Generalized Arterial Calcification of Infancy via the ENPP1 Gene

Generalized arterial calcification of infancy (also referred as Idiopathic infantile arterial calcification) is a rare infantile onset calcification of the internal elastic lamina of medium and large arteries and arterial stenosis due to myointimal proliferation (Rutsch et al. 2003. PubMedID: 12881724; Chong and Hutchins. 2008. PubMed ID: 17990935). The major early clinical features include fetal distress, heart failure, hydramnios, respiratory distress, hydrops fetalis, fetal edema, cyanosis, effusions in the pleural, peritoneal, pericardial spaces and cardiomegaly. The major late clinical features are respiratory distress, cyanosis, feeding difficulties, and heart failure (Chong and Hutchins. 2008. PubMed ID: 17990935). Without proper medical management, ~60% of the patients die from cardiovascular complications or renal artery stenosis within the first 6 months of life (Rutsch et al. 2001. PubMed ID: 11159191; Rutsch et al. 2008. PubMed ID: 20016754; Ferreira et al. 2014. PubMed ID: 25392903).

Generalized arterial calcification of infancy is inherited in an autosomal recessive manner caused by pathogenic variants in the ENPP1 and ABCC6 genes.

Pathogenic variants in the ENPP1 gene have been reported in 75% of patients with autosomal recessive generalized arterial calcification of infancy (Rutsch et al. 2008. PubMed ID: 20016754). The ENPP1 protein coded by the ENPP1 gene is a member of the nucleotide pyrophosphatase/phosphodiesterase family and plays a role in regulating pyrophosphate levels. ENPP1 functions in bone mineralization and soft tissue calcification (Rutsch et al. 2001. PubMed ID: 11159191). To date, almost 70 unique pathogenic variants in the ENPP1 gene have been reported. They are: missense (67%), truncating including nonsense, small frameshift del/dup and indels (23%), splicing (10%) and one large deletion involving exons 24-25 of the ENPP1 gene (Rutsch et al. 2008. PubMed ID: 20016754; Lorenz-Depiereux et al. 2010. PubMed ID: 20137773, Human Gene Mutation Database). Pathogenic variants in ENPP1 have also been reported in patient with autosomal dominant Cole disease (Eytan et al. 2013. PubMed ID: 24075184), and autosomal recessive hypophosphatemic rickets (Steichen-Gersdorf et al. 2015. PubMed ID: 25741938).

In one study, pathogenic variants in the ENPP1 gene have been reported in 75% of patients with clinically diagnosed generalized arterial calcification of infancy (Rutsch et al. 2008. PubMed ID: 20016754). Only one large deletion involving exons 24-25 of the ENPP1 gene has been reported (Lorenz-Depiereux et al. 2010. PubMed ID: 20137773).

This test is performed using Next-Generation sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the ENPP1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.