Genetics and inheritance of hypophosphatasia (HPP)
The underlying genetic basis of hypophosphatasia (HPP) is loss-of-function mutations in the alkaline phosphatase, liver/bone/kidney (ALPL) gene, which encodes the TNSALP isozyme.1-4 Two hundred fifty-four distinct mutations have been described in the ALPL gene. For a comprehensive list of mutations, go to The ALPL Gene Mutation Database here.
Mode of inheritance
Both autosomal dominant and autosomal recessive patterns of inheritance of HPP are described, and compound heterozygotes may complicate a genetic analysis. Genetic counseling is an important first step in family risk assessment.4-6
Role of genetic testing
While not required for establishing a diagnosis, genetic testing is important to enable carrier testing of at-risk relatives, prenatal diagnosis, and preimplantation genetic diagnosis.6
Genetic testing to determine specific mutations may be conducted by either targeted mutation analysis (if a specific mutation is suspected) or by sequence analysis of the ALPL genomic DNA.6 Find a genetic testing facility.
Analytical sensitivity of gene testing is nearly 95% and analytical specificity is nearly 100%. Both clinical sensitivity and specificity may be dependent on age or family history.6
References: 1. Whyte MP. Physiological role of alkaline phosphatase explored in hypophosphatasia. Ann N Y Acad Sci. 2010;1192:190-200. 2. Barvencik F, Beil FT, Gebauer M, et al. Skeletal mineralization defects in adult hypophosphatasia—a clinical and histological analysis. Osteoporos Int. 2011;22(10):2667-2675. 3. Mornet E. Hypophosphatasia. Orphanet J Rare Dis. 2007;2:40. http://www.ojrd.com/content/2/1/40. Accessed February 29, 2012. 4. Whyte MP. Hypophosphatasia: nature’s window on alkaline phosphatase function in humans. In: Bilezikian JP, Raisz LG, Martin TJ, eds. Principles of Bone Biology. Vol 1. 3rd ed. San Diego, CA: Academic Press; 2008:1573-1598. 5. Fauvert D, Brun-Heath I, Lia-Baldini A-S, et al. Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles. BMC Med Genet. 2009;10:51. http://www.biomedcentral.com/1471-2350/10/51. Accessed February 29, 2012. 6. Mornet E, Nunes ME. Hypophosphatasia. In: Pagon RA, Bird TD, Dolan CR, Stephen K, eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993. http://www.ncbi.nlm.nih.gov/books/NBK1150/. Published November 20, 2007. Updated August 5, 2010. Accessed July 11, 2011. 7. Whyte MP. Hypophosphatasia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 4. 8th ed. New York, NY: McGraw-Hill; 2001:5313-5329.