Zollino Marcella, Lecce Rosetta, Fischetto Rita, Murdolo Marina, Faravelli Francesca, Selicorni Angelo, Buttè Cinzia, Memo Luigi, Capovilla Giuseppe, Neri Giovanni
Istituto di Genetica Medica, Facoltà di Medicina A. Gemelli, Université Cattolica Sacro Cuore, Roma, Italy.
Am J Hum Genet. 2003 Mar;72(3):590-7. doi: 10.1086/367925. Epub 2003 Jan 30.
In an attempt to define the distinctive Wolf-Hirschhorn syndrome (WHS) phenotype, and to map its specific clinical manifestations, a total of eight patients carrying a 4p16.3 microdeletion were analyzed for their clinical phenotype and their respective genotypes. The extent of each individual deletion was established by fluorescence in situ hybridization, with a cosmid contig spanning the genomic region from MSX1 (distal half of 4p16.1) to the subtelomeric locus D4S3359. The deletions were 1.9-3.5 Mb, and all were terminal. All the patients presented with a mild phenotype, in which major malformations were usually absent. It is worth noting that head circumference was normal for height in two patients (those with the smallest deletions [1.9 and 2.2 Mb]). The currently accepted WHS critical region (WHSCR) was fully preserved in the patient with the 1.9-Mb deletion, in spite of a typical WHS phenotype. The deletion in this patient spanned the chromosome region from D4S3327 (190 b4 cosmid clone included) to the telomere. From a clinical point of view, the distinctive WHS phenotype is defined by the presence of typical facial appearance, mental retardation, growth delay, congenital hypotonia, and seizures. These signs represent the minimal diagnostic criteria for WHS. This basic phenotype maps distal to the currently accepted WHSCR. Here, we propose a new critical region for WHS, and we refer to this region as "WHSCR-2." It falls within a 300-600-kb interval in 4p16.3, between the loci D4S3327 and D4S98-D4S168. Among the candidate genes already described for WHS, LETM1 (leucine zipper/EF-hand-containing transmembrane) is likely to be pathogenetically involved in seizures. On the basis of genotype-phenotype correlation analysis, dividing the WHS phenotype into two distinct clinical entities, a "classical" and a "mild" form, is recommended for the purpose of proper genetic counseling.
为了明确独特的沃尔夫-赫希霍恩综合征（WHS）表型，并绘制其特定临床表现图谱，我们对8例携带4p16.3微缺失的患者进行了临床表型和各自基因型分析。通过荧光原位杂交确定每个个体缺失的范围，所用黏粒重叠群覆盖从MSX1（4p16.1远端一半）到端粒位点D4S3359的基因组区域。缺失范围为1.9 - 3.5 Mb，均为末端缺失。所有患者均表现为轻度表型，通常无主要畸形。值得注意的是，两名患者（缺失最小[1.9和2.2 Mb]的患者）的头围与身高相比正常。尽管具有典型的WHS表型，但1.9 Mb缺失患者中目前公认的WHS关键区域（WHSCR）得以完全保留。该患者的缺失跨越从D4S3327（包含190 b4黏粒克隆）到端粒的染色体区域。从临床角度来看，独特的WHS表型由典型面容、智力发育迟缓、生长发育延迟、先天性肌张力低下和癫痫发作来界定。这些体征代表了WHS的最低诊断标准。这种基本表型定位于目前公认的WHSCR远端。在此，我们提出一个新的WHS关键区域，并将该区域称为“WHSCR - 2”。它位于4p16.3中300 - 600 kb的区间内，在D4S3327和D4S98 - D4S168位点之间。在已描述的WHS候选基因中，LETM1（含亮氨酸拉链/EF手型结构域的跨膜蛋白）可能在癫痫发病机制中起作用。基于基因型 - 表型相关性分析，为了进行恰当的遗传咨询，建议将WHS表型分为两种不同的临床类型，即“经典型”和“轻型”。
