The Invitae HPRT1-Related Disorders Test analyzes the HPRT1 gene, which is associated with uric acid overproduction, resulting in a spectrum of conditions including isolated hyperuricemia and gout at the mild end of the spectrum, and Lesch-Nyhan syndrome at the severe end of the spectrum. Lesch-Nyhan syndrome is characterized by neurological dysfunction, cognitive impairment and behavioural disturbances in affected males.
Genetic testing of this gene may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant can inform recurrence-risk assessment and genetic counseling.
Lesch-Nyhan syndrome is characterized by overproduction of uric acid causing neurological dysfunction, cognitive impairment and behavioral disturbances in affected males. Hypotonia and developmental delay usually present by age 3-6 months. Dystonia, spasticity and other neurologic abnormalities develop in the first few years of life. Persistent self-harming behavior is characteristic of this condition and usually develops in the first few years of life. Gouty arthritis and renal disease may occur later in life as a result of hyperuricemia. Carrier females are generally unaffected although may develop gout later in life.
HPRT1 is the only gene known to be associated with Lesch-Nyhan syndrome. Approximately 90-95% of males with a clinical diagnosis of Lesch-Nyhan syndrome are found to have a pathogenic variant in HRPT1. The percentage of individuals with HPRT1-related hyperuricemia and gout who have a pathogenic change in HPRT1 is unknown.
HPRT1-related disorders are inherited in an X-linked recessive pattern.
HPRT1-related disorders are completely penetrant however clinical variability exists depending on the presence of residual HPRT1 enzymatic activity.
The incidence of Lesch-Nyhan syndrome is approximately 1 in 380,000.
Suspicion of a Lesch-Nyhan syndrome diagnosis should be considered in the following scenarios:
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|