Exome sequencing identifies a novel homozygous variant in NDRG4 in a family with infantile myofibromatosis
Exome sequencing identifies a novel homozygous variant in NDRG4 in a family with infantile myofibromatosis
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DOI：
10.1016/j.ejmg.2014.08.010
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发表时间：
2014-11-01
影响因子：
1.9
通讯作者：
Pena, Sergio D. J.
中科院分区：
文献类型：
--
作者：
Linhares, Natalia D.;Freire, Maira C. M.;Pena, Sergio D. J.
婴儿肌纤维瘤病（IM）是一种罕见的疾病，其特点是在皮肤，肌肉，骨骼和内脏的良性肿瘤的发展。发病率为1/15万活产，该疾病是婴儿纤维性肿瘤的最常见原因。没有内脏受累的病例通常有一个更良性的过程，通常是肿瘤的自发消退。另一方面，当累及重要器官时，预后往往是不利的，这可能导致显著的死亡率。鉴定可能导致IM的罕见基因变异是实现靶向治疗可能性的第一步；然而，IM的分子发病机制尚不清楚。在本研究中，我们报告了诊断为内脏多中心婴儿肌纤维瘤病的两个兄弟及其健康的近亲父母的外显子组序列分析结果。在两兄弟中，我们发现了NDRG4基因（N-myc下调基因家族成员4）和RLTPR基因（RGD基序，富含亮氨酸重复序列，原调节蛋白结构域和富含脯氨酸）的新纯合变异。健康父母对这两种变异都是杂合的。与IM表型一致，NDRG4是肿瘤相关基因；它的表达在许多肿瘤类型中都有所下降，这表明它可能是一种肿瘤抑制基因。此外，研究表明NDRG4可能在细胞存活和肿瘤侵袭中发挥作用。因此，我们认为NDRG4的这种纯合变异可能是研究家族中常染色体隐性形式的IM的致病变异，并且应该在其他常染色体隐性婴儿肌纤维瘤病病例中进行调查。(C) 2014 Elsevier Masson SAS。版权所有。
Infantile myofibromatosis (IM) is a rare disorder characterized by the development of benign tumors in the skin, muscle, bone, and viscera. The incidence is 1/150,000 live births and the disease is the most common cause of fibrous tumors in infancy. Cases which lack visceral involvement generally have a more benign course, usually with spontaneous regression of the tumors. On the other hand, the prognosis tends to be unfavorable when there is involvement of vital organs, which can lead to significant mortality.The identification of rare variants in genes that may cause IM is the first step towards the possibility of targeted treatments; however, the molecular pathogenesis of IM is poorly understood. In the present study, we report the results of exome sequence analysis of two brothers diagnosed with visceral multicentric infantile myofibromatosis, and their healthy consanguineous parents. In the two brothers we identified novel homozygous variants in NDRG4 gene (N-myc downregulated gene family member 4) and in RLTPR gene (RGD motif, leucine rich repeats, tropomodulin domain and proline-rich containing). The healthy parents were heterozygous for both variants. Consistent with the phenotype of IM, NDRG4 is a tumor-related gene; its expression has been shown to be decreased in numerous tumor types, suggesting that it might be a tumor suppressor gene. Additionally, studies have demonstrated that NDRG4 may have a role in cell survival and tumor invasion. We thus propose that this homozygous variant in NDRG4 may be the causative variant of the autosomal recessive form of IM in the studied family and that it should be investigated in other cases of autosomal recessive infantile myofibromatosis. (C) 2014 Elsevier Masson SAS. All rights reserved.