Alford R L, Redman J B, O'Brien W E, Caskey C T
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Prenat Diagn. 1995 Apr;15(4):329-38. doi: 10.1002/pd.1970150406.
We report the results of carrier and prenatal diagnosis for hypoxanthine guanine phosphoribosyltransferase (HPRT) deficiency, Lesch-Nyhan syndrome, by carrier testing of 83 women and prenatal analysis of 26 pregnancies. Our diagnostic methodologies include mutation detection and linkage analysis for probands and their families and biochemical measurement of HPRT enzyme activity for at-risk pregnancies. Identification of the mutation in the index case of each family permits precise carrier diagnosis using polymerase chain reaction (PCR) amplification of HPRT gene sequences and automated DNA sequencing. We demonstrate 100 per cent sensitivity for the detection of mutations in the HPRT gene of affected males and highly efficient carrier testing of at-risk females. Two other molecular methods proven to have high utility include PCR-based dosage analysis and linkage analysis by PCR amplification of a short tandem repeat (STR) in intron 3 of the HPRT gene. As a result, 45 at-risk women, 56 per cent of those tested, were identified not to be carriers of their family's HPRT gene mutation. Seven of these women were the mothers of affected males and prenatal testing for future pregnancies was recommended because of the possibility of gonadal mosaicism. Thirty-eight of these women were more distant relatives of affected males, thereby eliminating the need for future prenatal procedures. These studies illustrate the utility and precision of molecular methodologies for carrier and prenatal diagnosis of Lesch-Nyhan syndrome. These studies also illustrate that molecular diagnostic studies of affected males and carrier testing prior to pregnancy can clarify genetic risk predictions and eliminate unnecessary prenatal procedures.
我们报告了对83名女性进行次黄嘌呤鸟嘌呤磷酸核糖转移酶（HPRT）缺乏症（莱施-奈恩综合征）携带者检测以及对26例妊娠进行产前分析的携带者和产前诊断结果。我们的诊断方法包括对先证者及其家族进行突变检测和连锁分析，以及对有风险的妊娠进行HPRT酶活性的生化测定。确定每个家族索引病例中的突变后，可通过聚合酶链反应（PCR）扩增HPRT基因序列并进行自动DNA测序来进行精确的携带者诊断。我们证明了对受影响男性HPRT基因中突变检测的灵敏度为100%，以及对有风险女性进行高效的携带者检测。另外两种经证明具有高实用性的分子方法包括基于PCR的剂量分析和通过PCR扩增HPRT基因第3内含子中的短串联重复序列（STR）进行连锁分析。结果，45名有风险的女性（占检测者的56%）被确定不是其家族HPRT基因突变的携带者。其中7名女性是受影响男性的母亲，由于存在性腺嵌合的可能性，建议对未来妊娠进行产前检测。这些女性中有38名是受影响男性的远亲，因此无需进行未来的产前检查。这些研究说明了分子方法在莱施-奈恩综合征携带者和产前诊断中的实用性和精确性。这些研究还表明，对受影响男性进行分子诊断研究以及在怀孕前进行携带者检测可以明确遗传风险预测并消除不必要的产前检查。
