Wilson Meredith, Peters Gregory, Bennetts Bruce, McGillivray George, Wu Zan He, Poon Christopher, Algar Elizabeth
Department of Clinical Genetics, Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, Australia.
Am J Med Genet A. 2008 Jan 15;146A(2):137-48. doi: 10.1002/ajmg.a.32172.
Recently, mosaicism for genome-wide paternal uniparental disomy (patUPD), attributed to androgenetic/biparental mosaicism, has been shown to underlie placental mesenchymal dysplasia (PMD), a distinctive cystic placental phenotype. Manifestations of Beckwith-Wiedemann syndrome (BWS) have been observed in approximately one-third of fetuses or liveborn infants from pregnancies complicated by PMD. There are very few reports describing liveborn individuals with proven mosaicism for genome-wide patUPD in somatic tissues. We report two further children with complex phenotypes including some findings of BWS, congenital hyperinsulinemic hypoglycemia, prolonged feeding difficulty and failure to thrive in infancy. The first developed short stature, bilateral pheochromocytomas and progressive arterial stenoses, and the second had congenital adrenal cysts, and later developed hepatoblastoma and patchy hyperpigmentation. Leukocyte DNA methylation studies of KCNQ1OT1/LIT1 and H19 loci (11p15.5) showed almost complete loss of maternal methylation (LOM) in patient 1 and partial LOM in patient 2. Microsatellite marker panels showed whole chromosome 11 patUPD. SNP array studies in both were consistent with mosaic genome-wide patUPD in leukocytes, while fibroblast DNA in Patient 1 showed biparental inheritance. This report further illustrates the clinical consequences of mosaicism for genome-wide patUPD, which results in complex and variable phenotypes. Studies for genome-wide UPD should be considered in individuals with atypical UPD phenotypes.
最近，因孤雄/双亲嵌合现象导致的全基因组父源单亲二体性（patUPD）嵌合体已被证明是胎盘间充质发育异常（PMD）的基础，PMD是一种独特的囊性胎盘表型。在患有PMD的妊娠中，约三分之一的胎儿或活产婴儿出现了贝克威思-维德曼综合征（BWS）的表现。关于体细胞组织中存在经证实的全基因组patUPD嵌合体的活产个体的报道非常少。我们报告了另外两名具有复杂表型的儿童，包括一些BWS的表现、先天性高胰岛素性低血糖、喂养困难持续时间长以及婴儿期生长发育迟缓。第一名儿童出现身材矮小、双侧嗜铬细胞瘤和进行性动脉狭窄，第二名儿童患有先天性肾上腺囊肿，后来发展为肝母细胞瘤和斑片状色素沉着。对KCNQ1OT1/LIT1和H19基因座（11p15.5）进行的白细胞DNA甲基化研究显示，患者1的母源甲基化几乎完全缺失（LOM），患者2则为部分LOM。微卫星标记面板显示11号染色体全染色体patUPD。两人的单核苷酸多态性（SNP）阵列研究均与白细胞中的全基因组patUPD嵌合体一致，而患者1的成纤维细胞DNA显示为双亲遗传。本报告进一步说明了全基因组patUPD嵌合体的临床后果，即导致复杂多变的表型。对于具有非典型UPD表型的个体，应考虑进行全基因组UPD研究。
