You have full access to this open access article. All 16 patients had ALP activity below the normal range. Positive findings for other gene variants were identified in 4 patients: 1 patient presented with variants in COL1A1 , NLRP12 , and SCN9A , coding for collagen, type, I alpha-1 chain, nod-like receptor pyrin domain containing 12, and sodium voltage-gated channel alpha subunit 9, respectively; 1 presented with a heterozygous, likely pathogenic variant in P3H1 coding for prolyl 3 hydroxylase 1; 1 presented with a heterozygous pathogenic variant in SGCE , coding for sarcoglycan epsilon; and 1 presented with a heterozygous variant of uncertain significance in VDR , encoding vitamin D receptor.
The accumulation of PPi, a potent inhibitor of bone mineralization, can cause defective skeletal mineralization, while impaired dephosphorylation of PLP into pyridoxal can result in vitamin B 6 —responsive seizures [ 1 , 2 ]. While the clinical spectrum of HPP is extremely broad across different age groups, it is often associated with severe systemic morbidity, particularly due to musculoskeletal deficits e.
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Accurate, timely diagnosis of HPP is important for appropriate disease management [ 1 ]. A clinical diagnosis of HPP is based on identification of characteristic manifestations [ 1 ]. To date, more than variants of the ALPL gene, predominantly missense variants, have been identified [ 5 ], indicating substantial allelic heterogenicity. The primary study objective was to compare the results of WGS with those of standard sequencing carried out for detection of ALPL variants.
Eligible patients had a clinical diagnosis of HPP based on age- and sex-adjusted low serum ALP activity and clinical symptoms. ALP activity was determined on 2 occasions, at least 1 month apart, using a commercially available assay. Patients were required to have an available sequencing report indicating no pathogenic variants, no likely pathogenic variants, or no variants of uncertain significance VUS in ALPL. For each patient, medical history was obtained using a standardized questionnaire indicating specified signs and symptoms as present or absent, and entering the history and date of use of specified medications.
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Data were collated by means of an electronic case report form. Patient-level data were de-identified by assigning project-specific codes i. The study was conducted in compliance with guidelines for Good Clinical Practice and the ethical principles of the Declaration of Helsinki. Written informed consent was obtained from patients prior to initiation of study procedures. Kits containing the Centogene GmbH Rostock, Germany proprietary dry blood spot card CentoCard were used to collect blood samples from patients and were returned to Centogene for analysis.
