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Lipa Gene Mutation in PED-LIPIGEN (Pediatric FH Subjects)

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ClinicalTrials.gov Identifier: NCT03984149
Recruitment Status : Recruiting
First Posted : June 12, 2019
Last Update Posted : June 12, 2019
Sponsor:
Information provided by (Responsible Party):
Fondazione SISA (Societa Italiana per lo Studio della Arteriosclerosi)

Tracking Information
First Submitted Date May 21, 2019
First Posted Date June 12, 2019
Last Update Posted Date June 12, 2019
Actual Study Start Date September 1, 2017
Estimated Primary Completion Date December 31, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: June 11, 2019)
Prevalence of patients with mutations of LIPA gene among clinically diagnosed FH subjects [ Time Frame: 2 years from start of the study ]
Percentage of patients with at least one mutation of LIPA gene among clinically diagnosed FH subjects according to a "Dutch Lipid Clinic Network" score of 6 or above
Original Primary Outcome Measures Same as current
Change History No Changes Posted
Current Secondary Outcome Measures
 (submitted: June 11, 2019)
Frequency of specific mutations of LIPA gene among clinically diagnosed FH subjects [ Time Frame: 2 years from start of the study ]
Numbers of patients carrying specific mutations of LIPA gene among clinically diagnosed FH subjects for each mutation identified by sequencing of all 10 exons of LIPA gene.
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Lipa Gene Mutation in PED-LIPIGEN (Pediatric FH Subjects)
Official Title Prevalence and Mutation Rate of Lipa Gene in LIPIGEN Subjects With Clinical Diagnosis of FH
Brief Summary

Familial Hypercholesterolemia (FH) is a monogenic autosomal dominant disease also known as Autosomal Dominant Hypercholesterolemia - ADH) that leads to dramatically increased levels of Low Density Lipoprotein (LDL) and total cholesterol associated to tendon xanthomas, xanthelasma, corneal arcus, premature atherosclerosis and to an increased risk of coronary artery disease (CAD) and myocardial infarction.

FH is mainly caused by mutations in genes encoding for proteins affecting hepatic LDL cholesterol uptake including the LDL receptor (LDLR) gene or the gene encoding the only apolipoprotein of LDL, the apolipoprotein B (APOB), or the gene encoding a protease regulating LDLR levels on the cell membrane Lysosomal Acid Lipase A (LIPA) gene encode for Lysosomal acid lipase (LAL) enzyme responsible for hydrolyzing cholesterol esters and triglycerides that are delivered to lysosomes. Mutations in LIPA that completely inactivate LAL are the molecular cause of Wolman disease, a rapidly lethal disease of infancy while mutations in LIPA that result in residual enzymatic activity of LAL are responsible of a disorder characterized by a less severe phenotype known as cholesterol ester storage disease (CESD). Patients with CESD usually show a phenotype characterized by hepatic disease and mixed hyperlipidemia with elevated levels of LDL-C and triglycerides (TG) and decreased HDL-C levels.

A broader phenotypic presentation for loss of function mutations in LIPA suggests that LIPA mutations may be considered in patients with apparently monogenic FH in whom mutations in the known candidate genes are not detectable.

The project is aimed to evaluate the prevalence and the mutation rate of LIPA gene in subjects with a clinical diagnosis of FH and already genetically characterized in whom pathogenic mutations in the known candidate genes have not been identified. The analysis will be performed in about 250 FH pediatric subjects and putative causal mutations will be also tested for co-segregation in available families in affected and unaffected members.

Detailed Description

Lysosomal acid lipase (LAL) is encoded by LIPA gene located on chromosome 10q23.3-q23 and consists of 10 exons. LIPA mRNA (messenger RiboNucleic Acid) (GenBank accession number NM_000235) is 2782 bp long and encodes a mature protein of 375 residues (GenBank accession number NP_000226). The sequencing of all 10 exons of LIPA gene will consist of 10 PCR (Polymerase Chain Reaction) amplification reactions (for the 10 exons and the proximal promoter) followed by 20 sequence reactions (forward and reverse sequencing) with appropriate primers designed to include the intron-exon boundaries. This analysis will be performed in about 250 FH pediatric subjects as specified in project description.

The sequencing work will be performed taking advantage of 2 automated 8 capillaries automated DNA Sequencer (3500 Genetic Analyzer, Thermo Fisher Scientific, Monza, Italy) currently available in the laboratory of the Units involved in the project.

In case of identification of unreported sequence variants, the presence of these mutations will be assessed in a sample of at least 100 normolipidemic subjects of the population, in order to define whether the nucleotide changes are rare sequence variations (with a putative functional effect) or represent common polymorphisms. In case of finding of rare variants in the coding regions, an in silico analysis will be performed by using two different softwares (Polyphen, http://genetics.bwh.harvard.edu/pph/ and Panther, http://www.pantherdb.org/) to predict the putative damaging role of the mutations on the protein. In case of intronic variants, the specifically designed software Automated Splice Site Analysis will be applied (https://www.splice.uwo.ca/).

Putative causal mutations will be also tested for co-segregation in available families in affected and unaffected members.

In order to test the effect of variants on enzyme activity LAL-activity will be assayed with dried blood spot (DBS) technique using the inhibitors Lalistat 2 in carriers and non carriers of these mutations belonging to available kindred.

Study Type Observational
Study Design Observational Model: Other
Time Perspective: Retrospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:

Venous blood samples were taken after 12 hours of fasting. Serum total cholesterol, triglycerides and HDL-cholesterol levels were measured in a centralized laboratory using enzymatic methods.

DNA samples, serum, plasma and whole blood were aliquoted and preserved at -80°C.

Sampling Method Non-Probability Sample
Study Population Clinically diagnosed FH pediatric patients (age <18 years) included in the Lipid TransPort Disorders italian Genetic Network (LIPIGEN) database, already genetically characterized.
Condition Lysosomal Acid Lipase Deficiency
Intervention Other: Observational study
Observational study: There is no intervention.
Study Groups/Cohorts FH pediatric patients
1000 clinically diagnosed FH pediatric patients (age <18 years) included in the LIPIGEN (Lipid TransPort Disorders italian Genetic Network) database
Intervention: Other: Observational study
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: June 11, 2019)
1000
Original Estimated Enrollment Same as current
Estimated Study Completion Date December 31, 2019
Estimated Primary Completion Date December 31, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • Pediatric subjects (<18 years old) with a clinical diagnosis of FH and without identified pathogenic mutations in the known candidate genes.

Exclusion Criteria:

  • Subjects with a clinical diagnosis of FH with identified pathogenic mutations in the known candidate genes.
Sex/Gender
Sexes Eligible for Study: All
Ages up to 18 Years   (Child, Adult)
Accepts Healthy Volunteers No
Contacts
Contact: Alberico L Catapano alberico.catapano@unimi.it
Contact: Alessia Tincani +39026173276 catapano.centroatero@gmail.com
Listed Location Countries Italy
Removed Location Countries  
 
Administrative Information
NCT Number NCT03984149
Other Study ID Numbers LIPIGEN-002
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: Yes
Plan Description: Upon preventive request for a scientific collaboration
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Supporting Materials: Analytic Code
Time Frame: For three years from the end of the study
Access Criteria: Upon preventive request for a scientific collaboration
Responsible Party Fondazione SISA (Societa Italiana per lo Studio della Arteriosclerosi)
Study Sponsor Fondazione SISA (Societa Italiana per lo Studio della Arteriosclerosi)
Collaborators Not Provided
Investigators
Study Director: Maurizio Averna Fondazione SISA
PRS Account Fondazione SISA (Societa Italiana per lo Studio della Arteriosclerosi)
Verification Date June 2019