United States Hypophosphatasia Molecular Research Center

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.

Study Overview

• Status: Completed
• Conditions: Hypophosphatasia
• Intervention / Treatment: Genetic: Whole Genome Sequencing

Detailed Description

Primary Study Objectives:

Determine if cryptic alterations exist within or near to the ALPL gene in patients with clinical diagnosis of hypophosphatasia, but without identifiable pathogenic or likely pathogenic variant on commercial testing.

Secondary Study Objective(s):

Characterize functional effects of variants of uncertain significance in patients with clinical diagnosis of hypophosphatasia

Further characterize the differential diagnosis of hypophosphatasemia in patients with skeletal disease

• Study Type: Observational
• Enrollment (Actual): 29

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 120 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Clinical diagnosis of hypophosphatasia with negative molecular testing.

Description

Inclusion Criteria:

Aim 1-

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
2. 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-

1. Missense variant in ALPL which is interpreted as a variant of uncertain significance by the American College of Medical Genetics Guidelines for Variant Interpretation
2. Variant has been interpreted as pathogenic, likely pathogenic, likely benign, or benign using ex-US interpretation guidelines

Exclusion Criteria:

Aim 1-

1. History and physical examination incompatible with a diagnosis of hypophosphatasia OR
2. Absence of hypophosphatasemia as measured by age and sex-matched control OR
3. Absence of at least one elevated natural substrate of alkaline phosphatase OR
4. Alternate diagnosis which could overlap with signs and symptoms of hypophosphatasia

Aim 2-

1. Inability to express variant in plasmid for residual enzyme and co-transfection analyses

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Finding of alternate diagnoses among the cohort of nominated patients	Finding of alternate diagnoses among the cohort of nominated patients, expanding the differential diagnosis of hypophosphatasemia	3 years

Collaborators and Investigators

• Sponsor: Children's Mercy Hospital Kansas City
• Investigators: Principal Investigator: Eric Rush, Children's Mercy Hospital Kansas City

Publications and helpful links

Helpful Links

• Study Website

Study record dates

Study Major Dates

• Study Start (Actual): August 24, 2021
• Primary Completion (Actual): February 25, 2026
• Study Completion (Actual): February 25, 2026

Study Registration Dates

• First Submitted: September 21, 2021
• First Submitted That Met QC Criteria: September 21, 2021
• First Posted (Actual): September 30, 2021

Study Record Updates

• Last Update Posted (Actual): May 19, 2026
• Last Update Submitted That Met QC Criteria: May 18, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Metal Metabolism, Inborn Errors; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Hypophosphatasia; Investigative Techniques; Genetic Techniques; Sequence Analysis; Sequence Analysis, DNA; Whole Genome Sequencing
• Other Study ID Numbers: STUDY00001708

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No