Wimplinger Isabella, Rauch Anita, Orth Ulrike, Schwarzer Ulrich, Trautmann Udo, Kutsche Kerstin
Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, Campus Forschung, Gebäude 146, Martinistrasse 52, D-20246 Hamburg, Germany.
Eur J Med Genet. 2007 Nov-Dec;50(6):421-31. doi: 10.1016/j.ejmg.2007.07.004. Epub 2007 Aug 6.
The microphthalmia with linear skin defects (MLS or MIDAS) syndrome is a rare X-linked dominant inherited disorder with male lethality, associated with segmental aneuploidy of the Xp22.2 region in most of the cases. However, we recently described heterozygous sequence alterations in a single gene, HCCS, in females with MLS. Beside the classical MLS phenotype, occasional features such as sclerocornea, agenesis of the corpus callosum, and congenital heart defects can occur. Although the majority of cases are sporadic, mother-to-daughter transmission has been observed and a high intra- and interfamilial phenotypic variability exists. We describe an asymptomatic mother and her daughter presenting with the typical features of MLS syndrome. By cytogenetic analysis both females were found to have a terminal Xp deletion with the breakpoint in Xp22.2, mapping near to or within the MSL3L1 gene which is located centromeric to HCCS. FISH analysis revealed that the mother is a mosaic with 45,X(11)/46,X,del(X)(p22.2)(89), while in all cells of the MLS-affected daughter a hybridization pattern consistent with a 46,X,del(X)(p22.2) karyotype was detected. By haplotype analysis we identified the paternal X chromosome of the mother to carry the terminal Xp deletion. X-inactivation studies showed a completely skewed pattern in mother and daughter with the deleted X chromosome to be preferentially inactivated in their peripheral blood cells. We suggest that both chromosomal mosaicism as well as functional X chromosome mosaicism could contribute to the lack of any typical MLS feature in individuals with a heterozygous MLS-associated mutation. The 45,X cell population, that most likely is also present in other tissues of the mother, might have protected her from developing MLS. Nonetheless, a non-random X-inactivation pattern in favor of activity of the wild-type X chromosome in the early blastocyte could also account for the apparent lack of any disease sign in this female.
小眼畸形合并线状皮肤缺损（MLS或MIDAS）综合征是一种罕见的X连锁显性遗传性疾病，男性致死，大多数病例与Xp22.2区域的节段性非整倍体有关。然而，我们最近描述了患有MLS的女性中单个基因HCCS的杂合序列改变。除了典型的MLS表型外，还可能出现巩膜角膜、胼胝体发育不全和先天性心脏缺陷等偶发特征。虽然大多数病例是散发性的，但已观察到母女间的传递，并且存在高度的家族内和家族间表型变异性。我们描述了一位无症状母亲及其女儿，她们表现出MLS综合征的典型特征。通过细胞遗传学分析，发现两名女性均有Xp末端缺失，断点位于Xp22.2，定位于MSL3L1基因附近或该基因内部，MSL3L1基因位于HCCS的着丝粒侧。荧光原位杂交（FISH）分析显示，母亲是45,X(11)/46,X,del(X)(p22.2)(89)的嵌合体，而在受MLS影响的女儿的所有细胞中，检测到与46,X,del(X)(p22.2)核型一致的杂交模式。通过单倍型分析，我们确定母亲的父源X染色体携带Xp末端缺失。X染色体失活研究显示，母亲和女儿的X染色体失活模式完全偏向，缺失的X染色体在其外周血细胞中优先失活。我们认为，染色体嵌合以及功能性X染色体嵌合都可能导致携带杂合MLS相关突变的个体缺乏任何典型的MLS特征。母亲其他组织中很可能也存在的45,X细胞群可能保护了她未患MLS。尽管如此，早期胚泡中有利于野生型X染色体活性的非随机X染色体失活模式也可能解释了该女性明显没有任何疾病体征的原因。
