Weksberg Rosanna, Stachon Andrea C, Squire Jeremy A, Moldovan Laura, Bayani Jane, Meyn Stephen, Chow Eva, Bassett Anne S
Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, 555 University Ave., M5G 1X8, Toronto, ON, Canada.
Hum Genet. 2007 Feb;120(6):837-45. doi: 10.1007/s00439-006-0242-x. Epub 2006 Oct 7.
22q11 Deletion syndrome (22q11DS) is a common microdeletion syndrome with variable expression, including congenital and later onset conditions such as schizophrenia. Most studies indicate that expression does not appear to be related to length of the deletion but there is limited information on the endpoints of even the common deletion breakpoint regions in adults. We used a real-time quantitative PCR (qPCR) approach to fine map 22q11.2 deletions in 44 adults with 22q11DS, 22 with schizophrenia (SZ; 12 M, 10 F; mean age 35.7 SD 8.0 years) and 22 with no history of psychosis (NP; 8 M, 14 F; mean age 27.1 SD 8.6 years). QPCR data were consistent with clinical FISH results using the TUPLE1 or N25 probes. Two subjects (one SZ, one NP) negative for clinical FISH had atypical 22q11.2 deletions confirmed by FISH using the RP11-138C22 probe. Most (n = 34; 18 SZ, 16 NP) subjects shared a common 3 Mb hemizygous 22q11.2 deletion. However, eight subjects showed breakpoint variability: a more telomeric proximal breakpoint (n = 2), or more centromeric (n = 3) or more telomeric distal breakpoint (n = 3). One NP subject had a proximal nested 1.4 Mb deletion. COMT and TBX1 were deleted in all 44 subjects, and PRODH in 40 subjects (19 SZ, 21 NP). The results delineate proximal and distal breakpoint variants in 22q11DS. Neither deletion extent nor PRODH haploinsufficiency appeared to explain the clinical expression of schizophrenia in the present study. Further studies are needed to elucidate the molecular basis of schizophrenia and clinical heterogeneity in 22q11DS.
22q11缺失综合征（22q11DS）是一种常见的微缺失综合征，表现多样，包括先天性疾病以及如精神分裂症等迟发性疾病。大多数研究表明，其表现似乎与缺失长度无关，但关于成人中常见缺失断点区域的端点信息有限。我们采用实时定量聚合酶链反应（qPCR）方法对44名患有22q11DS的成人的22q11.2缺失进行精细定位，其中22名患有精神分裂症（SZ；男性12名，女性10名；平均年龄35.7岁，标准差8.0岁），22名无精神病病史（NP；男性8名，女性14名；平均年龄27.1岁，标准差8.6岁）。qPCR数据与使用TUPLE1或N25探针的临床荧光原位杂交（FISH）结果一致。两名临床FISH检测为阴性的受试者（一名SZ，一名NP），使用RP11 - 138C22探针进行FISH检测确认存在非典型22q11.2缺失。大多数（n = 34；18名SZ，16名NP）受试者共享一个常见的3 Mb半合子22q11.2缺失。然而，8名受试者表现出断点变异性：一个更靠近端粒的近端断点（n = 2），或更靠近着丝粒的（n = 3）或更靠近端粒的远端断点（n = 3）。一名NP受试者有一个近端嵌套的1.4 Mb缺失。所有44名受试者的儿茶酚-O-甲基转移酶（COMT）和T-box1（TBX1）基因均缺失，40名受试者（19名SZ，21名NP）的脯氨酸脱氢酶（PRODH）基因缺失。研究结果描绘了22q11DS近端和远端断点变异情况。在本研究中，缺失程度和PRODH单倍剂量不足似乎均无法解释精神分裂症的临床表现。需要进一步研究以阐明22q11DS中精神分裂症的分子基础和临床异质性。
