Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia

Abstract

Hypophosphatasia (HPP) is a rare autosomal dominant or recessive metabolic disorder caused by mutations in the tissue nonspecific alkaline phosphatase gene (ALPL). To date, over 300 different mutations in ALPL have been identified. Disease severity is widely variable with severe forms usually manifesting during perinatal and/or infantile periods while mild forms are sometimes only diagnosed in adulthood or remain undiagnosed. Common clinical features of HPP are defects in bone and tooth mineralization along with the biochemical hallmark of decreased serum alkaline phosphatase activity. The incidence of severe HPP is approximately 1 in 300,000 in Europe and 1 in 100,000 in Canada. We present the clinical and molecular findings of 83 probands and 28 family members, referred for genetic analysis due to a clinical and biochemical suspicion of HPP. Patient referrals included those with isolated low alkaline phosphatase levels and without any additional clinical features, to those with a severe skeletal dysplasia. Thirty-six (43.3%) probands were found to have pathogenic ALPL mutations. Eleven previously unreported mutations were identified, thus adding to the ever increasing list of ALPL mutations. Seven of these eleven were inherited in an autosomal dominant manner while the remaining four were observed in the homozygous state. Thus, this study includes a large number of well-characterized patients with hypophosphatasemia which has permitted us to study the genotype:phenotype correlation. Accurate diagnosis of patients with a clinical suspicion of HPP is crucial as not only is the disease life-threatening but the patients may be offered bone targeted enzymatic replacement therapy. © 2017 Wiley Periodicals, Inc.

Can we identify individuals with an ALPL variant in adults with persistent hypophosphatasaemia?

“…The ALPL disease-causing variants database (http://www.se-sep.uvsq. fr/03_hypo_mutations.php) was also consulted to obtain up-to-date information about the genetic variants included in our study (Additional file 1: Table S1) already identified [25][26][27][28][29][30][31][32][33][34][35][36]. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines [20].…”

Perinatal form hypophosphatasia caused by a novel large duplication of ALPL gene and one year follow-up under enzyme replacement therapy; a case report

“…To our knowledge large duplications on the ALPL gene have not been reported to date, but minor duplications is not rare (8,9). Herein, we report a novel large homozygote duplication encompassing exons 2 to 6 of the ALPL gene.…”

Gene coexpression network analysis revealed biomarkers correlated with blast cells and survival in acute myeloid leukemia

“…Our data show that CSF3R is tended to underexpressed in AML patients with a normal karyotype and may serve as a special genetic biomarker for the prognosis and treatment of AML patients with a normal karyotype. Tissue-nonspecific alkaline phosphatase (ALPL) plays a role in bone biomineralization, and mutations in this gene are used to diagnose hypophosphatasia (27). Further studies are needed to reveal the functions of ALPL in AML.…”