Not just a carrier: Clinical presentation and management of patients with heterozygous disease‐causing alkaline phosphatase (ALPL) variants identified through expanded carrier screening
Abstract 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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-01-01
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| Series: | Molecular Genetics & Genomic Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mgg3.2056 |
| _version_ | 1797955520771915776 |
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| author | Natalie M. Beck Katelynn G. Sagaser Cathleen S. Lawson Christine Hertenstein Ashley Jachens Katherine R. Forster Kristen A. Miller Angie C. Jelin Karin J. Blakemore Julie Hoover‐Fong |
| author_facet | Natalie M. Beck Katelynn G. Sagaser Cathleen S. Lawson Christine Hertenstein Ashley Jachens Katherine R. Forster Kristen A. Miller Angie C. Jelin Karin J. Blakemore Julie Hoover‐Fong |
| author_sort | Natalie M. Beck |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-10T23:34:28Z |
| format | Article |
| id | doaj.art-e1750050062b436c8d1f51dc91e06db3 |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-04-10T23:34:28Z |
| publishDate | 2023-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-e1750050062b436c8d1f51dc91e06db32023-01-12T04:03:44ZengWileyMolecular Genetics & Genomic Medicine2324-92692023-01-01111n/an/a10.1002/mgg3.2056Not just a carrier: Clinical presentation and management of patients with heterozygous disease‐causing alkaline phosphatase (ALPL) variants identified through expanded carrier screeningNatalie M. Beck0Katelynn G. Sagaser1Cathleen S. Lawson2Christine Hertenstein3Ashley Jachens4Katherine R. Forster5Kristen A. Miller6Angie C. Jelin7Karin J. Blakemore8Julie Hoover‐Fong9Greenberg Center for Skeletal Dysplasias, Department Genetic of Medicine Johns Hopkins University School of Medicine Baltimore Maryland USADivision of Maternal Fetal Medicine, Department of Gynecology and Obstetrics Johns Hopkins University School of Medicine Baltimore Maryland USADivision of Maternal Fetal Medicine, Department of Gynecology and Obstetrics Johns Hopkins University School of Medicine Baltimore Maryland USADivision of Maternal Fetal Medicine, Department of Gynecology and Obstetrics Johns Hopkins University School of Medicine Baltimore Maryland USACenter for Maternal and Fetal Medicine Howard County General Hospital, Johns Hopkins Hospital Baltimore Maryland USACenter for Fetal Therapy Johns Hopkins University School of Medicine Baltimore Maryland USADivision of Maternal Fetal Medicine, Department of Gynecology and Obstetrics Johns Hopkins University School of Medicine Baltimore Maryland USADivision of Maternal Fetal Medicine, Department of Gynecology and Obstetrics Johns Hopkins University School of Medicine Baltimore Maryland USADivision of Maternal Fetal Medicine, Department of Gynecology and Obstetrics Johns Hopkins University School of Medicine Baltimore Maryland USAGreenberg Center for Skeletal Dysplasias, Department Genetic of Medicine Johns Hopkins University School of Medicine Baltimore Maryland USAAbstract 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.https://doi.org/10.1002/mgg3.2056ALPLcarrier screeninggenetic testinghypophosphatasiaincidental diagnosis |
| spellingShingle | Natalie M. Beck Katelynn G. Sagaser Cathleen S. Lawson Christine Hertenstein Ashley Jachens Katherine R. Forster Kristen A. Miller Angie C. Jelin Karin J. Blakemore Julie Hoover‐Fong Not just a carrier: Clinical presentation and management of patients with heterozygous disease‐causing alkaline phosphatase (ALPL) variants identified through expanded carrier screening Molecular Genetics & Genomic Medicine ALPL carrier screening genetic testing hypophosphatasia incidental diagnosis |
| title | Not just a carrier: Clinical presentation and management of patients with heterozygous disease‐causing alkaline phosphatase (ALPL) variants identified through expanded carrier screening |
| title_full | Not just a carrier: Clinical presentation and management of patients with heterozygous disease‐causing alkaline phosphatase (ALPL) variants identified through expanded carrier screening |
| title_fullStr | Not just a carrier: Clinical presentation and management of patients with heterozygous disease‐causing alkaline phosphatase (ALPL) variants identified through expanded carrier screening |
| title_full_unstemmed | Not just a carrier: Clinical presentation and management of patients with heterozygous disease‐causing alkaline phosphatase (ALPL) variants identified through expanded carrier screening |
| title_short | Not just a carrier: Clinical presentation and management of patients with heterozygous disease‐causing alkaline phosphatase (ALPL) variants identified through expanded carrier screening |
| title_sort | not just a carrier clinical presentation and management of patients with heterozygous disease causing alkaline phosphatase alpl variants identified through expanded carrier screening |
| topic | ALPL carrier screening genetic testing hypophosphatasia incidental diagnosis |
| url | https://doi.org/10.1002/mgg3.2056 |
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