Array analysis and karyotyping: Workflow consequences based on a retrospective study of 36,325 patients with idiopathic developmental delay in the Netherlands
Array analysis and karyotyping: Workflow consequences based on a retrospective study of 36,325 patients with idiopathic developmental delay in the Netherlands
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DOI：
10.1016/j.ejmg.2009.03.015
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发表时间：
2009-07-01
影响因子：
1.9
通讯作者：
Poot, Martin
中科院分区：
文献类型：
--
作者：
Hochstenbach, Ron;van Binsbergen, Ellen;Poot, Martin
染色体数目和结构异常被认为是原因不明、非综合征性发育迟缓和智力低下（DD/MR）的最常见原因。高分辨率，全基因组，基于阵列的节段性异染色体分析已成为检测致病基因组失衡的高灵敏度技术。对DD/MR患者的29项基于阵列的研究进行的综述表明，如果将30-70 kb中位探针间距的阵列平台用作初始基因检测方法，则在连续的DD/MR转诊中，可获得至少类似于19%致病性畸变的产量。这大约相当于经典细胞遗传学速率的两倍。这就提出了一个问题，是否染色体显带研究，结合有针对性的方法，如荧光原位杂交检测微缺失，仍然持有实质性的相关性，这些患者的临床研究。为了解决这个问题，我们回顾了1996年至2005年期间，在基于阵列的基因组调查出现之前，在荷兰所有36，325例DD/MR转诊的细胞遗传学研究结果。我们估计，在所有转诊的至少0.78%的平衡染色体重排将仍然未被检测到的阵列为基础的调查。这些包括家族性重排（占所有转诊的0.48%）、从头相互易位和倒位（占所有转诊的0.23%）、从头罗伯逊易位（占所有转诊的0.04%）和69，XXX三倍体（占所有转诊的0.03%）。我们的结论是，在最初的基于阵列的调查之后，核型分析仅会使致病性异常的数量有限地增加，即，具有从头的、明显平衡的、相互易位或倒位的所有转诊的0.23%（假设所有这些都是致病性的），以及具有69，XXX三倍体的所有转诊的0.03%。我们建议，由于其高诊断率，基于高分辨率阵列的基因组研究应该是DD/MR病例中进行的第一项研究，检测>99%的所有致病性异常。当实验室面临需要限制每个患者可用的基因检测数量时，执行阵列调查和核型分析可能不是一个可行的选择。然而，通过基于阵列的调查取代核型分析的实验室应该意识到，如这里所示，染色体异常可能对患者或家庭造成致病后果，在所有DD/MR转诊中约有0.78%会逃脱检测。(C)2009年Elsevier Masson SAS。All rights reserved.
Anomalies of chromosome number and structure are considered to be the most frequent cause of unexplained, non-syndromic developmental delay and mental retardation (DD/MR). High-resolution, genome-wide, array-based segmental aneusomy profiling has emerged as a highly sensitive technique for detecting pathogenic genomic imbalances. A review of 29 array-based studies of DD/MR patients showed that a yield of at least similar to 19% pathogenic aberrations is attainable in unselected, consecutive DD/MR referrals if array platforms with 30-70 kb median probe spacing are used as an initial genetic testing method. This corresponds to roughly twice the rate of classical cytogenetics. This raises the question whether chromosome banding studies, combined with targeted approaches, such as fluorescence in situ hybridisation for the detection of microdeletions, still hold substantial relevance for the clinical investigation of these patients. To address this question, we reviewed the outcome of cytogenetic studies in all 36,325 DD/MR referrals in the Netherlands during the period 1996-2005, a period before the advent of array-based genome investigation. We estimate that in a minimum of 0.78% of all referrals a balanced chromosomal rearrangement would have remained undetected by array-based investigation. These include familial rearrangements (0.48% of all referrals), de novo reciprocal translocations and inversions (0.23% of all referrals), de novo Robertsonian translocations (0.04% of all referrals), and 69,XXX triploidy (0.03% of all referrals). We conclude that karyotyping, following an initial array-based investigation, would give only a limited increase in the number of pathogenic abnormalities, i.e. 0.23% of all referrals with a de novo, apparently balanced, reciprocal translocation or inversion (assuming that all of these are pathogenic), and 0.03% of all referrals with 69,XXX triploidy. We propose that, because of its high diagnostic yield, high-resolution array-based genome investigation should be the first investigation performed in cases of DD/MR, detecting >99% of all pathogenic abnormalities. Performing both array investigation and karyotyping may not be a feasible option when laboratories are faced with a need to limit the number of genetic tests available for each patient. However, laboratories that supplant karyotyping by array-based investigation should be aware that, as shown here, a chromosomal abnormality, with possible pathogenic consequences for the patient or the family, will escape detection in about 0.78% of all DD/MR referrals. (C) 2009 Elsevier Masson SAS. All rights reserved.