings, selected family cases are discussed. The whole genome sequencing analysis was performed for selected patients and their relatives. The genetic diagnosis was established for four patients and several potentially pathogenic genetic variants have been found in others. Further analysis is necessary. The data analysis algorithm is still being developed and improved. In parallel, available row data from patients’ previous genetic tests, for example, whole exome or gene panel sequencing, are re-analysed.
Information published 30.09.2020.
Progress of the project:
1 October 2020 – 31 December 2020
As part of the ERDF 096 project, the enrolment of patients suffering from rare inherited diseases and their relatives in the Genome Database of Latvian Population was continued. It is including the collection of clinical and phenotypical data, DNA and tissue samples. Joint meetings between the project’s executors and involved clinical specialists are held on a regular basis (monthly). During these meetings, selected family cases are discussed. Up to now, we have involved about 60 patients suffering from rare diseases and their relatives. Additionally, we have involved 79 pediatric patients suffering from suspected hereditary cancer.
The whole genome sequencing analysis was performed for selected patients and their relatives. The genetic diagnosis was established for several patients and some potentially pathogenic genetic variants have been found in others. Further analysis is necessary. The developed data analysis algorithm is still being improved. In parallel, available row data from patients’ previous genetic tests, for example, whole exome or gene panel sequencing, are re-analysed.
Information published 30.12.2020.
Progress of the project:
1 January 2021 – 31 March 2021
As part of the ERDF 096 project, the enrolment of patients suffering from rare inherited diseases and their relatives in the Genome Database of Latvian Population was continued. It is including the collection of clinical and phenotypical data, DNA and tissue samples. Joint meetings between the project’s executors and involved clinical specialists are held on a regular basis (monthly). During these meetings, selected family cases are discussed. The whole genome sequencing analysis and was performed for selected patients and their relatives. The analysis of obtained data is ongoing. Further biochemical and molecular studies are necessary for potentially pathogenic genetic variants. The developed data analysis algorithm is still being improved.
The obtained data on rare pathogenic genetic variants and connected diagnoses was presented in frame of RSU Research Week 2021 Knowledge for Use in Practice as two oral presentations: J. Stavusus et al. “The first case in Latvia, caused by mutation in the Prion-related protein” and I. Mičule et al. “A second family with a multisystemic mitochondrial disease caused by PTCD3 mutations”.
Information published 31.03.2021.
Progress of the project:
1 April 2021 – 30 June 2021
As part of the ERDF 096 project, the enrolment of patients suffering from rare inherited diseases and their relatives in the Genome Database of Latvian Population was continued. It is including the collection of clinical and phenotypical data, DNA and tissue samples. Joint meetings between the project’s executors and involved clinical specialists are held on a regular basis (monthly). During these meetings, selected family cases are discussed. The whole genome sequencing analysis and was performed for selected patients and their relatives. The analysis of obtained data is ongoing. Further biochemical and molecular studies are necessary for potentially pathogenic genetic variants. The genetic diagnosis was established for several patients. The developed data analysis algorithm is still being improved.
Information published 30.06.2021.
Progress of the project:
1 July 2021 – 30 September 2021
As part of the ERDF 096 project, the enrolment of patients suffering from rare inherited diseases and their relatives in the Genome Database of Latvian Population was continued. It is including the collection of clinical and phenotypical data, DNA and tissue samples. Joint meetings between the project’s executors and involved clinical specialists are held on a regular basis (monthly). During these meetings, selected family cases are discussed. The whole genome sequencing analysis and was performed for selected patients and their relatives. The analysis of obtained data is ongoing. Further biochemical and molecular studies are necessary for potentially pathogenic genetic variants. The genetic diagnosis was established for several patients. The developed data analysis algorithm is still being improved.
The obtained data on rare pathogenic genetic variants in CAPN3 gene was presented in frame of The World Muscle Societe 2021 Virtual Congress as poster presentation: B. Lāce et al. “The most common CAPN3 disease causing variant in Nothern-Eastern Europe population or controversial coincidence”.
Information published 30.09.2021.
Progress of the project:
1 October 2021 – 31 December 2021
As part of the ERDF 096 project, the enrolment of patients suffering from rare inherited diseases and their relatives in the Genome Database of Latvian Population was continued. It is including the collection of clinical and phenotypical data, DNA and tissue samples. Joint meetings between the project’s executors and involved clinical specialists are held on a regular basis (monthly). During these meetings, selected family cases are discussed. The whole genome sequencing analysis and was performed for selected patients and their relatives. The analysis of obtained data is ongoing. Further biochemical and molecular studies are necessary for potentially pathogenic genetic variants. The genetic diagnosis was established for several patients. The developed data analysis algorithm is still being improved; a new structural change analysis algorithm is currently being developed.
The obtained data on rare pathogenic genetic variants in CAPN3 gene was analyzed and variant c.1746-20C > G was classified as a hypnomorphic (risk allele). Our data, together with the data of our partners, were summarized in a manuscript and submitted to journal “Human Mutations” (Mroczek et al. “CAPN3 c .1746-20C > G variant is hypomorphic for LGMD R1 calpain 3-related”.
Information published 30.12.2021.
Progress of the project:
1 January 2022 – 31 March 2022
During the reference period, we continued transgenic mice colony maintenance of a new knock-in mouse model for the MYBPC1 mutation (p.Y247H, total number of animals reached 110 pcs), as well as worked on new analysis of these transgenic animals. Muscle strength tests (righting reflex, inverted hang) were performed, as well as functional (open-field, grip force, rotating rod) tests. The dynamics of weight gain and determination of tremor in new-born babies were also performed. As well as muscle samples collected for a variety of studies, for analysis of transcriptome RNAseq, electron microscopy and immunofluorescence analyses.
The involvement of patients suffering from inherited neuromuscular diseases and their relatives in the Genome Database of Latvian Population was continued. Samples of selected patients and their relatives were transferred to our partner MGI Latvia for whole genome sequencing. Analysis, annotating and interpretation of the data and validation of obtained variants were performed. Several potentially pathogenic genetic variants have been found in some patients. Further analysis is necessary. The genetic diagnosis was established for several patients.
Information published 31.03.2022.