Estimation of ENPP1 deficiency genetic prevalence using a comprehensive literature review and population databases

  • Orphanet J Rare Dis. 2022 Dec 2;17(1):421. doi: 10.1186/s13023-022-02577-2.
Lauren M Chunn  1 ,  Jeffrey Bissonnette  1 ,  Stefanie V Heinrich  1 ,  Stephanie A Mercurio  1 ,  Mark J Kiel  2 ,  Frank Rutsch  3 ,  Carlos R Ferreira  4
Affiliations
  • 1. Genomenon, Inc., Ann Arbor, MI, 48109, USA.
  • 2. Genomenon, Inc., Ann Arbor, MI, 48109, USA. [email protected].
  • 3. Department of General Paediatrics, Muenster University Children's Hospital, Münster, Germany.
  • 4. Metabolic Medicine Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
PMID: 36461014 DOI: 10.1186/s13023-022-02577-2
Abstract

Background: ENPP1 Deficiency-caused by biallelic variants in ENPP1-leads to widespread arterial calcification in early life (Generalized Arterial Calcification of Infancy, GACI) or hypophosphatemic rickets in later life (Autosomal Recessive Hypophosphatemic Rickets type 2, ARHR2). A prior study using the Exome Aggregation Consortium (ExAC)-a database of exomes obtained from approximately 60,000 individuals-estimated the genetic prevalence at approximately 1 in 200,000 pregnancies.

Methods: We estimated the genetic prevalence of ENPP1 Deficiency by evaluating allele frequencies from a population database, assuming Hardy-Weinberg equilibrium. This estimate benefitted from a comprehensive literature review using Mastermind ( https://mastermind.genomenon.com/ ), which uncovered additional variants and supporting evidence, a larger population database with approximately 140,000 individuals, and improved interpretation of variants as per current clinical guidelines.

Results: We estimate a genetic prevalence of approximately 1 in 64,000 pregnancies, thus more than tripling the prior estimate. In addition, the carrier frequency of ENPP1 variants was found to be highest in East Asian populations, albeit based on a small sample.

Conclusion: These results indicate that a significant number of patients with ENPP1 Deficiency remain undiagnosed. Efforts to increase disease awareness as well as expand genetic testing, particularly in non-European populations are warranted, especially now that clinical trials for enzyme replacement therapy, which proved successful in animal models, are underway.

Keywords
Autosomal recessive hypophosphatemic rickets type 2 (ARHR2); ENPP1 deficiency; Generalized arterial calcification of infancy (GACI); Population database; Prevalence.
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