Barlow G M, Chen X N, Shi Z Y, Lyons G E, Kurnit D M, Celle L, Spinner N B, Zackai E, Pettenati M J, Van Riper A J, Vekemans M J, Mjaatvedt C H, Korenberg J R
Department of Medical Genetics, Cedars-Sinai Medical Center and UCLA, Los Angeles, California, USA.
Genet Med. 2001 Mar-Apr;3(2):91-101. doi: 10.1097/00125817-200103000-00002.
Down syndrome (DS) is a major cause of congenital heart disease (CHD) and the most frequent known cause of atrioventricular septal defects (AVSDs). Molecular studies of rare individuals with CHD and partial duplications of chromosome 21 established a candidate region that included D21S55 through the telomere. We now report human molecular and cardiac data that narrow the DS-CHD region, excluding two candidate regions, and propose DSCAM (Down syndrome cell adhesion molecule) as a candidate gene.
A panel of 19 individuals with partial trisomy 21 was evaluated using quantitative Southern blot dosage analysis and fluorescence in situ hybridization (FISH) with subsets of 32 BACs spanning the region defined by D21S16 (21q11.2) through the telomere. These BACs span the molecular markers D21S55, ERG, ETS2, MX1/2, collagen XVIII and collagen VI A1/A2. Fourteen individuals are duplicated for the candidate region, of whom eight (57%) have the characteristic spectrum of DS-CHD.
Combining the results from these eight individuals suggests the candidate region for DS-CHD is demarcated by D21S3 (defined by ventricular septal defect), through PFKL (defined by tetralogy of Fallot).
These data suggest that the presence of three copies of gene(s) from the region is sufficient for the production of subsets of DS-CHD. This region does not include genes located near D21S55, previously proposed as a "DS critical region," or the genes encoding collagens VI and XVIII. Of the potential gene candidates in the narrowed DS-CHD region, DSCAM is notable in that it encodes a cell adhesion molecule, spans more than 840 kb of the candidate region, and is expressed in the heart during cardiac development. Given these properties, we propose DSCAM as a candidate for DS-CHD.
唐氏综合征（DS）是先天性心脏病（CHD）的主要病因，也是房室间隔缺损（AVSD）最常见的已知病因。对患有CHD且21号染色体部分重复的罕见个体进行的分子研究确定了一个候选区域，该区域从D21S55一直延伸到端粒。我们现在报告人类分子和心脏数据，这些数据缩小了DS-CHD区域，排除了两个候选区域，并提出唐氏综合征细胞粘附分子（DSCAM）作为候选基因。
使用定量Southern印迹剂量分析和荧光原位杂交（FISH）对一组19名21号染色体部分三体的个体进行评估，所用的32个细菌人工染色体（BAC）子集跨越由D21S16（21q11.2）定义的区域直至端粒。这些BAC跨越分子标记D21S55、ERG、ETS2、MX1/2、ⅩⅧ型胶原和ⅥA1/A2型胶原。14名个体在候选区域存在重复，其中8名（57%）具有DS-CHD的特征性谱系。
综合这8名个体的结果表明，DS-CHD的候选区域由D21S3（由室间隔缺损定义）到磷酸果糖激酶L（PFKL，由法洛四联症定义）划定。
这些数据表明，该区域中基因的三个拷贝的存在足以产生DS-CHD的子集。该区域不包括先前被提议为“DS关键区域”的D21S55附近的基因，也不包括编码Ⅵ型和ⅩⅧ型胶原的基因。在缩小的DS-CHD区域中的潜在候选基因中，DSCAM值得注意，因为它编码一种细胞粘附分子，跨越候选区域超过840 kb，并且在心脏发育过程中在心脏中表达。鉴于这些特性，我们提出DSCAM作为DS-CHD的候选基因。
