Greenberg Center for Skeletal Dysplasias, Department Genetic of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Genome Medical Services, San Francisco, California, USA.
Mol Genet Genomic Med. 2023 Jan;11(1):e2056. doi: 10.1002/mgg3.2056. Epub 2022 Nov 28.
Hypophosphatasia (HPP) is an underrecognized, complex bone mineralization disorder with variable manifestations caused by one or two deleterious variants in the alkaline phosphatase (ALPL) gene. Expanded carrier screening (ECS), inclusive of ALPL, intends to inform reproductive risk but may incidentally reveal an HPP diagnosis with 50% familial risks. We sought to investigate at-risk individuals and develop a multidisciplinary referral and evaluation protocol for ECS-identified ALPL heterozygosity. A retrospective database query of ECS results from 8 years to 1 month for heterozygous pathogenic/likely pathogenic ALPL variants was completed. We implemented a clinical protocol for diagnostic testing and imaging, counseling, and interdisciplinary care management for identified patients, and outcomes were documented. Heterozygous ALPL variants were identified in 12/2248 unrelated patients undergoing ECS (0.53%; heterozygote frequency 1/187). Of 10 individuals successfully contacted, all demonstrated symptomatology and/or alkaline phosphatase values consistent with HPP. ECS may reveal incidental health risks, including recognition of missed HPP diagnoses in ALPL heterozygotes. In our cohort, all ECS-identified ALPL heterozygotes with clinical and/or biochemical data available demonstrated features of HPP. Referral to a genetics professional familiar with HPP is indicated for family history assessment, genetic counseling, cascade testing, and long-term bone health management.
低磷酸酯酶症（HPP）是一种未被充分认识的复杂骨矿化疾病，由碱性磷酸酶（ALPL）基因中的一个或两个有害变异引起，其临床表现具有变异性。扩展携带者筛查（ECS），包括 ALPL，旨在告知生殖风险，但可能偶然发现 HPP 诊断，其家族风险为 50%。我们旨在调查高危个体，并为 ECS 确定的 ALPL 杂合子制定多学科转诊和评估方案。对 8 年至 1 个月的 ECS 结果进行了回顾性数据库查询，以确定杂合致病性/可能致病性 ALPL 变体。我们为确定的患者实施了诊断测试和影像学、咨询以及跨学科护理管理的临床方案，并记录了结果。在接受 ECS 的 2248 名无关患者中，发现了 12 例杂合 ALPL 变体（0.53%；杂合子频率为 1/187）。在成功联系到的 10 个人中，所有人都表现出与 HPP 一致的症状和/或碱性磷酸酶值。ECS 可能会揭示偶然的健康风险，包括在 ALPL 杂合子中识别出遗漏的 HPP 诊断。在我们的队列中，所有 ECS 确定的 ALPL 杂合子，只要有临床和/或生化数据可用，均表现出 HPP 的特征。建议向熟悉 HPP 的遗传专业人员转诊，以进行家族史评估、遗传咨询、级联测试和长期骨骼健康管理。
