The Invitae Lesch-Nyhan syndrome test analyzes the HPRT1 gene, which is associated with Lesch-Nyhan syndrome, a disorder with a phenotypic spectrum ranging from neurological dysfunction, cognitive impairment and behavioural disturbances in affected males at the severe end of the spectrum to isolated hyperuricemia and gout at the mild end of the spectrum. This test is indicated for any individual in whom Lesch-Nyhan syndrome is suspected based on clinical or laboratory findings. 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. Treatment, which prevents gout or renal damage, is available so early diagnosis is important.
For a broader analysis of the genetics of purine metabolism disorders:
Lesch-Nyhan syndrome is characterized by a congenital deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGprt), a purine salvage enzyme, resulting in marked overproduction of uric acid. The excess uric acid leads to hyperuricemia, urate nephrolithiasis (kidney stones), tophi (uric acid deposits under the skin), and gout.
Severely affected individuals have pathogenic HPRT variants which completely eliminate HGprt activity. Hypotonia and developmental delay usually present by age 3-6 months. Individuals also suffer from severe motor handicaps, mild or moderate intellectual disability (ID), and recurrent self-injurious behaviors which develop in the first few years of life. Gouty arthritis and renal disease may occur later in life as a result of hyperuricemia.
Individuals with more attenuated forms can show a range of phenotypic severity depending on the amount of residual HGprt enzyme activity. On the most mild end of the spectrum, patients may only experience the features directly related to excess uric acid, such as gout, and show no neurological features, while patients with intermediate phenotypes are affected by some degree of motor and/or cognitive handicap but do not display self-injurious behavior.
Treatment options, which can prevent gout or renal damage, are available for Lesch-Nyhan syndrome and should be started as soon as an HGprt deficiency is noted or a genetic diagnosis is made.
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 HPRT1. The percentage of individuals with HPRT1-related hyperuricemia and gout who have a pathogenic change in HPRT1 is unknown.
Lesch-Nyhan syndrome is inherited in an X-linked recessive manner. Although female carriers are generally unaffected, they can have elevations of uric acid and may develop gout later in life. A few female patients with Lesch-Nyhan have been reported who had preferential inactivation of the normal X or chromosome rearrangements affecting the X chromosome.
The prevalence of Lesch-Nyhan syndrome (all subtypes) is estimated to be approximately 1 in 235,000 to 380,000 live births based on studies in Spain and Canada, respectively. The prevalence of severe Lesch-Nyhan syndrome in the UK is 1 in 2,000,000.
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|