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Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21.

来自Gabriella Miller Kids First儿科研究联盟的口面裂三联体的全基因组测序确定了 21 号染色体上的一个新位点。

  • 影响因子:4.34
  • DOI:10.1007/s00439-019-02099-1
  • 作者列表:"Mukhopadhyay N","Bishop M","Mortillo M","Chopra P","Hetmanski JB","Taub MA","Moreno LM","Valencia-Ramirez LC","Restrepo C","Wehby GL","Hecht JT","Deleyiannis F","Butali A","Weinberg SM","Beaty TH","Murray JC","Leslie EJ","Feingold E","Marazita ML
  • 发表时间:2020-02-01

:Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic, and the genetic etiology of non-syndromic OFCs is only partially determined. Here, we analyze whole genome sequence (WGS) data for association with risk of OFCs in European and Colombian families selected from a multicenter family-based OFC study. This is the first large-scale WGS study of OFC in parent-offspring trios, and a part of the Gabriella Miller Kids First Pediatric Research Program created for the study of childhood cancers and structural birth defects. WGS provides deeper and more specific genetic data than using imputation on present-day single nucleotide polymorphic (SNP) marker panels. Genotypes of case-parent trios at single nucleotide variants (SNV) and short insertions and deletions (indels) spanning the entire genome were called from their sequences using human GRCh38 genome assembly, and analyzed for association using the transmission disequilibrium test. Among genome-wide significant associations, we identified a new locus on chromosome 21 in Colombian families, not previously observed in other larger OFC samples of Latin American ancestry. This locus is situated within a region known to be expressed during craniofacial development. Based on deeper investigation of this locus, we concluded that it contributed risk for OFCs exclusively in the Colombians. This study reinforces the ancestry differences seen in the genetic etiology of OFCs, and underscores the need for larger samples when studying for OFCs and other birth defects in populations with diverse ancestry.


: 口面裂隙 (ofc) 是世界上最普遍的颅面出生缺陷之一,并造成了显著的公共卫生负担。大多数OFCs是非综合征型,非综合征型OFCs的遗传病因仅部分确定。在此,我们分析了欧洲和哥伦比亚家系的全基因组序列 (WGS) 数据与OFC风险的相关性,该家系选自一项多中心基于家系的OFC研究。这是第一个大规模的WGS研究OFC在父母-后代三重奏,和加布里埃拉米勒儿童第一个儿科研究计划的一部分,创建儿童癌症和结构性出生缺陷的研究。WGS提供了比在当今单核苷酸多态性 (SNP) 标记面板上使用插补更深入、更具体的遗传数据。使用人类GRCh38 基因组组装,从其序列中调用跨越整个基因组的单核苷酸变异 (SNV) 和短插入和缺失 (indel) 的病例亲本三联体的基因型,并利用传递不平衡检验进行关联分析。在全基因组显著关联中,我们在哥伦比亚家族的 21 号染色体上发现了一个新的位点,以前在拉丁美洲血统的其他更大的OFC样本中没有观察到。该位点位于已知在颅面发育过程中表达的区域内。基于对该位点的更深入调查,我们得出结论,它仅在哥伦比亚人中对OFCs有风险。本研究加强了在OFCs的遗传病因中看到的祖先差异,并强调了在研究OFCs和其他出生缺陷的不同血统人群时需要更大的样本。



作者列表:["Denadai R","Seo HJ","Lo LJ"]

METHODS:BACKGROUND:The anterior oronasal fistulae neighboring the alveolar cleft could persist or reappear after the alveolar reconstruction with cancellous bone grafting. The persistent symptomatic anterior oronasal fistulae need to be repaired, but surgery remains a challenge in cleft care. Surprisingly, this issue has rarely been reported in the literature. The purpose of this long-term study was to report a single surgeon experience with a therapeutic protocol for persistent symptomatic anterior oronasal fistula repair. METHODS:This is a retrospective study of consecutive patients with Veau type III and IV clefts and persistent symptomatic anterior oronasal fistulae managed according to a therapeutic protocol from 1997 to 2018. Depending on fistula size, patients were treated with local flaps associated with an interpositional graft or two-stage tongue flaps (small/medium or large fistulae, respectively). The surgical outcomes were classified as "good" (complete fistula closure with no symptoms), "fair" (asymptomatic narrow fistula remained), or "poor" (failure with persistent symptoms). RESULTS:Forty-four patients with persistent symptomatic anterior oronasal fistulae were reconstructed with local flaps associated with interpositional fascia or dermal fat grafting (52.3%) or two-stage tongue flaps (47.7%). Most of patients (93.2%) presented "good" outcomes, ranging from 87% to 100% (local and tongue flaps, respectively). Three (6.8%) patients presented symptomatic residual fistula ("poor" outcomes). CONCLUSIONS:For the repair of persistent symptomatic anterior oronasal fistulae, this therapeutic protocol provided satisfactory outcome with low fistula recurrence rate.

翻译标题与摘要 下载文献
作者列表:["Cleary B","Loane M","Addor MC","Barisic I","de Walle HEK","Matias Dias C","Gatt M","Klungsoyr K","McDonnell B","Neville A","Pierini A","Rissmann A","Tucker DF","Zurriaga O","Dolk H"]

METHODS:OBJECTIVE:Methadone is a vital treatment for women with opioid use disorder in pregnancy. Previous reports suggested an association between methadone exposure and Pierre Robin sequence (PRS), a rare craniofacial anomaly. We assessed the association between gestational methadone exposure and PRS. DESIGN/SETTING:This case-malformed control study used European Surveillance of Congenital Anomalies population-based registries in Ireland, the Netherlands, Italy, Switzerland, Croatia, Malta, Portugal, Germany, Wales, Norway and Spain, 1995-2011. PATIENTS:Cases included PRS based on International Classification of Disease (ICD), Ninth Edition-British Paediatric Association (BPA) code 75 603 or ICD, Tenth Edition-BPA code Q8708. Malformed controls were all non-PRS anomalies, excluding genetic conditions, among live births, fetal deaths from 20 weeks' gestation and terminations of pregnancy for fetal anomalies. An exploratory analysis assessed the association between methadone exposure and other congenital anomalies (CAs) excluding PRS. Methadone exposure was ascertained from medical records and maternal interview. RESULTS:Among 87 979 CA registrations, there were 127 methadone-exposed pregnancies and 336 PRS cases. There was an association between methadone exposure and PRS (OR adjusted for registry 12.3, 95% CI 5.7 to 26.8). In absolute terms, this association reflects a risk increase from approximately 1-12 cases per 10 000 births. A raised OR was found for cleft palate (adjusted OR 5.0, 95% CI 2.7 to 9.2). CONCLUSIONS:These findings suggest that gestational methadone exposure is associated with PRS. The association may be explained by unmeasured confounding factors. The small increased risk of PRS in itself does not alter the risk-benefit balance for gestational methadone use. The association with cleft palate, a more common CA, should be assessed with independent data.

翻译标题与摘要 下载文献
作者列表:["Jahanbin A","Eslami N","Torkamanzadeh N"]

METHODS::Orthopedic treatment to improve deficient maxillary growth of cleft lip and palate patients is an important part of treatment. The success of this treatment is strongly dependent on the time of initiation of therapy. There has been a large controversy in the available literature regarding the skeletal age of these patients. The aim of the present study was to compare the skeletal age of cleft lip and palate patients with normal individuals.37 unilateral and 14 bilateral cleft lip and palate patients and 47 healthy individuals participated in this cross-sectional study. The patients were classified into 8 to 10 and 11 to 14-year-old individuals. Cervical vertebral maturational stage of participants was evaluated in the lateral cephalometry. The skeletal age of cleft lip and palate patients was compared with normal controls. Chi-square was used for statistical analysis. There was not a significant difference in the skeletal developmental stage of unilateral and bilateral cleft compared to their normal peers according to their age and sex. Also, significant difference in skeletal maturational stage of cleft lip and palate patients was not found between boys and girls (P = 0.8). Similarly, no significant difference was found in the skeletal age of the 3 studied groups without considering the age and sex of participants (P = 0.5). Regarding the similar skeletal maturational stage of cleft lip and palate patients with normal controls in our study, their maxillofacial orthopedic treatment can be initiated at similar time to normal peers.

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翻译标题与摘要 下载文献