The Invitae Alkaptonuria test analyzes the homogentisate 1,2-dioxygenase (HGD) gene which is associated with alkaptonuria (AKU). Genetic testing of this gene may confirm a diagnosis and help guide treatment and management decisions. Identification of disease-causing variants can also aid in determining carrier status and diagnosis of at-risk relatives.
Any individual presenting with a suspected diagnosis of alkaptonuria based on clinical presentation should be tested for HGD. There is no validated HGA test in blood.
Alkaptonuria is a rare inborn error of metabolism that results in the accumulation of the intermediary, homogentisate, that is released from the liver into the bloodstream and is excreted through the urine. In contact with oxygen in the air, homogentisate turns into a dark pigment known as alkapton that confers the urine of alkaptonuric patients its characteristic color. The dark urine color may present as early as childhood.
Homogentisate also accumulates in the connective tissues, where it oxidizes and polymerizes, conferring a characteristic ochre coloration known as ochronosis. This deposition is cumulative, being more striking in the dermis of sweat glands, ear cartilages and the sclera of the eye. This visible ochronosis is usually manifested in the 4th decade of life. With age the deposition of alkapton in the cartilage of the larger joints causes their degeneration. This arthrosis (ochronotic arthropathy) represents the most common clinically relevant symptom of the disease and usually occurs in the 3rd o 4th decade of life of the patient. Other secondary symptoms are caused by ochronotic deposits in kidney, prostate and cardiac valves. Ochronotic deposits in prostate may lead in the 4th decade of life to severe prostate obstructions that may require prostatectomy. Obstruction of the kidneys are also observed in the 5th and 6th decade of life. Obstruction of the kidneys may cause the increase of homogentisate in the plasma and tissues, and may also lead to renal failure. The accumulation of the ochronotic pigment has been observed in cardiac valves where it has been occasionally implicated in arteriosclerosis and aortic stenosis.
There is no formal treatment for the disease. Dietary restriction of phenylalanine and tyrosine intake to reduce the homogentisate production may reduce the progression of the symptoms. The intake of ascorbic acid has been reported to reduce the oxidation of homogentisate into alkapton.
HGD is the only gene known to be associated with alkaptonuria. However, due to the rarity of this condition, the percent of alkaptonuria attributed to pathogenic variants in HGD is currently unknown.
Alkaptonuria is inherited in an autosomal recessive manner.
The estimated incidence of alkaptonuria in the United States 1:250,000 to 1:1,000,000.
This test may be appropriate for any individual with:
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|