Conclusion of diagnostic odysseys due to inversions disrupting GLI3 and FBN1.
Conclusion of diagnostic odysseys due to inversions disrupting GLI3 and FBN1.
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DOI：
10.1136/jmg-2022-108753
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发表时间：
2023-05
影响因子：
4
通讯作者：
中科院分区：
文献类型：
--
作者：
许多基因测试方法偏向于挑选改变拷贝数的结构变异（SV）。因此，诸如倒位之类的复制中性重排可能会受到不确定性的影响。在这项研究中，在虚拟多学科团队会议的推动下，对 100K 基因组计划的数据进行了人工审查，随后对 43 个与明确的骨骼疾病相关的基因进行了生物信息优先排序。来自三个独立家庭的十个人被发现患有诊断倒置。在两个家族中，1.2/14.8Mb 的倒置节段明确破坏了 GLI3，并与与 Greig 头多指并指综合征一致的骨骼特征分离。对于一个家族，表型混合是由于位于 HOXA13 约 45 kb 处的相反断点所致。在长期怀疑患有马凡综合征的第三个家庭中，发现了破坏 FBN1 的 2.0 Mb 倒位。这些发现解决了长达 9-20 年的漫长诊断过程，并强调了临床医生和数据分析师之间直接互动的重要性。这些罕见突变类别的范例为 NHS 基因组医学服务和类似基因组测序计划中未来的 SV 优先策略提供了信息。自从这两种疾病基因关联被发现以来的 30 多年来，大的倒位尚未被描述，因此我们的结果扩展了与这些疾病相关的突变谱。
Many genetic testing methodologies are biased towards picking up structural variants (SVs) that alter copy number. Copy-neutral rearrangements such as inversions are therefore likely to suffer from underascertainment. In this study, manual review prompted by a virtual multidisciplinary team meeting and subsequent bioinformatic prioritisation of data from the 100K Genomes Project was performed across 43 genes linked to well-characterised skeletal disorders. Ten individuals from three independent families were found to harbour diagnostic inversions. In two families, inverted segments of 1.2/14.8 Mb unequivocally disrupted GLI3 and segregated with skeletal features consistent with Greig cephalopolysyndactyly syndrome. For one family, phenotypic blending was due to the opposing breakpoint lying ~45 kb from HOXA13. In the third family, long suspected to have Marfan syndrome, a 2.0 Mb inversion disrupting FBN1 was identified. These findings resolved lengthy diagnostic odysseys of 9–20 years and highlight the importance of direct interaction between clinicians and data-analysts. These exemplars of a rare mutational class inform future SV prioritisation strategies within the NHS Genomic Medicine Service and similar genome sequencing initiatives. In over 30 years since these two disease-gene associations were identified, large inversions have yet to be described and so our results extend the mutational spectra linked to these conditions.
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影响因子：
5
作者：
Mannucci，Liliana;Luciano，Serena;Sangiuolo，Federica
通讯作者：
Sangiuolo，Federica
影响因子：
3.9
作者：
Johnston, Jennifer J.;Sapp, Julie C.;Turner, Joyce T.;Amor, David;Aftimos, Salim;Aleck, Kyrieckos A.;Bocian, Maureen;Bodurtha, Joann N.;Cox, Gerald F.;Curry, Cynthia J.;Day, Ruth;Donnai, Dian;Field, Michael;Fujiwara, Ikuma;Gabbett, Michael;Gal, Moran;Graham, John M., Jr.;Hedera, Peter;Hennekam, Raoul C. M.;Hersh, Joseph H.;Hopkin, Robert J.;Kayserili, Hulya;Kidd, Alexa M. J.;Kimonis, Virginia;Lin, Angela E.;Lynch, Sally Ann;Maisenbacher, Melissa;Mansour, Sahar;McGaughran, Julie;Mehta, Lakshmi;Murphy, Helen;Raygada, Margarita;Robin, Nathaniel H.;Rope, Alan F.;Rosenbaum, Kenneth N.;Schaefer, G. Bradley;Shealy, Amy;Smith, Wendy;Soller, Maria;Sommer, Annmarie;Stalker, Heather J.;Steiner, Bernhard;Stephan, Mark J.;Tilstra, David;Tomkins, Susan;Trapane, Pamela;Tsai, Anne Chun-Hui;Van Allen, Margot I.;Vasudevan, Pradeep C.;Zabel, Bernhard;Zunich, Janice;Black, Graeme C. M.;Biesecker, Leslie G.
通讯作者：
Biesecker, Leslie G.
DOI：
10.1038/s41436-021-01297-5
发表时间：
2021-12
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Hyder Z;Calpena E;Pei Y;Tooze RS;Brittain H;Twigg SRF;Cilliers D;Morton JEV;McCann E;Weber A;Wilson LC;Douglas AGL;McGowan R;Need A;Bond A;Tavares ALT;Thomas ERA;Genomics England Research Consortium;Hill SL;Deans ZC;Boardman-Pretty F;Caulfield M;Scott RH;Wilkie AOM
通讯作者：
Wilkie AOM
影响因子：
2
作者：
Mortier, Geert R.;Cohn, Daniel H.;Warman, Matthew L.
通讯作者：
Warman, Matthew L.
影响因子：
9.8
作者：
Mantere, Tuomo;Neveling, Kornelia;El Khattabi, Laila
通讯作者：
El Khattabi, Laila