Ferguson B M, Thomas N S, Munoz F, Morgan D, Clarke A, Zonana J
Department of Molecular and Medical Genetics, Oregon Health Sciences University, Portland 97201-3098, USA.
J Med Genet. 1998 Feb;35(2):112-5. doi: 10.1136/jmg.35.2.112.
Indirect molecular diagnosis of X linked hypohidrotic ectodermal dysplasia (XLHED), a congenital disorder of hair, teeth, and eccrine sweat glands, has been possible by linkage analysis. Direct mutation detection would enable carrier detection in female relatives of sporadic cases, as well as help distinguish XLHED from the rarer, clinically indistinguishable, autosomal recessive disorder ARHED. Recently, a candidate gene for XLHED has been identified. Genomic DNA from 162 affected males and 21 females, who were either obligate carriers or had manifestations of the disorder, were screened by SSCP analysis. A subset of the patients had been previously screened for large genomic deletions and had limited screening of a single exon by SSCP analysis. The two known exons were amplified using flanking primers. Approximately 7% of patients, all males, had putative mutations identified within exon 1, but no variants were found within exon 2. Ten different putative mutations and four probable polymorphisms were identified. Both of the known exons were sequenced in 10 patients who had no detectable SSCP changes, but no additional mutations were found. No correlation between phenotype and genotype was evident between either affected subjects or subjects with or without detectable mutations. The results of the study indicate that only a small minority of affected males can be diagnosed by direct mutation analysis, and that the remainder of the patients are likely to have mutations in as yet unidentified exons of the EDA gene. Linkage analysis, in informative situations, therefore remains the only practical diagnostic option available.
通过连锁分析对X连锁少汗型外胚层发育不良（XLHED）进行间接分子诊断已成为可能，XLHED是一种毛发、牙齿和小汗腺的先天性疾病。直接突变检测能够在散发病例的女性亲属中进行携带者检测，同时有助于将XLHED与更罕见的、临床难以区分的常染色体隐性疾病ARHED区分开来。最近，已鉴定出XLHED的一个候选基因。通过单链构象多态性（SSCP）分析对162名受影响男性和21名女性的基因组DNA进行了筛查，这些女性要么是确定的携带者，要么有该疾病的表现。一部分患者之前已接受过大基因组缺失筛查，并且通过SSCP分析对单个外显子进行了有限的筛查。使用侧翼引物扩增两个已知外显子。约7%的患者（均为男性）在外显子1中鉴定出推定突变，但在外显子2中未发现变异。鉴定出10种不同的推定突变和4种可能的多态性。对10名未检测到SSCP变化的患者的两个已知外显子进行了测序，但未发现其他突变。在受影响的个体之间或有或无可检测到的突变的个体之间，表型与基因型之间均无明显相关性。研究结果表明，只有一小部分受影响男性可通过直接突变分析进行诊断，其余患者可能在EDA基因尚未鉴定的外显子中存在突变。因此，在信息充分的情况下，连锁分析仍然是唯一可行的诊断选择。
