肢体异常的分子景观:诊断率和新的候选基因。

IF 2.3 3区 医学 Q2 GENETICS & HEREDITY
Akram Mokhtari, Jade Charbonneau, Valancy Miranda, Khadijé Jizi, Marie-Ange Delrue, Patricia Egerszegi, Isabelle Thiffault, Philippe M Campeau
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引用次数: 0

摘要

在高达65%的患者中,先天性肢体异常仍然没有病因学诊断。为了帮助缩小这一差距,我们描述了一个大队列的遗传诊断结果。从2014年到2024年,遗传咨询的主要指征是肢体异常的患者被纳入。提取、描述和比较人口统计学、调查和诊断信息。132例患者被纳入最终队列,平均分子诊断率为36%。最常见的情况是多指畸形(24%)和桡骨异常(19%)。50%的人有综合症特征。7例(5%)患者仅接受了染色体微阵列(CMA), 81例(63%)患者接受了CMA和基因面板,43例(32%)患者随后接受了外显子组测序。外显子组诊断11例(25%)。我们在已知的致病基因中发现了25个新的突变,包括TBX3(3例),并扩展了几个基因座的表型,包括BMP4和HNRNPH2。最后,我们确定了两个新的肢体异常候选位点:HOXA11和一个涉及HOXD10和HOXD12的2q31.1缺失位点,此前发表的其他小鼠研究表明它们在肢体发育中起作用。这代表了第二大已描述的肢体异常队列。外显子组全测序与文献和数据库检索小鼠数据相关联,为确定这组疾病的新病因提供了机会,包括我们确定的两个候选基因座。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Molecular Landscape in Limb Anomalies: Diagnostic Yield and New Candidate Genes.

Congenital limb anomalies remain without an etiological diagnosis in up to 65% of patients. To help close this gap, we describe the genetic diagnostic outcomes of a large cohort. Patients whose primary indication for genetic consultation was a limb anomaly were included from 2014 to 2024. Demographic, investigation, and diagnostic information were extracted, described, and compared. One hundred and thirty-two patients were included in the final cohort, with an average molecular diagnostic yield of 36%. The most common conditions were polydactyly (24%) and radial anomalies (19%). Fifty percent had syndromic features. Seven (5%) patients underwent chromosomal microarray (CMA) only, 81 (63%) CMA and a gene panel, and 43 (32%) subsequently underwent exome sequencing. Exome yielded a diagnosis in 11 (25%). We identified 25 novel mutations in known disease-causing genes, including TBX3 (3 cases) and expanded the phenotype of several loci, including BMP4 and HNRNPH2. Finally, we identified two new limb anomalies candidate loci, for which previously published mouse studies from other groups suggested roles in limb development: HOXA11 and a 2q31.1 deletion involving HOXD10 and HOXD12. This represents the second largest described limb anomalies cohort. Exome-wide sequencing associated with literature and database searches for mouse data represents an opportunity to identify novel etiologies in this group of disorders, including two candidate loci we identified.

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来源期刊
Clinical Genetics
Clinical Genetics 医学-遗传学
CiteScore
6.50
自引率
0.00%
发文量
175
审稿时长
3-8 weeks
期刊介绍: Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice. Topics of particular interest are: • Linking genetic variations to disease • Genome rearrangements and disease • Epigenetics and disease • The translation of genotype to phenotype • Genetics of complex disease • Management/intervention of genetic diseases • Novel therapies for genetic diseases • Developmental biology, as it relates to clinical genetics • Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease
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