United States Hypophosphatasia Molecular Research Center
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 29
- 试验地点
- 2
- 主要终点
- Identification of cryptic alterations in the ALPL
研究概览
简要总结
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.
详细描述
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
研究设计
- 研究类型
- Observational
- 观察模型
- Other
- 时间视角
- Retrospective
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •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
排除标准
- •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
- •1. Inability to express variant in plasmid for residual enzyme and co-transfection analyses
结局指标
主要结局
Identification of cryptic alterations in the ALPL
时间窗: 3 years
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
次要结局
- Finding of alternate diagnoses among the cohort of nominated patients(3 years)
研究者
Eric Rush
Clinical Geneticist
Children's Mercy Hospital Kansas City