Ginsburg C, Fokstuen S, Schinzel A
Institute of Medical Genetics, University of Zürich, Zürich, Switzerland.
Am J Med Genet. 2000 Dec 18;95(5):454-60.
Most instances of maternal uniparental disomy (UPD) start as trisomies and, similar to the latter, show a significant increase of mean maternal age at delivery. To investigate the incidence of UPD in offspring of older mothers, we investigated two groups of patients: 1) 50 patients with unclassified developmental defects born to mothers 35 years or older at delivery were tested for UPD for all autosomes by means of microsatellite marker analysis; 2) The incidence of UPD versus other etiologies in correlation, with maternal age below versus 35 years and above at delivery was studied in patients investigated in our laboratory for maternal UPD 15 (Prader-Willi syndrome, PWS), paternal UPD 15 (Angelman syndrome, AS), and maternal UPD 7 (Silver-Russell syndrome, SRS). In group 1, four patients of 50 showed UPD for an autosome that clarified the etiology of their developmental problems: a 27-year-old woman with growth retardation and early puberty disclosed maternal heterodisomy 14; a 15-year-old girl revealed paternal isodisomy 15; a 6-year-old boy with suspected Smith-Lemli-Opitz syndrome was shown to have maternal heterodisomy 16 with additional mosaic partial trisomy 16(pter-p13); a 16-month-old girl with intrauterine growth retardation and a dysmorphic pattern revealed maternal heterodisomy 7. In group 2 the offspring of older mothers showed a clear increase of UPD compared with the mothers below 35 years at delivery. The binomial distribution gave P-values of 1.9 x 10(-10), 2.6 x 10(-4), and 0.01 for PWS, AS, and SRS, respectively. The correlation between increase of paternal UPD 15 with advanced maternal age might be explained by maternal non-disjunction leading to hypohaploid gamete (nullisomy) for chromosome 15 with subsequent or concomitant duplication of the paternal homologue (paternal isodisomy). The three UPD 15 AS cases with mothers older than 35 years at delivery revealed isodisomy, whereas the three cases from younger mothers showed heterodisomy. This study confirms the hypothesis that uniparental disomy is a not negligible cause of congenital developmental anomalies in children of older mothers.
大多数母源单亲二倍体（UPD）情况起始于三体，并且与三体相似，分娩时母亲的平均年龄显著增加。为了研究高龄母亲后代中UPD的发生率，我们调查了两组患者：1）对50例分娩时母亲年龄在35岁及以上且患有未分类发育缺陷的患者，通过微卫星标记分析检测所有常染色体的UPD；2）在我们实验室对母源UPD 15（普拉德-威利综合征，PWS）、父源UPD 15（安吉尔曼综合征，AS）和母源UPD 7（西尔弗-拉塞尔综合征，SRS）进行调查的患者中，研究了分娩时母亲年龄低于35岁与35岁及以上时UPD与其他病因的相关性。在第1组中，50例患者中有4例显示某条常染色体存在UPD，这明确了其发育问题的病因：一名27岁患有生长发育迟缓及性早熟的女性显示母源异源二体14；一名15岁女孩显示父源同源二体15；一名6岁疑似史密斯-勒米利-奥皮茨综合征的男孩显示母源异源二体16并伴有额外的嵌合型部分三体16（pter-p13）；一名16个月大患有宫内生长发育迟缓及畸形模式的女孩显示母源异源二体7。在第2组中，与分娩时年龄低于35岁的母亲相比，高龄母亲的后代中UPD明显增加。二项分布分别给出PWS、AS和SRS的P值为1.9×10⁻¹⁰、2.6×10⁻⁴和0.01。父源UPD 15增加与母亲高龄之间的相关性可能是由于母源不分离导致15号染色体的亚单倍体配子（缺体），随后或同时父源同源染色体重复（父源同源二体）。3例分娩时母亲年龄大于35岁的AS患者显示为同源二体，而3例母亲年龄较小的患者显示为异源二体。本研究证实了这一假说，即单亲二倍体是高龄母亲子女先天性发育异常的一个不可忽视的原因。
