Next generation sequencing in a large cohort of patients presenting with neuromuscular disease before or at birth.
Next generation sequencing in a large cohort of patients presenting with neuromuscular disease before or at birth.
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DOI：
10.1186/s13023-015-0364-0
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发表时间：
2015-11-17
影响因子：
3.7
通讯作者：
Ravenscroft G
中科院分区：
文献类型：
--
作者：
Todd EJ;Yau KS;Ong R;Slee J;McGillivray G;Barnett CP;Haliloglu G;Talim B;Akcoren Z;Kariminejad A;Cairns A;Clarke NF;Freckmann ML;Romero NB;Williams D;Sewry CA;Colley A;Ryan MM;Kiraly-Borri C;Sivadorai P;Allcock RJ;Beeson D;Maxwell S;Davis MR;Laing NG;Ravenscroft G
胎儿运动不能/运动减退、关节弯曲和严重先天性肌病是通常在出生前或出生时出现的异质性疾病。虽然已经为这些疾病组中的每一个确定了许多致病基因，但在许多情况下，特定的基因诊断仍然难以捉摸。由于下一代测序的出现，现在几乎可以通过“整个”外显子组测序来分析个体DNA的整个编码区，从而能够研究几乎所有已知和新的疾病基因。对来自38个不相关家族的45名患有胎儿运动不能/运动减退、关节弯曲或严重先天性肌病的患者的基因组DNA样品进行下一代测序。每例患者的临床特征和诊断由转诊临床医生提供。基因组DNA用于全外显子组测序或定制设计的神经肌肉亚外显子组超捕获阵列，该阵列包含负责各种神经肌肉疾病的277个基因。使用桑格测序研究并确认候选致病变体。本队列研究中的一些病例先前已作为单独研究发表。在38个家庭中，有18个家庭获得了决定性的遗传诊断。在该队列中，在8个先前已知的神经肌肉疾病基因（CHRND、CHNRG、ECEL 1、GBE 1、MTM 1、MYH 3、NEB和RYR 1）中发现了突变，并鉴定了4个新的神经肌肉疾病基因，并已作为单独的报告发表（GPR 126、KLHL 40、KLHL 41和SPEG）。此外，在CHRND、KLHL 40、NEB和RYR 1中鉴定了新的突变。观察到常染色体显性、常染色体隐性、X连锁和从头遗传模式。通过对38个患有胎儿运动不能/运动功能减退、关节弯曲或严重先天性肌病的无亲缘关系家庭进行下一代测序，我们获得了47%家庭的基因诊断。这项研究强调了下一代测序的力量和能力：（i）确定遗传异质性神经肌肉疾病的病因，（ii）在小家系或孤立病例中识别新的疾病基因，（iii）完善遗传诊断与临床评估和管理之间的相互作用。本文的在线版本（doi：10.1186/s13023-015-0364-0）包含补充材料，可供授权用户使用。
Fetal akinesia/hypokinesia, arthrogryposis and severe congenital myopathies are heterogeneous conditions usually presenting before or at birth. Although numerous causative genes have been identified for each of these disease groups, in many cases a specific genetic diagnosis remains elusive. Due to the emergence of next generation sequencing, virtually the entire coding region of an individual’s DNA can now be analysed through “whole” exome sequencing, enabling almost all known and novel disease genes to be investigated for disorders such as these. Genomic DNA samples from 45 patients with fetal akinesia/hypokinesia, arthrogryposis or severe congenital myopathies from 38 unrelated families were subjected to next generation sequencing. Clinical features and diagnoses for each patient were supplied by referring clinicians. Genomic DNA was used for either whole exome sequencing or a custom-designed neuromuscular sub-exomic supercapture array containing 277 genes responsible for various neuromuscular diseases. Candidate disease-causing variants were investigated and confirmed using Sanger sequencing. Some of the cases within this cohort study have been published previously as separate studies. A conclusive genetic diagnosis was achieved for 18 of the 38 families. Within this cohort, mutations were found in eight previously known neuromuscular disease genes (CHRND, CHNRG, ECEL1, GBE1, MTM1, MYH3, NEB and RYR1) and four novel neuromuscular disease genes were identified and have been published as separate reports (GPR126, KLHL40, KLHL41 and SPEG). In addition, novel mutations were identified in CHRND, KLHL40, NEB and RYR1. Autosomal dominant, autosomal recessive, X-linked, and de novo modes of inheritance were observed. By using next generation sequencing on a cohort of 38 unrelated families with fetal akinesia/hypokinesia, arthrogryposis, or severe congenital myopathy we therefore obtained a genetic diagnosis for 47 % of families. This study highlights the power and capacity of next generation sequencing (i) to determine the aetiology of genetically heterogeneous neuromuscular diseases, (ii) to identify novel disease genes in small pedigrees or isolated cases and (iii) to refine the interplay between genetic diagnosis and clinical evaluation and management. The online version of this article (doi:10.1186/s13023-015-0364-0) contains supplementary material, which is available to authorized users.