Pajusalu Sander, Žilina Olga, Yakoreva Maria, Tammur Pille, Kuuse Kati, Mölter-Väär Triin, Nõukas Margit, Reimand Tiia, Õunap Katrin
Department of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia; Department of Biomedicine, Institute of Biomedicine and Translational Medicine, Tartu, Estonia.
Department of Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia; Institute of Molecular and Cell Biology, Tartu, Estonia.
Mol Syndromol. 2015 Sep;6(3):135-40. doi: 10.1159/000438776. Epub 2015 Aug 15.
We present data from our clinical department's experience with chromosomal microarray analysis (CMA) regarding the diagnostic utility of 1 or 2 long contiguous stretches of homozygosity (LCSHs) in an outbred population. The study group consisted of 2,110 consecutive patients from 2011 to 2014 for whom CMA was performed. The minimum cut-off size for defining a homozygous stretch was 5 Mb. To focus on cases with no parental consanguinity, we further studied only patients in whom the total length of homozygous stretches did not exceed 28 Mb or 1% of the autosomal genome length. We identified 6 chromosomal regions where homozygous stretches appeared in at least 3 patients and excluded these from further analysis. In 2 out of 120 patients with an isolated finding of 1 or 2 non-recurrent LCSHs, a plausible candidate gene associated with their phenotype was identified within the homozygous stretch. In both of these cases, a pathogenic mutation was detected, leading to diagnoses of pyruvate kinase deficiency and Marinesco-Sjögren syndrome. To clarify whether previously found homozygous stretches could be important for the interpretation of genome-wide sequencing data, we report 7 cases in which homozygous stretches not encompassing a clinically associated gene were first found on CMA, followed by the diagnostic whole-exome sequencing. The diagnostic utility of single LCSHs, unlikely to be caused by uniparental disomy, is discussed in detail.
我们展示了来自我们临床科室对染色体微阵列分析（CMA）的经验数据，内容涉及在一个非近亲繁殖人群中1个或2个长的连续纯合片段（LCSHs）的诊断效用。研究组包括2011年至2014年连续接受CMA检测的2110例患者。定义纯合片段的最小截断大小为5 Mb。为了聚焦于无父母近亲关系的病例，我们进一步仅研究纯合片段总长度不超过28 Mb或常染色体基因组长度1%的患者。我们确定了6个染色体区域，其中纯合片段在至少3例患者中出现，并将这些区域排除在进一步分析之外。在120例仅发现1个或2个非复发性LCSHs的患者中，有2例在纯合片段内鉴定出与其表型相关的一个合理候选基因。在这两个病例中，均检测到致病突变，从而诊断为丙酮酸激酶缺乏症和马里内斯科 - 舍格伦综合征。为了阐明先前发现的纯合片段对全基因组测序数据的解释是否重要，我们报告了7例病例，这些病例中首先在CMA上发现不包含临床相关基因的纯合片段，随后进行了诊断性全外显子测序。我们详细讨论了不太可能由单亲二体导致的单个LCSHs的诊断效用。
