Pseudodeficiency alleles are DNA variants that can lead to false positive results on biochemical enzyme studies, but are not known to cause clinical symptoms or lead to disease. Enzyme studies cannot differentiate between true pathogenic variants and pseudodeficiency alleles, so these must be distinguished by molecular studies.
Enzyme studies measure enzyme activity, or the ability of an enzyme to convert a specific substrate to a product. The inability (or reduced ability) of an enzyme to catalyze this conversion can lead to disease. In a laboratory enzyme assay, synthetic substrates are commonly used instead of the substrate naturally found in the body. Pseudodeficiency alleles are known to impair an enzyme’s ability to convert this artificial substrate to product, which can lead to a false positive result on enzyme tests. Enzymes encoded by pseudodeficiency alleles can process natural substrate normally, or at a level that does not result in disease.
Why does Invitae report pseudodeficiency alleles?
Invitae reports pseudodeficiency alleles to help clinicians interpret abnormal biochemical results. Both diagnostic studies and large-scale screening programs (such as newborn screening, prenatal carrier screening, and Tay-Sachs carrier screening) frequently utilize enzyme studies to identify at-risk individuals, and false positive results are not uncommon. Molecular analysis can identify variants known to be pseudodeficiency alleles and is able to discriminate a true positive (abnormal) biochemical result from a false positive (abnormal) biochemical result.
Invitae reports pseudodeficiency alleles identified by sequencing in our results because these variants can provide an explanation for previous or future abnormal enzyme testing. This information can reassure the clinician and the patient that the patient is not considered to be affected with the respective disorder despite abnormal enzyme studies.
How common are pseudodeficiency alleles?
The overall incidence of pseudodeficiency alleles is unknown, but large-scale screening programs have found that approximately 2% of Ashkenazi Jewish individuals are carriers of a pseudodeficiency allele for Tay-Sachs disease (HEXA gene), while approximately 36% of the non-Ashkenazi population is a carrier for a HEXA pseudodeficiency allele.1 Approximately 3.9% of the healthy Japanese population is homozygous for a common glycogen storage disease: type II (Pompe disease; GAA gene) pseudodeficiency allele.2 Pseudodeficiency alleles have also been identified in metachromatic leukodystrophy (ARSA gene), mucopolysaccharidosis (MPS) type 1 (also known as Hurler syndrome or Scheie syndrome; IDUA gene), GM1 gangliosidosis (GLB1 gene), Krabbe disease (GALC gene), Sandhoff disease (HEXB gene), Fabry disease (GLA gene), MPS type 7 (also known as Sly syndrome; GUSB gene) and fucosidosis (FUCA1 gene).3 In addition, a pseudodeficiency allele has also been reported in a non-lysosomal storage disorder, tyrosinemia type I (FAH gene).4
Are pseudodeficiency alleles inherited?
These DNA changes are inherited just like any other genetic variant and can be passed to offspring. Individuals may be heterozygous, compound heterozygous, or homozygous for a pseudodeficiency allele.
Can two pseudodeficiency alleles in the same gene or a pseudodeficiency allele inherited with a known pathogenic allele in the same gene cause disease?
Based on currently available data, pseudodeficiency alleles are not thought to be associated with clinical symptoms. Many unaffected individuals with two pseudodeficiency alleles or a pathogenic allele and a pseudodeficiency allele have been identified in the population (data obtained from ExAC and Gnomad databases).
Can the the presence of a pseudodeficiency allele in an affected individual with two pathogenic variants cause more severe disease?
At this time, there is no evidence showing a more severe clinical presentation in individuals with two pathogenic variants and one or more pseudodeficiency alleles.
- Park NJ, Morgan C, Sharma R, et al. Pediatr Res. 2010;67(2):217-20.
- Labrousse P, Chien YH, Pomponio RJ, et al. Mol Genet Metab. 2010;99(4):379-83.
- Thomas GH. Am J Hum Genet. 1994;54(6):934-40.
- Rootwelt H, Brodtkorb E, Kvittingen EA. Am J Hum Genet. 1994;55(6):1122-7.