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

NCT ID: NCT02380729

Last Updated: 2018-01-26

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 200 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2015-01-31
• Study Completion Date: 2017-12-31

Brief 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.

Detailed 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.

Conditions

Genetic Diseases

Study Design

• Observational Model Type: FAMILY_BASED
• Study Time Perspective: PROSPECTIVE

Study Groups

Index patients

Children between birth and 18 years of age manifesting with a suspected genetic disorder.

Investigation: First Gene Panel Sequencing and if no mutation ist found > Whole Genome Sequencing (WGS)

Gene Panel Sequencing

Intervention Type: GENETIC

Enrichment for and panel sequencing of 2942 disease genes listed in the Online Mendelian Inheritance of Man (OMIM) database.

Whole Genome Sequencing (WGS)

Intervention Type: GENETIC

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.

Parents of the index patient

Both parents of the index patient.

Investigation: Whole Genome Sequencing (WGS) if no mutation is found by Gene Panel Sequencing of the index patient.

Whole Genome Sequencing (WGS)

Intervention Type: GENETIC

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.

Interventions

Gene Panel Sequencing

Enrichment for and panel sequencing of 2942 disease genes listed in the Online Mendelian Inheritance of Man (OMIM) database.

Intervention Type: GENETIC

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.

Intervention Type: GENETIC

Eligibility Criteria

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.

• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

German Federal Ministry of Education and Research

OTHER_GOV

Sponsor Role: collaborator

Charite University, Berlin, Germany

OTHER

Sponsor Role: lead

Responsible Party

Markus Schuelke, M.D.

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Markus Schuelke, M.D.

Role: PRINCIPAL_INVESTIGATOR

Department of Neuropediatrics, Charité

Stefan Mundlos, M.D.

Role: PRINCIPAL_INVESTIGATOR

Institute of Medical Genetics and of Human Genetics, Charité

Heiko Krude, M.D.

Role: PRINCIPAL_INVESTIGATOR

Department of General Pediatrics, Charité

Locations

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, , Germany

Countries

Germany

References

Zemojtel T, Kohler S, Mackenroth L, Jager M, Hecht J, Krawitz P, Graul-Neumann L, Doelken S, Ehmke N, Spielmann M, Oien NC, Schweiger MR, Kruger U, Frommer G, Fischer B, Kornak U, Flottmann 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.

Reference Type: BACKGROUND

PMID: 25186178 (View on PubMed)

Other Identifiers

EA2_107_14

Identifier Type: -

Identifier Source: org_study_id