Molecular and clinical analyses of 16q24.1 duplications involving FOXF1 identify an evolutionarily unstable large minisatellite.
Molecular and clinical analyses of 16q24.1 duplications involving FOXF1 identify an evolutionarily unstable large minisatellite.
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DOI：
10.1186/s12881-014-0128-z
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发表时间：
2014-12-04
影响因子：
--
通讯作者：
Stankiewicz P
中科院分区：
文献类型：
--
作者：
Dharmadhikari AV;Gambin T;Szafranski P;Cao W;Probst FJ;Jin W;Fang P;Gogolewski K;Gambin A;George-Abraham JK;Golla S;Boidein F;Duban-Bedu B;Delobel B;Andrieux J;Becker K;Holinski-Feder E;Cheung SW;Stankiewicz P
FOXF 1的点突变或基因组缺失导致致命的发育性肺病肺泡毛细血管发育不良伴肺静脉错位。然而，组成性增加剂量的FOXF 1的临床后果是未知的。使用阵列CGH、长距离PCR、DNA测序和微卫星分析的组合鉴定拷贝数变异及其亲本来源。使用Gready聚类算法比较不同物种的小卫星序列，并使用R统计软件进行小卫星序列分布的全基因组分析。我们报告了四个不相关的家庭与16q24.1重复，包括整个FOXF 1。在一个4岁的男孩与语言延迟和咖啡牛奶斑，我们确定了一个~15 kb的16q24.1重复遗传自健康的父亲，除了一个从头~1.09 Mb的镶嵌17q11.2 NF 1缺失。在一名患有自闭症和情绪障碍的13岁患者中，我们发现了一个含有FOXF 1的~0.3 Mb重复序列和一个~0.5 Mb 16q23.3重复序列，两者都遗传自患有双相情感障碍的父亲。在一个47岁的患者幽门狭窄，肠系膜公社，阑尾发育不全，我们确定了一个约0.4 Mb的重复16 q24.1包含16个基因，包括FOXF 1。患者将复制传染给了她的女儿，她的女儿出现了类似的症状。在第四例患者的语言和运动延迟，和边缘智力残疾，我们确定了一个约1.7 Mb FOXF 1重复邻近一个大的小卫星。这种重复具有复杂的结构，并且在母体染色体上从头出现，可能是由于相邻的大串联重复序列引发的DNA复制错误。通过对小卫星进行生物信息学和阵列CGH分析，我们发现它的大小在几个不同的物种和个体中存在很大差异，这表明它在进化上的不稳定性和种群多态性。我们的数据表明，FOXF 1在人类中的体质性重复与任何儿科肺部异常无关。我们建议肠旋转不良、幽门或十二指肠狭窄、胆囊发育不全的患者应检测FOXF 1的改变。我们认为，大于1 kb的小卫星的不稳定性可能会导致结构变异，由于DNA复制错误。本文的在线版本（doi：10.1186/s12881-014-0128-z）包含补充材料，可供授权用户使用。
Point mutations or genomic deletions of FOXF1 result in a lethal developmental lung disease Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins. However, the clinical consequences of the constitutively increased dosage of FOXF1 are unknown. Copy-number variations and their parental origin were identified using a combination of array CGH, long-range PCR, DNA sequencing, and microsatellite analyses. Minisatellite sequences across different species were compared using a gready clustering algorithm and genome-wide analysis of the distribution of minisatellite sequences was performed using R statistical software. We report four unrelated families with 16q24.1 duplications encompassing entire FOXF1. In a 4-year-old boy with speech delay and a café-au-lait macule, we identified an ~15 kb 16q24.1 duplication inherited from the reportedly healthy father, in addition to a de novo ~1.09 Mb mosaic 17q11.2 NF1 deletion. In a 13-year-old patient with autism and mood disorder, we found an ~0.3 Mb duplication harboring FOXF1 and an ~0.5 Mb 16q23.3 duplication, both inherited from the father with bipolar disorder. In a 47-year old patient with pyloric stenosis, mesenterium commune, and aplasia of the appendix, we identified an ~0.4 Mb duplication in 16q24.1 encompassing 16 genes including FOXF1. The patient transmitted the duplication to her daughter, who presented with similar symptoms. In a fourth patient with speech and motor delay, and borderline intellectual disability, we identified an ~1.7 Mb FOXF1 duplication adjacent to a large minisatellite. This duplication has a complex structure and arose de novo on the maternal chromosome, likely as a result of a DNA replication error initiated by the adjacent large tandem repeat. Using bioinformatic and array CGH analyses of the minisatellite, we found a large variation of its size in several different species and individuals, demonstrating both its evolutionarily instability and population polymorphism. Our data indicate that constitutional duplication of FOXF1 in humans is not associated with any pediatric lung abnormalities. We propose that patients with gut malrotation, pyloric or duodenal stenosis, and gall bladder agenesis should be tested for FOXF1 alterations. We suggest that instability of minisatellites greater than 1 kb can lead to structural variation due to DNA replication errors. The online version of this article (doi:10.1186/s12881-014-0128-z) contains supplementary material, which is available to authorized users.
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影响因子：
11.2
作者：
Nilsson, Jeanette;Helou, Khalil;Kannius-Janson, Marie
通讯作者：
Kannius-Janson, Marie
FOXG1 综合征的核心表型包括出生后小头畸形、严重智力低下、语言缺失、运动障碍和胼胝体发育不全。
影响因子：
4
作者：
Kortüm F;Das S;Flindt M;Morris-Rosendahl DJ;Stefanova I;Goldstein A;Horn D;Klopocki E;Kluger G;Martin P;Rauch A;Roumer A;Saitta S;Walsh LE;Wieczorek D;Uyanik G;Kutsche K;Dobyns WB
通讯作者：
Dobyns WB
影响因子：
12.3
作者：
Pang, Andy W.;MacDonald, Jeffrey R.;Scherer, Stephen W.
通讯作者：
Scherer, Stephen W.
影响因子：
2
作者：
Kucharczyk, Marzena;Kochanski, Andrzej;Krajewska-Walasek, Malgorzata
通讯作者：
Krajewska-Walasek, Malgorzata
影响因子：
30.8
作者：
Levine, David M.;Ek, Weronica E.;Zhang, Rui;Liu, Xinxue;Onstad, Lynn;Sather, Cassandra;Lao-Sirieix, Pierre;Gammon, Marilie D.;Corley, Douglas A.;Shaheen, Nicholas J.;Bird, Nigel C.;Hardie, Laura J.;Murray, Liam J.;Reid, Brian J.;Chow, Wong-Ho;Risch, Harvey A.;Nyren, Olof;Ye, Weimin;Liu, Geoffrey;Romero, Yvonne;Bernstein, Leslie;Wu, Anna H.;Casson, Alan G.;Chanock, Stephen J.;Harrington, Patricia;Caldas, Isabel;Debiram-Beecham, Irene;Caldas, Carlos;Hayward, Nicholas K.;Pharoah, Paul D.;Fitzgerald, Rebecca C.;MacGregor, Stuart;Whiteman, David C.;Vaughan, Thomas L.
通讯作者：
Vaughan, Thomas L.