Genetics & Inheritance

Genetics

The two genes known to cause GACI are the ENPP1 gene and the ABCC6 gene. There are some cases of GACI where no genetic cause has been identified.  The gene known to cause ARHR2 is the ENPP1 gene.  GACI Type 1 and ARHR2 are caused by mutations in both copies of the ENPP1 gene and are part of the disease spectrum of ENPP1 Deficiency.  GACI Type 2 is caused by mutations in both copies of the ABCC6 gene and is part of the disease spectrum of ABCC6 Deficiency.

ENPP1 Gene

In 2003, it was discovered that the ENPP1 gene was the cause of almost two-thirds of GACI cases. The ENPP1 gene is responsible for encoding an enzyme that is necessary to make pyrophosphate. Without this enzyme, low pyrophosphate levels allow calcification to develop in the arteries.

ABCC6 Gene

The ABCC6 gene was identified as a cause of GACI in 2008. Mutations in the ABCC6 gene are also associated with low levels of pyrophosphate in the body.

Unknown Gene

In rare cases, patients with GACI do not have ENPP1 or ABCC6 gene mutations. Therefore, it is thought that there may still be at least one other unknown gene that could be responsible for causing GACI in patients or that the sequencing technology missed mutations in one of the two known genes.

For Healthcare Providers: Consider Genetic Testing for ENPP1 and ABCC6 Deficiencies

If your patient has been diagnosed with GACI Type 1, GACI Type 2, or hypophosphatemic rickets – or is experiencing symptoms consistent with these conditions – consider genetic testing for ENPP1 Deficiency and ABCC6 Deficiency.

These rare genetic disorders can present with overlapping features, and early identification through genetic testing can support more accurate diagnosis, management, and family counseling.

Individuals who meet the eligibility criteria for the testing program can receive a no-cost, third-party genetic test to determine if they have the condition or are a carrier for ENPP1 Deficiency or ABCC6 Deficiency.

For infants suspected of having GACI, sponsored ultra rapid whole genome sequencing is available through Rady Genomics Institute — for more information, please reach out to medinfo@bmrn.com.

For prenatal samples, children, or adults suspected of having ENPP1 Deficiency or pediatric onset ABCC6 Deficiency gene testing of the ENPP1 and ABCC6 gene is available through Prevention Genetics.

HCPs can contact Prevention Genetics at:

medinfo@bmrn.com
www.preventiongenetics.com/specialOrders

Inheritance Pattern

Photo Credit: Kashmiri, based on earlier work by Domaina

ENPP1 Deficiency and ABCC6 Deficiency are rare conditions that are inherited in an autosomal recessive pattern.  This means that people affected by the diseases inherit two mutated genes in each cell, one mutated gene from each parent.  As a result, both copies of the gene in each cell have mutations. The affected genes can be passed from generation to generation. People can carry the affected gene and not exhibit any symptoms. These people are referred to as healthy or unaffected carriers.

Each baby born to unaffected carrier parents has a 25% chance of being affected by ENPP1 Deficiency or ABCC6 Deficiency, a 50% chance of being an unaffected carrier, and a 25% of not inheriting any mutations at all.   This is also known as a “one in four” chance of inheriting the disease.