The contribution of uniparental disomy to congenital development defects in children born to mothers at advanced childbearing age.

American Journal of Medical Genetics Pub Date : 2000-12-18
C Ginsburg, S Fokstuen, A Schinzel
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Abstract

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.

单亲残疾对高龄母亲所生儿童先天发育缺陷的贡献。
大多数母亲单亲二体症(UPD)始于三体,与后者相似,产妇分娩时的平均年龄显着增加。为了研究高龄母亲的后代UPD的发病率,我们调查了两组患者:1)用微卫星标记分析方法检测了所有常染色体的UPD,检测了50例35岁及以上母亲分娩时所生的未分类发育缺陷患者;2)在我们实验室调查的产妇UPD 15 (Prader-Willi综合征,PWS)、父亲UPD 15 (Angelman综合征,AS)和母亲UPD 7 (Silver-Russell综合征,SRS)患者中,研究了产妇分娩时年龄低于35岁及以上的UPD与其他病因的相关发生率。在第1组中,50例患者中有4例出现常染色体UPD,这明确了其发育问题的病因:一名27岁的女性患有生长迟缓和性早熟,披露了母体异位14;一名15岁的女孩发现父亲15型同型体;一名疑似Smith-Lemli-Opitz综合征的6岁男孩被证实有母体异位体16和附加的马赛克部分16三体(ptp -p13);一名16个月大的宫内发育迟缓和畸形模式的女孩显示母亲异位7。在第二组中,高龄母亲的后代与35岁以下母亲相比,分娩时UPD明显增加。PWS、AS和SRS的二项分布p值分别为1.9 × 10(-10)、2.6 × 10(-4)和0.01。父亲upd15的增加与母亲年龄的增加之间的相关性可能是由于母亲不分离导致15号染色体的低单倍体配子(无染色体),随后或伴随父亲同源物的重复(父亲同位体)。分娩时母亲年龄大于35岁的3例UPD - 15as患儿表现为同位体,而分娩时母亲年龄较小的3例患儿表现为异位体。本研究证实了单亲失体是大龄母亲的孩子先天性发育异常的一个不可忽视的原因。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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