Molecular diagnoses in the congenital malformations caused by ciliopathies cohort of the 100,000 Genomes Project.
Molecular diagnoses in the congenital malformations caused by ciliopathies cohort of the 100,000 Genomes Project.
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DOI：
10.1136/jmedgenet-2021-108065
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发表时间：
2022-08
影响因子：
4
通讯作者：
中科院分区：
文献类型：
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原发性纤毛病是由“细胞的天线”——原发性纤毛缺陷引起的一组遗传性疾病。100,000基因组计划于2012年由英国基因组学公司（GEL）发起，招募符合条件的罕见疾病和癌症患者。序列数据与招募临床医生输入的人类表型本体（HPO）术语相关联。83名预先筛选的先证被招募到100,000基因组计划中，他们被怀疑患有由以下疾病类别的纤毛病引起的先天性畸形：Bardet-Biedl综合征（n=45）， Joubert综合征（n=14）和“罕见多系统纤毛病”（n=24）。我们实施了定制的变异过滤和分析策略，以提高这些参与者的分子诊断率。我们确定了n=43/83（51.8%）先证者的研究分子诊断。这比GEL先前报道的数据高出19.3% （n=27/83(32.5%)）。很大比例的诊断是由于非纤毛病疾病基因的变异（n=19/43, 44.2%），这可能反映了临床识别纤毛病的困难。n=11/83先证（13.3%）在1级和2级变异优先分类（GEL的自动分类程序）之外至少有一个致病变异，这不会在标准的100,000基因组计划诊断策略中进行审查。这些包括四种结构变异和三种预测引起非规范剪接缺陷。两个不相关的参与者在LRRC45（一种假定的新型纤毛病基因）中具有双等位基因可能的致病变异。这些数据说明了将大规模基因组序列与表型信息联系起来的力量。它们展示了为了最大限度地解释基因组数据而进行研究合作的价值。
Primary ciliopathies represent a group of inherited disorders due to defects in the primary cilium, the ‘cell’s antenna’. The 100,000 Genomes Project was launched in 2012 by Genomics England (GEL), recruiting National Health Service (NHS) patients with eligible rare diseases and cancer. Sequence data were linked to Human Phenotype Ontology (HPO) terms entered by recruiting clinicians. Eighty-three prescreened probands were recruited to the 100,000 Genomes Project suspected to have congenital malformations caused by ciliopathies in the following disease categories: Bardet-Biedl syndrome (n=45), Joubert syndrome (n=14) and ‘Rare Multisystem Ciliopathy Disorders’ (n=24). We implemented a bespoke variant filtering and analysis strategy to improve molecular diagnostic rates for these participants. We determined a research molecular diagnosis for n=43/83 (51.8%) probands. This is 19.3% higher than previously reported by GEL (n=27/83 (32.5%)). A high proportion of diagnoses are due to variants in non-ciliopathy disease genes (n=19/43, 44.2%) which may reflect difficulties in clinical recognition of ciliopathies. n=11/83 probands (13.3%) had at least one causative variant outside the tiers 1 and 2 variant prioritisation categories (GEL’s automated triaging procedure), which would not be reviewed in standard 100,000 Genomes Project diagnostic strategies. These include four structural variants and three predicted to cause non-canonical splicing defects. Two unrelated participants have biallelic likely pathogenic variants in LRRC45, a putative novel ciliopathy disease gene. These data illustrate the power of linking large-scale genome sequence to phenotype information. They demonstrate the value of research collaborations in order to maximise interpretation of genomic data.
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影响因子：
7.2
作者：
Bujakowska KM;Liu Q;Pierce EA
通讯作者：
Pierce EA
影响因子：
12.3
作者：
McLaren W;Gil L;Hunt SE;Riat HS;Ritchie GR;Thormann A;Flicek P;Cunningham F
通讯作者：
Cunningham F
影响因子：
12.3
作者：
Shaheen R;Szymanska K;Basu B;Patel N;Ewida N;Faqeih E;Al Hashem A;Derar N;Alsharif H;Aldahmesh MA;Alazami AM;Hashem M;Ibrahim N;Abdulwahab FM;Sonbul R;Alkuraya H;Alnemer M;Al Tala S;Al-Husain M;Morsy H;Seidahmed MZ;Meriki N;Al-Owain M;AlShahwan S;Tabarki B;Salih MA;Ciliopathy WorkingGroup;Faquih T;El-Kalioby M;Ueffing M;Boldt K;Logan CV;Parry DA;Al Tassan N;Monies D;Megarbane A;Abouelhoda M;Halees A;Johnson CA;Alkuraya FS
通讯作者：
Alkuraya FS
影响因子：
7.3
作者：
Gabriel GC;Young CB;Lo CW
通讯作者：
Lo CW
影响因子：
16.6
作者：
Dougherty GW;Mizuno K;Nöthe-Menchen T;Ikawa Y;Boldt K;Ta-Shma A;Aprea I;Minegishi K;Pang YP;Pennekamp P;Loges NT;Raidt J;Hjeij R;Wallmeier J;Mussaffi H;Perles Z;Elpeleg O;Rabert F;Shiratori H;Letteboer SJ;Horn N;Young S;Strünker T;Stumme F;Werner C;Olbrich H;Takaoka K;Ide T;Twan WK;Biebach L;Große-Onnebrink J;Klinkenbusch JA;Praveen K;Bracht DC;Höben IM;Junger K;Gützlaff J;Cindrić S;Aviram M;Kaiser T;Memari Y;Dzeja PP;Dworniczak B;Ueffing M;Roepman R;Bartscherer K;Katsanis N;Davis EE;Amirav I;Hamada H;Omran H
通讯作者：
Omran H