Mutation Exploration in Non-acquired, Genetic Disorders and Its Impact on Health Economy and Life Quality

Genetic Diseases Clinical Trial

— MENDEL  

Official title:

Mutation Exploration in Non-acquired, Genetic Disorders and Its Impact on Health Economy and Life Quality

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02380729
• Other study ID #: EA2_107_14
• Status: Completed
• Phase: N/A
• First received: February 18, 2015
• Last updated: January 24, 2018
• Start date: January 31, 2015
• Est. completion date: December 31, 2017

Study information

• Verified date: January 2018
• Source: Charite University, Berlin, Germany
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The MENDEL-study will investigate whether the use of gene panel or whole genome sequencing (WGS) will:

1. improve the rate of diagnosis and through this compare the performance of the two diagnostic approaches (gene panel vs. WGS),

2. investigate whether use of said sequencing approaches early in the diagnostic process results in reduced health care spending, and

3. result in an improved quality of life for the patients and their parents.

Description:

Patients will be recruited from in- and outpatient clinics at the Otto Heubner Center, the Berlin Center for Rare Diseases, and the Institute for Medical Genetics and Human Genetics at Charité-Universitätsmedizin Berlin, Germany. Following informed consent, 5 ml EDTA blood will be obtained from the index case and 10 ml blood from each parent. Disease related phenotype information and the outcome of previous diagnostic tests and procedures will be recorded as part of Study visit #1.

[1] Study visit #1

1. A medical genetics physical will be performed. Detailed clinical symptoms (phenotype) will be recorded using Human Phenotype Ontology (HPO) terminology.

2. A detailed pedigree will be drawn.

3. Age of disease onset will be determined.

4. Results from previous diagnostic tests and procedures, as well as hospital stays, will be recorded.

5. The parents will be asked to complete a validated, standardized quality of life questionnaire adapted for for rare disease. The questionnaire is available online or in paper form.

[2] Study visit #2a (optional)

This study visit will only take place in the event that gene panel sequencing identifies a variant of uncertain significance, where additional information would be needed in order to determine its pathogenicity (e.g. confirmational biochemical testing, collection of additional information). Relevant research findings will be discussed and the nature and necessity of the additional testing will be explained.

[3] Study visit #2b (optional)

This study visit will only take place in the event that WGS identifies a variant of uncertain significance where additional information is needed in order to determine its pathogenicity > see Study visit #2a.

[4] Study visit #3 (results session)

Results will be returned in the context of a genetic counseling session.

[5] Study visit #4 (6 months after Study visit #3)

The parents will be asked to complete the validated, standardized quality of life questionnaire adapted for rare disease again.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 200
• Est. completion date: December 31, 2017
• Est. primary completion date: June 30, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

Inclusion Criteria:

1. Diagnosis: Suspicion of genetic disease. (Only one of the following criteria is required.) [1.1] Family member(s) with similar phenotype OR [1.2] At least two affected organ systems OR [1.3] One affected organ system that is known to be associated with multiple disease causing genes (e.g. long QT syndrome) OR [1.4] Multiple birth defects

2. Both parents must be available for blood draw in order to confirm phase (segregation analysis) or in order to perform WGS of the trio at a later time point.

3. Age: from birth up until age 18 years

4. Gender: Both sexes will be included

Exclusion Criteria:

1. Suspicion that the phenotype is due to an acquired disease

2. Missing informed consent from both parents or from all legal guardians for genetic testing in the setting of a clinical trial.

3. Clinical diagnosis of a disease with a known monogenic cause, e.g. Phenylketonuria or Cystic fibrosis.

Related Conditions & MeSH terms

• Genetic Diseases
• Genetic Diseases, Inborn

Intervention

Genetic:
• Gene Panel Sequencing
Enrichment for and panel sequencing of 2942 disease genes listed in the Online Mendelian Inheritance of Man (OMIM) database.
• Whole Genome Sequencing (WGS)
Whole Genome Sequencing of the index case and of both parents in the event that Gene Panel Sequencing did not identify a disease-causing mutation.

Locations

Country	Name	City	State
Germany	Department of General Pediatrics, Charité-Universitätsmedizin	Berlin
Germany	Department of Neuropediatrics, Charité-Universitätsmedizin	Berlin
Germany	Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin	Berlin

Sponsors (2)

Lead Sponsor	Collaborator
Charite University, Berlin, Germany	German Federal Ministry of Education and Research

Country where clinical trial is conducted

Germany, 

References & Publications (1)

Zemojtel T, Köhler S, Mackenroth L, Jäger M, Hecht J, Krawitz P, Graul-Neumann L, Doelken S, Ehmke N, Spielmann M, Oien NC, Schweiger MR, Krüger U, Frommer G, Fischer B, Kornak U, Flöttmann R, Ardeshirdavani A, Moreau Y, Lewis SE, Haendel M, Smedley D, Horn D, Mundlos S, Robinson PN. Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome. Sci Transl Med. 2014 Sep 3;6(252):252ra123. doi: 10.1126/scitranslmed.3009262. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Diagnostic yield through gene panel sequencing of 3089 known disease genes.	The number of confirmed disease causing mutations that can be identified in 200 patients following gene panel sequencing and analysis with the PhenIX software.	6 months.
Secondary	Quality of Life	Assessment of the parents' quality of life before and after molecular diagnostics and reception of a molecular genetic diagnosis.	2 years
Secondary	Manageability of a next generation sequencing (NGS) pipeline in routine clinical diagnostics	Calculation of the duration [months] between recruitment of a family and the final genetic counselling.	2 years
Secondary	Health economy of NGS	Comparison of the cost of "standard diagnostics" versus the use of gene panel sequencing or WGS at an early stage in the diagnostic process. Health economic analysis of the costs incurred for each patient through "the standard diagnostic approach" in comparison to costs incurred through the use of gene panel sequencing/WGS.	2 years

External Links

•   MENDEL study homepage