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

July 28, 2022 updated by: Fondazione SISA (Societa Italiana per lo Studio della Arteriosclerosi)

Prevalence and Mutation Rate of Lipa Gene in LIPIGEN Subjects With Clinical Diagnosis of FH

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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

Enrollment (Anticipated)

1000

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Italy
      • Modena, Italy
        • Recruiting
        • Laboratorio di biochimica delle lipoproteine - DIPARTIMENTO DI SCIENZE BIOMEDICHE
        • Contact:
      • Palermo, Italy
        • Recruiting
        • Centro Di Riferimento Regionale Per La Prevenzione, Diagnosi E Cura Delle Malattie Rare Del Metabolismo
        • Contact:
      • Roma, Italy
        • Recruiting
        • Centro Per L'Arteriosclerosi Dipartimento Di Medicina Interna E Specialità Mediche
        • Contact:
    • Mi
      • Cinisello Balsamo, Mi, Italy
        • Recruiting
        • CENTRO PER LO STUDIO DELL'ATEROSCLEROSI - Ospedale Bassini
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 18 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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.

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Other
  • Time Perspectives: Retrospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
FH pediatric patients
1000 clinically diagnosed FH pediatric patients (age <18 years) included in the LIPIGEN (Lipid TransPort Disorders italian Genetic Network) database
Other: Observational study
Observational study: There is no intervention.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
2 years from start of the study

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
2 years from start of the study

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fondazione SISA (Societa Italiana per lo Studio della Arteriosclerosi)

Investigators

  • Study Director: Maurizio Averna, Fondazione SISA

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2017

Primary Completion (Anticipated)

July 1, 2023

Study Completion (Anticipated)

July 1, 2023

Study Registration Dates

First Submitted

May 21, 2019

First Submitted That Met QC Criteria

June 11, 2019

First Posted (Actual)

June 12, 2019

Study Record Updates

Last Update Posted (Actual)

July 29, 2022

Last Update Submitted That Met QC Criteria

July 28, 2022

Last Verified

July 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • LIPIGEN-002

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

Upon preventive request for a scientific collaboration

IPD Sharing Time Frame

For three years from the end of the study

IPD Sharing Access Criteria

Upon preventive request for a scientific collaboration

IPD Sharing Supporting Information Type

  • Study Protocol
  • Statistical Analysis Plan (SAP)
  • Informed Consent Form (ICF)
  • Clinical Study Report (CSR)
  • Analytic Code

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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