Uncovering the burden of hidden ciliopathies in the 100 000 Genomes Project: a reverse phenotyping approach.
Uncovering the burden of hidden ciliopathies in the 100 000 Genomes Project: a reverse phenotyping approach.
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DOI：
10.1136/jmedgenet-2022-108476
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发表时间：
2022-12
影响因子：
4
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中科院分区：
文献类型：
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十万基因组计划（100K）在 2016 年至 2018 年间招募了患有符合条件的罕见疾病和癌症的国家卫生服务患者。根据招募临床医生输入的人类表型本体论（HPO）术语，PanelApp 虚拟基因面板应用于全基因组测序数据，以指导重点分析。我们开发了一种反向表型分析策略，以识别 10 万名参与者，其中九个优先疾病基因（BBS1、BBS10、ALMS1、OFD1、DYNC2H1、WDR34、NPHP1、TMEM67、CEP290）具有致病性变异，代表多系统原发性纤毛病的完整表型谱。我们将基因型数据“向后”映射到可用的临床数据上，以评估与表型的潜在匹配。向招募的临床医生报告具有新的分子诊断和与已确定的疾病基因相符的关键临床特征的参与者。我们鉴定了 62 种可报告的分子诊断，其中包含这 9 种纤毛病基因的变异。 100K 已报告 44 例，5 例之前未报告，13 例为新诊断。我们确定了 11 名具有未报告的新型分子诊断的参与者，他们缺乏关键的临床特征来证明向招募的临床医生报告的合理性。两名参与者可能具有致病性结构变异，一名参与者具有深层内含子预测剪接变异。标准 100K 诊断管道不会优先审查这些变体。反向表型分析提高了 10 万名未解决的原发性纤毛病参与者的分子诊断成功率。之前的分析可能错过了这些诊断，因为 HPO 术语输入不完整导致基因组选择不正确，这意味着致病性变异没有被优先考虑。因此，更好的表型数据对于准确的变异解释和改善患者利益至关重要。
The 100 000 Genomes Project (100K) recruited National Health Service patients with eligible rare diseases and cancer between 2016 and 2018. PanelApp virtual gene panels were applied to whole genome sequencing data according to Human Phenotyping Ontology (HPO) terms entered by recruiting clinicians to guide focused analysis. We developed a reverse phenotyping strategy to identify 100K participants with pathogenic variants in nine prioritised disease genes (BBS1, BBS10, ALMS1, OFD1, DYNC2H1, WDR34, NPHP1, TMEM67, CEP290), representative of the full phenotypic spectrum of multisystemic primary ciliopathies. We mapped genotype data ‘backwards’ onto available clinical data to assess potential matches against phenotypes. Participants with novel molecular diagnoses and key clinical features compatible with the identified disease gene were reported to recruiting clinicians. We identified 62 reportable molecular diagnoses with variants in these nine ciliopathy genes. Forty-four have been reported by 100K, 5 were previously unreported and 13 are new diagnoses. We identified 11 participants with unreportable, novel molecular diagnoses, who lacked key clinical features to justify reporting to recruiting clinicians. Two participants had likely pathogenic structural variants and one a deep intronic predicted splice variant. These variants would not be prioritised for review by standard 100K diagnostic pipelines. Reverse phenotyping improves the rate of successful molecular diagnosis for unsolved 100K participants with primary ciliopathies. Previous analyses likely missed these diagnoses because incomplete HPO term entry led to incorrect gene panel choice, meaning that pathogenic variants were not prioritised. Better phenotyping data are therefore essential for accurate variant interpretation and improved patient benefit.
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DOI：
10.1016/j.omtn.2018.07.010
发表时间：
2018-09-07
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
Dulla K;Aguila M;Lane A;Jovanovic K;Parfitt DA;Schulkens I;Chan HL;Schmidt I;Beumer W;Vorthoren L;Collin RWJ;Garanto A;Duijkers L;Brugulat-Panes A;Semo M;Vugler AA;Biasutto P;Adamson P;Cheetham ME
通讯作者：
Cheetham ME
影响因子：
2.6
作者：
Hartill V;Szymanska K;Sharif SM;Wheway G;Johnson CA
通讯作者：
Johnson CA
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：
4
作者：
通讯作者：
--
影响因子：
5.6
作者：
Duijkers L;van den Born LI;Neidhardt J;Bax NM;Pierrache LHM;Klevering BJ;Collin RWJ;Garanto A
通讯作者：
Garanto A