Tilden Daniel R, Sheehan Jonathan H, Newman John H, Meiler Jens, Capra John A, Ramirez Andrea, Simmons Jill, Dahir Kathryn
Division of Endocrinology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Ian M. Burr Division of Pediatric Endocrinology, Department of Pediatrics, Monroe Carroll Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee.
J Endocr Soc. 2020 Jun 28;4(8):bvaa084. doi: 10.1210/jendso/bvaa084. eCollection 2020 Aug 1.
Hypophosphatasia (HPP) is a syndrome marked by low serum alkaline phosphatase (AlkP) activity as well as musculoskeletal and/or dental disease. While the majority of subjects with HPP carry a pathogenic variant in the gene or its regulatory regions, individual pathogenic variants are often not tightly correlated with clinical symptomatology. We sought to better understand the genotype/phenotype correlation in HPP by examining the clinical and biochemical data of 37 subjects with 2 rare variants in .
Through BioVU, a DNA biobank that pairs individuals' genetic information with their de-identified medical records, we identified subjects with 2 rare variants with distinct reported clinical phenotypes (p.D294A and p.T273M). We then performed a manual review of these subjects' de-identified medical records along with computational modeling of protein structure to construct a genetic, biochemical and clinical phenotype for each subject and variant.
Twenty subjects with the p.D294A variant and 17 with the p.T273M variant had sufficient data for analysis. Among subjects in our cohort with the p.D294A variant, 6 (30.0%) had both clinical bone disease and serum AlkP activity below 40 IU/L while 4 subjects (23.5%) with the p.T273M variant met the same criteria despite the distinct clinical phenotypes of these variants.
Given the loose genotype/phenotype correlation in HPP seen in our cohort, clinical context is crucial for the interpretation of genetic test results to guide clinical care in this population. Otherwise, over- or under-diagnosis may occur, resulting in misidentification of those who may benefit from additional screening and perhaps pharmacologic intervention.
低磷酸酯酶症（HPP）是一种以血清碱性磷酸酶（AlkP）活性降低以及肌肉骨骼和/或牙齿疾病为特征的综合征。虽然大多数HPP患者在该基因或其调控区域携带致病变异，但个体致病变异通常与临床症状没有紧密关联。我们试图通过检查37名携带该基因两个罕见变异的受试者的临床和生化数据，来更好地理解HPP中的基因型/表型相关性。
通过BioVU（一个将个体遗传信息与其去识别化医疗记录配对的DNA生物样本库），我们识别出携带两种具有不同报告临床表型（p.D294A和p.T273M）的罕见变异的受试者。然后，我们对这些受试者的去识别化医疗记录进行人工审查，并对蛋白质结构进行计算建模，以构建每个受试者和变异的遗传、生化和临床表型。
20名携带p.D294A变异的受试者和17名携带p.T273M变异的受试者有足够的数据进行分析。在我们队列中携带p.D294A变异的受试者中，6名（30.0%）患有临床骨病且血清AlkP活性低于40 IU/L，而4名（23.5%）携带p.T273M变异的受试者尽管这些变异具有不同的临床表型，但也符合相同标准。
鉴于我们队列中HPP的基因型/表型相关性较弱，临床背景对于解释基因检测结果以指导该人群的临床护理至关重要。否则，可能会出现过度诊断或诊断不足，导致对那些可能从额外筛查甚至药物干预中受益的人误判。
