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首页> 外文期刊>BMC Medical Genetics >Novel ANKRD11 gene mutation in an individual with a mild phenotype of KBG syndrome associated to a GEFS+ phenotypic spectrum: a case report
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Novel ANKRD11 gene mutation in an individual with a mild phenotype of KBG syndrome associated to a GEFS+ phenotypic spectrum: a case report

机译：伴有GEFS +表型谱的KBG综合征轻型表型患者的新型ANKRD11基因突变：病例报告

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KBG syndrome is a very rare autosomal dominant disorder, characterized by macrodontia, distinctive craniofacial findings, skeletal findings, post-natal short stature, and developmental delays, sometimes associated with seizures and EEG abnormalities. So far, there have been over 100 cases of KBG syndrome reported. Here, we describe two sisters of a non-consanguineous family, both presenting generalized epilepsy with febrile seizures (GEFS+), and one with a more complex phenotype associated with mild intellectual disability, skeletal and dental anomalies. Whole exome sequencing (WES) analysis in all the family members revealed a heterozygous SCN9A mutation, p.(Lys655Arg), shared among the father and the two probands, and a novel de novo loss of function mutation in the ANKRD11 gene, p.(Tyr1715*), in the proband with the more complex phenotype. The reassessment of the phenotypic features confirmed that the patient fulfilled the proposed diagnostic criteria for KBG syndrome, although complicated by early-onset isolated febrile seizures. EEG abnormalities with or without seizures have been reported previously in some KBG cases. The shared variant, occurring in SCN9A, has been previously found in several individuals with GEFS+ and Dravet syndrome. This report describe a novel de novo variant in ANKRD11 causing a mild phenotype of KGB syndrome and further supports the association of monogenic pattern of SCN9A mutations with GEFS+. Our data expand the allelic spectrum of ANKRD11 mutations, providing the first Brazilian case of KBG syndrome. Furthermore, this study offers an example of how WES has been instrumental allowing us to better dissect the clinical phenotype under study, which is a multilocus variation aggregating in one proband, rather than a phenotypic expansion associated with a single genomic locus, underscoring the role of multiple rare variants at different loci in the etiology of clinical phenotypes making problematic the diagnostic path. The successful identification of the causal variant in a gene may not be sufficient, making it necessary to identify other variants that fully explain the clinical picture. The prevalence of blended phenotypes from multiple monogenic disorders is currently unknown and will require a systematic re-analysis of large WES datasets for proper diagnosis in daily practice.
机译：KBG综合征是一种非常罕见的常染色体显性遗传疾病，其特征是大牙畸形，独特的颅面发现，骨骼发现，产后矮小和发育迟缓，有时与癫痫发作和脑电图异常有关。迄今为止，已有超过100例KBG综合征报告。在这里，我们描述了一个非近亲家庭的两个姐妹，均表现为全身性癫痫伴高热惊厥（GEFS +），其中一个具有较复杂的表型，与轻度智力障碍，骨骼和牙齿异常有关。所有家庭成员的全外显子组测序（WES）分析显示，父亲和两个先证者共有一个杂合的SCN9A突变p。（Lys655Arg），以及ANKRD11基因一个新的从头丧失功能突变。 Tyr1715 *），具有更复杂的表型。对表型特征的重新评估证实，该患者符合KBG综合征的建议诊断标准，尽管并伴有早期发作的孤立性高热惊厥。先前在某些KBG病例中曾报告有或没有癫痫发作的脑电图异常。 SCN9A中发生的共享变体先前已在几位患有GEFS +和Dravet综合征的个体中发现。该报告描述了ANKRD11中的一种新的从头变异，该变异导致了KGB综合征的轻度表型，并进一步支持SCN9A突变的单基因模式与GEFS +的关联。我们的数据扩展了ANKRD11突变的等位基因谱，提供了巴西首例KBG综合征。此外，本研究提供了一个实例，说明WES如何发挥作用，使我们能够更好地剖析所研究的临床表型，这是一个先证者聚集的多基因座变异，而不是与单个基因组基因座相关的表型扩展，强调了WES的作用。临床表型的病因在不同位点存在多个罕见变体，使诊断路径出现问题。成功鉴定基因中的因果变体可能还不够，因此有必要鉴定出能够完全解释临床情况的其他变体。目前尚不清楚来自多种单基因疾病的混合表型的患病率，将需要对大型WES数据集进行系统的重新分析，以便在日常实践中进行正确的诊断。

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