TGFBR2 deletion in a 20-month-old female with developmental delay and microcephaly.
TGFBR2 deletion in a 20-month-old female with developmental delay and microcephaly.
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DOI：
10.1002/ajmg.a.34015
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发表时间：
2011-06
影响因子：
2
通讯作者：
Stankiewicz, Pawel
中科院分区：
文献类型：
--
作者：
Campbell, Ian M.;Kolodziejska, Katarzyna E.;Quach, Michael M.;Wolf, Varina Louise;Cheung, Sau Wai;Lalani, Seema R.;Ramocki, Melissa B.;Stankiewicz, Pawel
到目前为止，在洛伊斯 - 迪茨综合征（LDS）、2型马凡综合征（MFS2）或其他遗传性胸主动脉瘤和夹层患者中，已报道TGFBR2基因有70多种突变。尽管到目前为止分析的几乎所有突变都预计会破坏TGFBR2具有组成性活性的C末端丝氨酸/苏氨酸激酶结构域，但越来越多的证据表明，这些疾病的分子机制比单纯的单倍体不足更为复杂。利用外显子靶向寡核苷酸阵列比较基因组杂交技术，我们在一名20个月大的患有小头畸形和全面发育迟缓但无LDS特征的女性中鉴定出TGFBR2约896kb的缺失。荧光原位杂交（FISH）分析显示，在父母的外周血样本中没有这种缺失的证据；然而，通过聚合酶链反应（PCR）在外周血淋巴细胞和淋巴母细胞的父亲DNA中检测到体细胞嵌合现象。我们的数据表明，TGFBR2单倍体不足可能导致一种不同于LDS的表型。此外，我们提出，在患有基因组疾病的儿童无症状的父母中，低于FISH分析检测阈值的体细胞嵌合现象可能比以前所认识到的更为常见。
To date, over 70 mutations in the TGFBR2 gene have been reported in patients with Loeys–Dietz syndrome (LDS), Marfan syndrome type 2 (MFS2), or other hereditary thoracic aortic aneurysms and dissections. Whereas almost all of mutations analyzed thus far are predicted to disrupt the constitutively active C-terminal serine/threonine kinase domain of TGFBR2, mounting evidence suggests that the molecular mechanism underlying these diseases is more complex than simple haploinsufficiency. Using exon-targeted oligonucleotide array comparative genomic hybridization, we identified an ~896 kb deletion of TGFBR2 in a 20-month-old female with microcephaly and global developmental delay, but no stigmata of LDS. FISH analysis showed no evidence of this deletion in the parental peripheral blood samples; however, somatic mosaicism was detected using PCR in the paternal DNA from peripheral blood lymphocytes and lymphoblasts. Our data suggest that TGFBR2 haploinsufficiency may cause a phenotype, which is distinct from LDS. Moreover, we propose that somatic mosaicism below the detection threshold of FISH analysis in asymptomatic parents of children with genomic disorders may be more common than previously recognized.
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