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European Journal of Human Genetics (2010) 19; doi:10.1038/ejhg.2010.109 & 2010 Macmillan Publishers Limited All rights reserved 1018-4813/10
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CLINICAL UTILITY GENE CARD

Clinical utility gene card for: Lesch–Nyhan syndrome
` Rosa J Torres*,1, Juan G Puig2 and Irene Ceballos-Picot3
European Journal of Human Genetics (2010) 19, doi:10.1038/ejhg.2010.109; published online21 July 2010

1. DISEASE CHARACTERISTICS 1.1 Name of the disease (synonyms) Hypoxanthine guanine phosphoribosyltransferase (HPRT)-1 deficiency HPRT1 deficiency HPRT deficiency HPRT deficiency, complete HPRT deficiency, grade IV 1.2 OMIM# of the disease 300322. 1.3 Name of the analyzed genes or DNA/chromosome segments HPRT1. 1.4 OMIM# of the gene(s) 308000. 1.5 Mutational spectrum Human HPRT isencoded by a single structural gene spanning approximately 45 kb on the long arm of the X chromosome at Xq26, and consists of nine exons with a coding sequence of 654 bp. Documented mutations in HPRT deficiency show a high degree of heterogeneity in type and location within the HPRT1 gene: deletions, insertions, duplications, and point mutations have been described as the cause of HPRT deficiency. Todate, more than 300 diseaseassociated mutations have been found.1–4 1.6 Analytical methods HPRT1 gene is a housekeeping gene and it is expressed in peripheral blood. Most HPRT-deficient patients, biochemically diagnosed by a null HPRT activity in erythrocytes, present HPRT mRNA expression, and molecular diagnosis can be accomplished by RNA extraction, reverse transcription-PCR, and HPRT complementaryDNA (including 3¢ and 5¢ regions) sequencing. In other cases, genomic DNA sequencing of the nine HPRT1 exons, with its intronic flanquing sequences, may be necessary. In some cases, the HPRT coding region is normal and the patients present a decrease HPRT mRNA expression of unknown origin. In these patients quantification of HPRT mRNA by real-time PCR may be used for molecular diagnosis.5–9Inheritance of HPRT deficiency is X-linked recessive. Thus, males are generally affected and heterozygous females are carriers.

However, at least five females with Lesch–Nyhan syndrome have been described, with different molecular alterations accounting for their HPRT deficiency.10–16 Carrier diagnosis is an important issue for most HPRT-deficient families. Female carriers cannot be detected without thehelp of a laboratory, as they are usually asymptomatic. Carrier status cannot be accurately assessed by biochemical and enzymatic methods. HPRT activity is most often normal in hemolysate of the peripheral blood of female carriers due to selection against HPRT-deficient erythrocyte precursors. Enzymatic diagnosis of the carrier state can be performed by the identification of HPRT-deficient hairfollicles or cultured fibroblasts because of their mosaicism in terms of HPRT activity, although such diagnosis is not infallible. HPRT-deficient cells from carrier females can be selected based on their 6-thioguanine resistances. Proliferation assay of peripheral blood T lymphocytes in the presence of 6-thioguanine is diagnostic in most cases. However, faster and more accurate carrier diagnosis can beperformed by molecular methods. Carrier diagnosis can be accomplished by genomic DNA sequencing of the HPRT1 gene fragment where the mutation was found in the family propositus. When propositus mutation is not available, amplification of the nine HPRT1 exons, with its intronic flanquing sequences, may be necessary. If a deletion has been found in the propositus, gene dosage may be accomplished byquantitative PCR or multiplex ligation-dependent probe amplification.17–18 Prenatal diagnosis for Lesch–Nyhan syndrome can be performed with amniotic cells obtained by amniocentesis at about 15–18 week’s gestation, or chorionic villus cells obtained at about 10–12 week’s gestation. Both HPRT enzymatic assay and molecular analysis for the known disease-causing mutation can be performed. 1.7 Analytical...