Hospices Civils de Lyon, Hôpital Edouard Herriot, Service d'Hématologie Biologique, Lyon, France.
EAM 4174 Hémostase, Inflammation et Sepsis, Université Claude Bernard Lyon 1, Lyon, France.
J Thromb Haemost. 2016 Oct;14(10):1988-1993. doi: 10.1111/jth.13430. Epub 2016 Sep 17.
Essentials Some hemophilia B (HB) patients with complete F9 deletion present with intellectual disability (ID). We delineate six F9 complete deletions and investigate genotype/phenotype correlation. We identify SOX3 as a candidate gene for ID, acting through haploinsufficiency, in HB patients. All complete F9 deletions in ID patients should be explored with cytogenetic microarrays.
Background Large deletions encompassing both the complete F9 gene and contiguous genes have been detected in patients with severe hemophilia B (HB). Some of these patients present other clinical features, such as intellectual disability (ID). Objectives/Methods In this study, we characterized six unrelated large deletions encompassing F9, by cytogenetic microarray analysis (CMA), to investigate genotype/phenotype correlation. Results Five of the six patients included in this study presented with ID associated with HB. CMA showed that the six large deletions, ranging in size from approximately 933 kb to 9.19 Mb, were located within the Xq26.3 to Xq28 bands. In all cases, the complete deletion of F9 was associated with the loss of various neighboring genes (5-28 other genes). The smallest region of overlap for ID was a 1.26-Mb region encompassing seven OMIM genes (LOC389895, SOX3, LINC00632, CDR1, SPANXF1, LDOC1, SPANXC). SOX3, our candidate gene for ID, encodes an early transcription factor involved in pituitary development. All of the patients studied who had both HB and ID had deletion of the SOX3 gene. Conclusions All HB patients with an atypical phenotype, especially if complete deletion of F9 is suspected, should be referred to a geneticist for possible pangenomic assessment, because haploinsufficiency of genes flanking F9, such as SOX3 in particular, may result in a broader phenotype, including ID. Such assessment would be of particular value for the genetic counseling of female carriers with F9 deletions, as it would facilitate analysis of the risk of transmitting HB associated with ID.
目的/方法：在这项研究中，我们通过细胞遗传学微阵列分析 (CMA) 对 6 个不相关的包含 F9 的大片段缺失进行了表征，以研究基因型/表型相关性。结果：本研究纳入的 6 例患者中，有 5 例存在与 HB 相关的 ID。CMA 显示，这 6 个大片段缺失的大小从大约 933 kb 到 9.19 Mb，位于 Xq26.3 到 Xq28 带。在所有情况下，F9 的完全缺失都伴有各种邻近基因的缺失（5-28 个其他基因）。ID 的最小重叠区域是一个包含 7 个 OMIM 基因（LOC389895、SOX3、LINC00632、CDR1、SPANXF1、LDOC1、SPANXC）的 1.26 Mb 区域。SOX3 是我们 ID 的候选基因，它编码一种参与垂体发育的早期转录因子。所有研究的同时患有 HB 和 ID 的患者均缺失 SOX3 基因。结论：所有具有非典型表型的 HB 患者，尤其是如果怀疑 F9 完全缺失，都应转介给遗传学家进行可能的全基因组评估，因为 F9 侧翼基因的杂合性缺失，特别是 SOX3，可能导致更广泛的表型，包括 ID。对于携带 F9 缺失的女性携带者的遗传咨询，这种评估将特别有价值，因为它将有助于分析与 ID 相关的 HB 传播风险。
