Phenotypic Profiling in Subjects Heterozygous for 1 of 2 Rare Variants in the Hypophosphatasia Gene (ALPL)

Abstract

Context 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 ALPL 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 two rare variants in ALPL. Methods Through BioVU, a DNA biobank that pairs subjects’ genetic information with their de-identified medical record, we identified subjects with two 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. Results 20 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, six (30.0%) had both clinical bone disease and serum AlkP activity below 40 IU/L while four subjects (23.5%) with the p.T273M variant met the same criteria despite the distinct clinical phenotypes of these variants. Conclusions 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 misidentifying those who may benefit from additional screening and perhaps pharmacologic intervention.

Oral health status of adult hypophosphatasia patients: A cross‐sectional study

“…Characteristic clinical signs of HPP are associated with disturbances of bone and teeth mineralization (Feeney et al, 2018) including rickets, skeletal deformities, craniosynostosis and atraumatic premature loss of deciduous teeth in severely affected infants (Petkovic Ramadza et al, 2009; Rothenbuhler & Linglart, 2017; Whyte et al, 2019) as well as fractures, chronic bone and muscle pain, physical fatigue and supposed periodontal disease (PD) in adult life (Schmidt et al, 2017; Seefried et al, 2020; Tilden et al, 2020).…”

Gene Therapy Using Adeno-Associated Virus Serotype 8 Encoding TNAP-D10 Improves the Skeletal and Dentoalveolar Phenotypes in Alpl−/− Mice

“…hypophosphatasie.com), and their genotype/phenotype correlations are not well understood. (15,16) The inheritance pattern of perinatal and infantile HPP is often autosomal recessive, with most patients being compound heterozygotes for pathogenic ALPL mutations that result in almost null alkaline phosphatase (ALP) activity, but some are homozygous for recessive alleles and most adult and odonto-HPP patients harbor a single dominant-negative ALPL allele. (17,18) Asfotase alfa is a recombinant fusion protein comprising the TNAP ectodomain, a human IgG1 Fc domain for one-step purification, and a terminal deca-aspartate (D 10 ) motif for mineral targeting.…”

“…There are more than 400 mutant alleles identified for the ALPL gene (the ALPL mutation database http://alplmutationdatabase.hypophosphatasie.com ), and their genotype/phenotype correlations are not well understood. ( 15 , 16 ) The inheritance pattern of perinatal and infantile HPP is often autosomal recessive, with most patients being compound heterozygotes for pathogenic ALPL mutations that result in almost null alkaline phosphatase (ALP) activity, but some are homozygous for recessive alleles and most adult and odonto‐HPP patients harbor a single dominant‐negative ALPL allele. ( 17 , 18 )…”