HPRT1基因变异致Lesch-Nyhan综合征的产前诊断及遗传咨询

doi:10.12280/gjfckx.20210903

摘要/Abstract

摘要：

目的: 通过对HPRT1基因的点突变研究,对1个Lesch-Nyhan综合征家系进行产前诊断和遗传咨询。方法: 患者已生育的大儿为HPRT1基因（NM_000194）c.289_290delGT（p.V97Rfs*10）半合子变异导致的Lesch-Nyhan 综合征（先证者）,生育的小儿症状与大儿相似,已夭折（未行HPRT1基因检测）。第3次自然妊娠前未做孕前遗传咨询,在知情同意的原则下,应用聚合酶链反应结合Sanger测序的方法进行家系HPRT1基因点突变研究,并提供遗传咨询意见。结果: 先证者检测到HPRT1基因（NM_000194）c.289_290delGT（p.V97Rfs*10）半合子变异。患者检测到HPRT1基因（NM_000194）c.289_290delGT（p.V97Rfs*10）杂合变异。胎儿未检测到HPRT1基因（NM_000194）c.289_290delGT（p.V97Rfs*10）变异,建议患者继续妊娠,最终产下健康女婴且1岁时体检正常。结论: 先证者HPRT1基因变异位点遗传自母亲,临床应重视先证者家系成员的基因检测和产前诊断,并给予完善的遗传咨询意见,避免Lesch-Nyhan综合征等罕见遗传性疾病患儿的出生。

关键词: 莱施-奈恩综合征, 次黄嘌呤磷酸核糖转移酶, 遗传变异, 产前诊断, 遗传咨询, 高尿酸血症, 发育障碍

Abstract:

Objective: Prenatal diagnosis and genetic counseling of a Lesch-Nyhan syndrome family were performed by the studies of point mutation in the HPRT1 gene. Methods: The older child born by the patient was the Lesch-Nyhan Syndrome (proband),who was caused by the hemizygotic variation of HPRT1 gene (NM_000194) c.289_290delGT (p.V97Rfs *10). The second-born died, whose symptoms were similar to the older child, and HPRT1 gene test was not performed. Without pre-pregnancy genetic counseling before the third natural pregnancy, the method of polymerase chain reaction combined with Sanger sequencing was used to study the point mutation of HPRT1 gene in the family under the principle of informed consent, and genetic counseling was provided. Results: The hemizygotic variation c.289_290delGT(p.V97Rfs*10) of the HPRT1 gene (NM_000194) was detected in the proband. The heterozygous variation c.289_290delGT(p.V97Rfs*10) of the HPRT1 gene (NM_000194) was detected in the mother. The variation c.289_290delGT (p.V97Rfs*10) of the HPRT1 gene (NM_000194) was not detected in the fetus. The proband′s mother was advised to continue pregnancy, and finally gave birth to a healthy baby girl with normal physical examination at 1 year old. Conclusions: The mutation locus of HPRT1 gene of proband is inherited from the mother. Clinical attention should be paid to gene testing and prenatal diagnosis of other members of the proband′s lineage, and perfect genetic counseling should be given to avoid the birth of children with the Lesch-Nyhan syndrome and other rare genetic diseases.

Key words: Lesch-Nyhan syndrome, Hypoxanthine phosphoribosyltransferase, Genetic variation, Prenatal diagnosis, Genetic counseling, Hyperuricemia, Developmental disabilities

郜珊珊, 代鹏, 赵干业, 孔祥东. HPRT1基因变异致Lesch-Nyhan综合征的产前诊断及遗传咨询[J]. 国际妇产科学杂志, 2022, 49(3): 345-349.

GAO Shan-shan, DAI Peng, ZHAO Gan-ye, KONG Xiang-dong. Prenatal Diagnosis and Genetic Counseling of Lesch-Nyhan Syndrome Family Caused by HPRT1 Gene Mutation[J]. Journal of International Obstetrics and Gynecology, 2022, 49(3): 345-349.

图/表 3

参考文献 23

[1]	Lesch M, Nyhan WL. A familial disorder of uric acid metabolism and central nervous system function[J]. Am J Med, 1964, 36(4):561-570. doi: 10.1016/0002-9343(64)90104-4. doi: 10.1016/0002-9343(64)90104-4
[2]	Fu R, Sutcliffe D, Zhao H, et al. Clinical severity in Lesch-Nyhan disease: the role of residual enzyme and compensatory pathways[J]. Mol Genet Metab, 2015, 114(1):55-61. doi: 10.1016/j.ymgme.2014.11.001. doi: 10.1016/j.ymgme.2014. 11.001
[3]	McCarthy GT, Green EM, Ogunbona O, et al. A population study of Lesch-Nyhan disease in the UK[J]. Dev Med Child Neurol, 2011, 53(1):34-39. doi: 10.1111/j.1469-8749.2010.03786.x. doi: 10.1111/j.1469-8749.2010.03786.x pmid: 21126241
[4]	Jolly DJ, Okayama H, Berg P, et al. Isolation and characterization of a full-length expressible cDNA for human hypoxanthine phosphoribosyl transferase[J]. Proc Natl Acad Sci U S A, 1983, 80(2):477-481. doi: 10.1073/pnas.80.2.477. doi: 10.1073/pnas.80.2.477 pmid: 6300847
[5]	Keebaugh AC, Sullivan RT, Thomas JW. Gene duplication and inactivation in the HPRT gene family[J]. Genomics, 2007, 89(1):134-142. doi: 10.1016/j.ygeno.2006.07.003. doi: 10.1016/j.ygeno.2006.07.003 pmid: 16928426
[6]	Inokuchi T, Moriwaki Y, Takahashi S, et al. Identification of a new point mutation in hypoxanthine phosphoribosyl transferase responsible for hyperuricemia in a female patient[J]. Metabolism, 2004, 53(11):1500-1502. doi: 10.1016/j.metabol.2004.04.016. doi: 10.1016/j.metabol.2004.04.016
[7]	Bell S, McCarty V, Peng H, et al. Lesch-Nyhan disease causes impaired energy metabolism and reduced developmental potential in midbrain dopaminergic cells[J]. Stem Cell Reports, 2021, 16(7):1749-1762. doi: 10.1016/j.stemcr.2021.06.003. doi: 10.1016/j.stemcr.2021.06.003
[8]	Harris JC. Lesch-Nyhan syndrome and its variants: examining the behavioral and neurocognitive phenotype[J]. Curr Opin Psychiatry, 2018, 31(2):96-102. doi: 10.1097/YCO.0000000000000388. doi: 10.1097/YCO.0000000000000388
[9]	Rylance HJ, Wallace RC, Nuki G. Hypoxanthine-guanine phosphoribosyl transferase: assay using high performance liquid chromatography[J]. Clin Chim Acta, 1982, 121(2):159-165. doi: 10.1016/0009-8981(82)90054-7. doi: 10.1016/0009-8981(82)90054-7 pmid: 7094337
[10]	Halley D, Heukels-Dully MJ. Rapid prenatal diagnosis of the Lesch-Nyhan syndrome[J]. J Med Genet, 1977, 14(2):100-102. doi: 10.1136/jmg.14.2.100. doi: 10.1136/jmg.14.2.100 pmid: 856956
[11]	Mizuno TI, Yugari Y. Letter: Self mutilation in Lesch-Nyhan syndrome[J]. Lancet, 1974, 1(7860):761. doi: 10.1016/s0140-6736(74)92990-0. doi: 10.1016/s0140-6736(74)92990-0
[12]	Frith CD, Johnston EC, Joseph MH, et al. Double-blind clinical trial of 5-hydroxytryptophan in a case of Lesch-Nyhan syndrome[J]. J Neurol Neurosurg Psychiatry, 1976, 39(7):656-662. doi: 10.1136/jnnp.39.7.656. doi: 10.1136/jnnp.39.7.656
[13]	Goldstein M, Anderson LT, Reuben R, et al. Self-mutilation in Lesch-Nyhan disease is caused by dopaminergic denervation[J]. Lancet, 1985, 1(8424):338-339. doi: 10.1016/s0140-6736(85)91107-9. doi: 10.1016/s0140-6736(85)91107-9 pmid: 2857386
[14]	Sabus A, Feinstein J, Romani P, et al. Management of Self-injurious Behaviors in Children with Neurodevelopmental Disorders: A Pharmacotherapy Overview[J]. Pharmacotherapy, 2019, 39(6):645-664. doi: 10.1002/phar.2238. doi: 10.1002/phar.2238
[15]	Colley AF, Leversha MA, Voullaire LE, et al. Five cases demonstrating the distinctive behavioural features of chromosome deletion 17(p11.2 p11.2) (Smith-Magenis syndrome)[J]. J Paediatr Child Health, 1990, 26(1):17-21. doi: 10.1111/j.1440-1754.1990.tb02372.x. doi: 10.1111/j.1440-1754.1990.tb02372.x.
[16]	Crapper L, Ernst C. Comparative analysis of self-injury in people with psychopathology or neurodevelopmental disorders[J]. Pediatr Clin North Am, 2015, 62(3):619-631. doi: 10.1016/j.pcl.2015.03.001. doi: 10.1016/j.pcl.2015.03.001
[17]	Schwartz L, Caixàs A, Dimitropoulos A, et al. Behavioral features in Prader-Willi syndrome (PWS): consensus paper from the International PWS Clinical Trial Consortium[J]. J Neurodev Disord, 2021, 13(1):25. doi: 10.1186/s11689-021-09373-2. doi: 10.1186/s11689-021-09373-2 pmid: 34148559
[18]	郜珊珊, 代鹏, 赵干业, 等. 两例Prader-Willi综合征患儿的临床特征及致病基因分析[J]. 中华肥胖与代谢病电子杂志, 2021, 7(3):203-206. doi: 10.3877/cma.j.issn.2095-9605.2021.03.012. doi: 10.3877/cma.j.issn.2095-9605.2021.03.012
[19]	Peron A, Canevini MP, Ghelma F, et al. Phenotypes in adult patients with Rett syndrome: results of a 13-year experience and insights into healthcare transition[J]. J Med Genet, 2022, 59(1):39-45. doi: 10.1136/jmedgenet-2020-107333. doi: 10.1136/jmedgenet-2020-107333
[20]	Selicorni A, Mariani M, Lettieri A, et al. Cornelia de Lange Syndrome: From a Disease to a Broader Spectrum[J]. Genes (Basel), 2021, 12(7):1075. doi: 10.3390/genes12071075. doi: 10.3390/genes12071075
[21]	Kim KJ, Yamada Y, Suzumori K, et al. Molecular analysis of hypoxanthine guanine phosphoribosyltransferase (HPRT) gene in five Korean families with Lesch-Nyhan syndrome[J]. J Korean Med Sci, 1997, 12(4):332-339. doi: 10.3346/jkms.1997.12.4.332. doi: 10.3346/jkms.1997.12.4.332 pmid: 9288634
[22]	Veeramachaneni V. Data Analysis in Rare Disease Diagnostics[J]. J Indian Inst Sci, 2020, 100(4):733-751. doi: 10.1007/s41745-020-00189-y. doi: 10.1007/s41745-020-00189-y
[23]	Li X, Liu M, Lin J, et al. A questionnaire-based study to comprehensively assess the status quo of rare disease patients and care-givers in China[J]. Orphanet J Rare Dis, 2021, 16(1):327. doi: 10.1186/s13023-021-01954-7. doi: 10.1186/s13023-021-01954-7