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【资讯翻译】Whole Exome Sequencing in Fetuses with Abnormal Ultrasound ...

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发表于 2016-3-17 10:38:03 | 显示全部楼层 |阅读模式
Whole Exome Sequencing in Fetuses with Abnormal Ultrasound Findings Leading to Fetal Demise or Pregnancy Termination

With enhancements in fetal imaging and the rapid growth of genetic screening and diagnostic testing options, a growing number of human genetic disorders that manifest in utero can be diagnosed prenatally. These include aneuploidies, large chromosomal deletion and duplication syndromes, common and rare single gene disorders, and genetic etiologies of pregnancy complications that may lead to adverse pregnancy outcomes. To better understand the contribution of genetic disorders to structural fetal abnormalities and fetal demise, we have analyzed the results of whole exome sequencing (WES) on 61 fetal samples. Of those for which gestational age was reported (69%, n= 42), 62% (n=26) were second trimester fetal terminations and demises and 38% (n=16) were third trimester demises. Clinical indications for testing encompassed isolated or multiple fetal anomalies, fetal hydrops, intrauterine growth restriction, and discordant genetic and phenotypic fetal gender. 36% (n=22) of cases had central nervous system anomalies including ventriculomegaly/hydrocephalus (n=9) and absence of the corpus callusom (n=6). Congenital heart disease including structural heart defects (n=6) and cardiomyopathy (n=2) was reported in 21% (n=13) of cases. Cystic hygroma or hydrops was reported in 26% (n=16) of cases. Other ultrasound anomalies included facial anomalies (n=14), rocker bottom feet (n=9), shortened long bones (n=7), congenital diaphragmatic hernia (n=6), renal anomalies (n=6), and omphalocele (n=2). Of the 61 cases, 61% (n=37) were male, 36% (n=22) were female, and 3% (n=2) had discordant genetic and phenotypic fetal gender. 56% (n=34) cases had prior reported normal karyotype and 69% (n=42) had prior reported normal chromosomal microarray. One fetus had a chromosomal deletion inherited from a phenotypically normal father.  Prior negative genetic testing was performed in 8% (n=5) of cases, including panel testing for Noonan syndrome, fetal akinesia deformation, lysosomal storage disease, and single gene testing for LAMB2, NPHS2, PLCE1, NPHS1, or FGFR3. WES analysis was predominantly performed in fetus-parent trios (52%, n=32) or singleton cases (33%, n=20). The remainder included fetus-parent duos or siblings. Overall, 21% (n=13) of cases yielded a definitive molecular diagnosis, 34% (n=21) had reportable variants associated with a probable diagnosis, and 30% (n=18) tested negative. The number of cases with only one variant (47%, n=20) was similar to those with two or more variants (53%, n=23) identified. The only gene with pathogenic variants in more than one case was FGFR2, seen in two fetuses with features suggestive of skeletal dysplasia. In all other positive cases, distinct molecular diagnoses were made, including among others, MYH3-related distal arthrogryposis, PIK3CA-related megalencephaly-capillary malformation-polymicrogyria syndrome, L1CAM-related hydrocephalus, RIPK4-realted Bartsocas-Papas syndrome, MRPS22-related mitochondrial dysfunction, PKHD1-related polycystic kidney disease, and CYP11A1-related adrenal insufficiency. Whole exome sequencing can be a useful tool in identifying a molecular cause in fetal anomalies which is important for prognosis, pregnancy management, recurrence risk, and reproductive options in subsequent pregnancies.

信源地址:https://acmg.expoplanner.com/ind ... amp;session_id=1529

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发表于 2016-3-18 10:06:02 | 显示全部楼层
get ..............

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发表于 2016-3-18 14:29:32 | 显示全部楼层
这篇送其他小伙伴吧,,,,

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发表于 2016-3-18 14:31:09 | 显示全部楼层
领了。。。。。

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发表于 2016-3-18 20:15:30 | 显示全部楼层
全外显子组测序在导致胎儿死亡或终止妊娠的胎儿超声异常病例中的应用

       在胎儿影像更加清晰化和遗传筛查及诊断测试选择快速增长的背景下,越来越多的在子宫内表现出来的人类遗传性疾病可以进行产前诊断。这些遗传性疾病包括包括非整倍体,大染色体缺失和重叠综合征,常见和罕见的单基因疾病,和由遗传病因导致不良妊娠的妊娠并发症等。为了更好地了解遗传性疾病对胎儿结构异常和胎儿死亡的贡献,我们对61例胎儿样品全外显子组测序(WES)结果进行了分析。对那些有胎龄记录的样品(69%,n= 42),62%(n = 26)的病例在孕中期发生胎儿终止和死亡;38%(n = 16)的病例在第三期发生胎儿死亡。用于测试的临床适应症包括孤立是或多个胎儿畸形、胎儿水肿、胎儿宫内生长受限和具有不和谐的遗传和表型的胎儿性别。36%(n = 22)的病例有中枢神经系统异常,包括脑室/脑积水(n = 9)和胼胝体缺失(n = 6)。21%的病例患有先天性心脏病(n=13),包括心脏结构缺陷(6例)和心肌病(2例)。26%的病例患有囊状水瘤或积水(n = 16)。其他超声异常包括面部异常(N = 14),摇杆底足(n = 9),长骨缩短(n = 7),先天性膈疝(n = 6),肾脏异常(N = 6),和脐膨出(n = 2)。61例病例中,37例男性(61%),22例女性(36%),2例据有不一致的遗传和表型的胎儿性别(3%)。在前期检测中,34例有正常的染色体核型(56%),42例有正常的染色体微阵列分析结果(69%)。一个胎儿从表型正常的父亲那里继承了缺失的染色体。之前对5例病例进行了负遗传测试(8%),包括努南综合征,胎儿运动机能丧失变形,溶酶体贮积病的面板测试和 LAMB2,NPHS2,PLCE1,NPHS1或FGFR3的单基因测试。WES分析主要在胎儿父母三重(52%,n = 32)或单例(33%,n = 20)中进行。其余的WES分析包括对胎儿父母二重或兄弟姐妹减的WES分析。总体而言,21%(n = 13)的病例得到明确的分子诊断,34%(n = 21)的病例得出可能有变异的诊断,和30%病理(n = 18)的测试呈阴性。单变异病例(47%,20)和有2个及以上变异的病例(53%,23)数量差不过。FGFR2基因是唯一一个在不止一个病例中具有致病性变异的基因(两个胎儿具有骨骼发育异常的特点)。对其他所有阳性病例进行了不同的分子诊断,这些病例包括MYH3相关远端关节挛缩,PIK3CA基因相关的巨脑毛细血管畸形小脑综合征,L1CAM相关的脑积水,RIPK4相关小萨里曼身患罕见蹼足病,MRPS22相关的线粒体功能障碍,PKHD1相关的多囊肾、CYP11A1相关肾上腺功能不全。全外显子组测序可以在鉴定由分子原因造成的胎儿异常中成为一个有用的工具,并对随后的怀孕的预测,孕期管理,复发风险和生育选择是非常重要。

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 楼主| 发表于 2016-3-22 16:11:52 | 显示全部楼层
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