United States Hypophosphatasia Molecular Research Center

NCT05062629 | Active Not Recruiting

• 1 other identifier: STUDY00001708
• Study Type: observational
• Target: 66
• Locations: 1 country
• Sites: 1

Brief Summary

This study is being done to determine if cryptic alterations exist within or near to the ALPL gene in patients with a clinical diagnosis of hypophosphatasia, but without identifiable alteration on commercial testing. Additionally, the study aims to characterize functional effects of certain variants of uncertain significance in patients with clinical diagnosis of hypophosphatasia.

Conditions

Hypophosphatasia

Outcome Measures

Primary Outcomes (1)

• Identification of cryptic alterations in the ALPL

  Identification of cryptic alterations in the ALPL, with careful focus on cryptic variants within the 12 exons, intronic variants, and variants in regulatory elements. Characterization of loss of function or dominant negative effect in variants which are considered to be of uncertain clinical significance by American College of Medical Genetics guidelines for variants interpretation such that variants are able to be reclassified into actionable (pathogenic, likely pathogenic) or nonactionable (benign, likely benign) class

  3 years

Secondary Outcomes (1)

• Finding of alternate diagnoses among the cohort of nominated patients

  3 years

Interventions

Whole Genome Sequencing GENETIC

Whole Genome Sequencing

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Clinical diagnosis of hypophosphatasia with negative molecular testing.

You may qualify if:

• Aim 1-
• Diagnosis of Hypophosphatasia based on clinical features that include
• History consistent with diagnosis of hypophosphatasia AND
• Physical examination findings consistent with a diagnosis of hypophosphatasia AND
• Presence of low serum alkaline phosphatase level for age and sex AND
• Elevation of at least one natural substrate of alkaline phosphatase
• Lack of detection of a variant on molecular analysis of the ALPL gene. When possible, first degree relatives (parents, siblings, or child) will be included for the sole purpose of trio testing. No additional information will be collected on first degree relatives.
• Aim 2-
• Missense variant in ALPL which is interpreted as a variant of uncertain significance by the American College of Medical Genetics Guidelines for Variant Interpretation
• Variant has been interpreted as pathogenic, likely pathogenic, likely benign, or benign using ex-US interpretation guidelines

You may not qualify if:

• Aim 1-
• History and physical examination incompatible with a diagnosis of hypophosphatasia OR
• Absence of hypophosphatasemia as measured by age and sex-matched control OR
• Absence of at least one elevated natural substrate of alkaline phosphatase OR
• Alternate diagnosis which could overlap with signs and symptoms of hypophosphatasia
• Aim 2-
• \. Inability to express variant in plasmid for residual enzyme and co-transfection analyses

Sponsors & Collaborators

• Children's Mercy Hospital Kansas City: lead

Study Sites (1)

Children's Mercy Hospital

Kansas City, Missouri, 64108, United States

Location

Biospecimen

Retention: SAMPLES WITH DNA

whole genome sequencing

MeSH Terms

Conditions

Hypophosphatasia

Interventions

Whole Genome Sequencing

Condition Hierarchy (Ancestors)

Metal Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Sequence Analysis, DNA; Sequence Analysis; Genetic Techniques; Investigative Techniques

Study Officials

• Eric Rush

  Children's Mercy Hospital Kansas City

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Geneticist

Study Record Dates

• First Submitted: September 21, 2021
• First Posted: September 30, 2021
• Study Start: August 24, 2021
• Primary Completion: April 30, 2026
• Study Completion (Estimated): June 5, 2026
• Last Updated: May 6, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)