Hypophosphatasia via the ALPL Gene

Hypophosphatasia (HPP) is characterized by defective mineralization of bone or teeth in the presence of low activity of serum and bone alkaline phosphatase. Clinical features range from stillbirth without mineralized bone at the severe end to pathologic fractures of the lower extremities in later adulthood at the mild end. At least six clinical forms are currently recognized based on age at diagnosis and severity of features, including: (1) perinatal lethal HPP characterized by respiratory insufficiency and hypercalcemia; (2) perinatal benign HPP with prenatal skeletal manifestations that slowly resolve into the milder childhood or adult form; (3) infantile HPP (OMIM#241500) with onset between birth and six months characterized by rickets without elevated serum alkaline phosphatase activity; (4) childhood HPP (OMIM#241510) that ranges from low bone mineral density for age with unexplained fractures to rickets; (5) adult HPP (OMIM#146300) characterized by early loss of adult dentition and stress fractures and pseudofractures of the lower extremities in middle age; and (6) odontohypophosphatasia characterized by premature exfoliation of primary teeth or severe dental caries as an isolated finding or as part of the above forms of HPP (Mornet & Nunes. GeneReviews. 2010).

ALPL is the only gene known to be associated with HPP. ALPL encodes alkaline phosphatase, tissue-nonspecific isozyme (TNSALP), which is present in liver, kidney, and bone. Perinatal and infantile HPP are inherited in an autosomal recessive manner. The milder forms, especially adult and odontohypophosphatasia, may be inherited in an autosomal recessive or dominant manner depending on the effect that the variant has on TNSALP activity. In recessive HPP, heterozygotes either are asymptomatic, manifesting biochemical but not clinical abnormality, or may manifest milder symptoms depending on the variant. A good correlation exists between the severity of the phenotype and the residual enzymatic activity (Zurutuza et al. Hum Mol Genet 8:1039–1046, 1999; Orimo et al. J Bone Miner Res 16:2313–2319, 2001). A variety of variants in ALPL have been reported with the majority being missense changes.

Sequencing of ALPL is predicted to detect disease variants in 95% of cases with severe perinatal and infantile HPP. In milder forms, variant detection rate is difficult to estimate. Overall, ~50% of cases with a clinical diagnosis of HPP have two ALPL variants and ~40%-45% have one variant. The milder the disease, the higher the proportion in which only one ALPL variant is detected (Mornet & Nunes GeneReviews 2010).

This test provides full coverage of all coding exons of the ALPL gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.