Recurrent third-trimester fetal loss and maternal mosaicism for long-QT syndrome
Recurrent third-trimester fetal loss and maternal mosaicism for long-QT syndrome
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DOI：
10.1161/01.cir.0000130666.81539.9e
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发表时间：
2004-06-22
期刊：
影响因子：
37.8
通讯作者：
Bishopric, NH
中科院分区：
文献类型：
--
作者：
Miller, TE;Estrella, E;Bishopric, NH
背景-生殖系嵌合现象在遗传病中的重要性可能被低估了，尽管最近的研究表明，在几种显性遗传遗传病的明显新生病例中，它可能涉及10%至20%。方法和结果-我们在这里描述了一例来自无症状母亲的严重形式的长qt综合征（LQTS）的重复种系传播，其心脏钠通道SCN5A突变嵌合。一例男婴28周时在子宫内被诊断为室性心律失常和心脏失代偿，出生后被诊断为LQTS，最终需要心脏移植来控制室性心动过速。母亲没有心电图异常，但她之前的妊娠在妊娠7个月时因心脏失代偿以死产告终。第三次怀孕也在7个月时以死产告终，同样是由于非免疫性胎儿水肿。存活的婴儿被发现有SCN5A杂合突变（R1623Q），先前报道是一种导致新生儿室性心律失常和LQTS的新生突变。对母亲的初步研究未发现遗传异常，但一种基于限制性内切酶的灵敏检测发现，在她的血液、皮肤和颊粘膜中，有一小部分（8%至10%）细胞携带突变。来自第三个胎儿的脐带血也含有突变等位基因，这表明所有3例晚期胎儿窘迫都是由lqts相关突变的种系转移引起的。结论：反复发生的晚期胎儿丢失或婴儿猝死可能是由于未预料到的lqts相关突变亲代嵌合，这对遗传咨询具有重要意义。
Background - The importance of germ-line mosaicism in genetic disease is probably underestimated, even though recent studies indicate that it may be involved in 10% to 20% of apparently de novo cases of several dominantly inherited genetic diseases.Methods and Results - We describe here a case of repeated germ-line transmission of a severe form of long-QT syndrome (LQTS) from an asymptomatic mother with mosaicism for a mutation in the cardiac sodium channel, SCN5A. A male infant was diagnosed with ventricular arrhythmias and cardiac decompensation in utero at 28 weeks and with LQTS after birth, ultimately requiring cardiac transplantation for control of ventricular tachycardia. The mother had no ECG abnormalities, but her only previous pregnancy had ended in stillbirth with evidence of cardiac decompensation at 7 months' gestation. A third pregnancy also ended in stillbirth at 7 months, again with nonimmune fetal hydrops. The surviving infant was found to have a heterozygous mutation in SCN5A (R1623Q), previously reported as a de novo mutation causing neonatal ventricular arrhythmia and LQTS. Initial studies of the mother detected no genetic abnormality, but a sensitive restriction enzyme - based assay identified a small (8% to 10%) percentage of cells harboring the mutation in her blood, skin, and buccal mucosa. Cord blood from the third fetus also harbored the mutant allele, suggesting that all 3 cases of late-term fetal distress resulted from germ-line transfer of the LQTS-associated mutation.Conclusions - Recurrent late-term fetal loss or sudden infant death can result from unsuspected parental mosaicism for LQTS-associated mutations, with important implications for genetic counseling.