Klein Roger D, Dykas Daniel J, Bale Allen E
DNA Diagnostic Laboratory, Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
Genet Med. 2005 Nov-Dec;7(9):611-9. doi: 10.1097/01.gim.0000182879.57182.b4.
This study determines which clinical features predict positive test results among samples submitted for DNA-based diagnostic nevoid basal cell carcinoma syndrome (NBCCS) testing, and further defines the mutational spectrum of the PTCH gene.
DNA was extracted from peripheral blood leukocytes, and polymerase chain reaction products from exons 1 to 23 of the PTCH gene were directly sequenced. Pedigree phenotypic information was obtained by written questionnaire.
Among 106 presumably unrelated pedigrees, 44 independent mutations were found in 47 families. There were 11 nonsense mutations; 1 in-frame deletion; 17 deletions, 6 insertions, and 1 deletion-insertion that generated frameshifts; 5 splice-site mutations; 1 in-frame duplication; and 2 presumptive missense mutations. Twenty-seven of 46 pedigrees (58.7%) with two or more typical radiographic or pathologic features of NBCCS tested positive for PTCH mutations. Of these, 26 had jaw cysts in combination with other characteristics or neoplasms including basal cell carcinomas, palmar pits, skeletal abnormalities, ocular abnormalities, medulloblastomas, cardiac or ovarian fibromas, calcification of the falx cerebri, polydactyly, cleft lip and/or palate, and agenesis of the corpus callosum or other central nervous system malformations. None of the 13 pedigrees solely affected by multiple or early-onset basal cell carcinomas and none of the four pedigrees with jaw cysts alone had PTCH mutations.
Pedigrees with multiple features of NBCCS were most likely to test positive for PTCH mutations. Pedigrees with multiple or early-onset basal cell carcinomas without other features of the disease did not test positive for PTCH mutations.
本研究确定在提交进行基于DNA的诊断痣样基底细胞癌综合征（NBCCS）检测的样本中，哪些临床特征可预测检测结果为阳性，并进一步明确PTCH基因的突变谱。
从外周血白细胞中提取DNA，并对PTCH基因第1至23外显子的聚合酶链反应产物进行直接测序。通过书面问卷获取家系表型信息。
在106个可能无亲缘关系的家系中，47个家族发现了44个独立突变。其中有11个无义突变；1个框内缺失；17个缺失、6个插入以及1个导致移码的缺失-插入；5个剪接位点突变；1个框内重复；以及2个推定的错义突变。46个具有两种或更多NBCCS典型影像学或病理学特征的家系中，27个（58.7%）PTCH突变检测呈阳性。其中，26个家系有颌骨囊肿并伴有其他特征或肿瘤，包括基底细胞癌、掌跖凹陷、骨骼异常、眼部异常、髓母细胞瘤、心脏或卵巢纤维瘤、大脑镰钙化、多指畸形、唇裂和/或腭裂以及胼胝体发育不全或其他中枢神经系统畸形。仅受多发性或早发性基底细胞癌影响的13个家系以及仅患有颌骨囊肿的4个家系均未检测到PTCH突变。
具有多种NBCCS特征的家系最有可能PTCH突变检测呈阳性。具有多发性或早发性基底细胞癌但无该病其他特征的家系PTCH突变检测未呈阳性。
