PDF(Pubmed)
Abstract：
The 15q11.2 BP1-BP2 deletion (Burnside-Butler) syndrome is emerging as the most common cytogenetic finding in patients with neurodevelopmental or autism spectrum disorders (ASD) presenting for microarray genetic testing. Clinical findings in Burnside-Butler syndrome include developmental and motor delays, congenital abnormalities, learning and behavioral problems, and abnormal brain findings. To better define symptom presentation, we performed comprehensive cognitive and behavioral testing, collected medical and family histories, and conducted clinical genetic evaluations. The 15q11.2 BP1-BP2 region includes the TUBGCP5, CYFIP1, NIPA1, and NIPA2 genes. To determine if additional genomic variation outside of the 15q11.2 region influences expression of symptoms in Burnside-Butler syndrome, whole-exome sequencing was performed on the parents and affected children for the first time in five families with at least one parent and child with the 15q1l.2 BP1-BP2 deletion. In total, there were 453 genes with possibly damaging variants identified across all of the affected children. Of these, 99 genes had exclusively de novo variants and 107 had variants inherited exclusively from the parent without the deletion. There were three genes (APBB1, GOLGA2, and MEOX1) with de novo variants that encode proteins evidenced to interact with CYFIP1. In addition, one other gene of interest (FAT3) had variants inherited from the parent without the deletion and encoded a protein interacting with CYFIP1. The affected individuals commonly displayed a neurodevelopmental phenotype including ASD, speech delay, abnormal reflexes, and coordination issues along with craniofacial findings and orthopedic-related connective tissue problems. Of the 453 genes with variants, 35 were associated with ASD. On average, each affected child had variants in 6 distinct ASD-associated genes (x¯ = 6.33, sd = 3.01). In addition, 32 genes with variants were included on clinical testing panels from Clinical Laboratory Improvement Amendments (CLIA) approved and accredited commercial laboratories reflecting other observed phenotypes. Notably, the dataset analyzed in this study was small and reported results will require validation in larger samples as well as functional follow-up. Regardless, we anticipate that results from our study will inform future research into the genetic factors influencing diverse symptoms in patients with Burnside-Butler syndrome, an emerging disorder with a neurodevelopmental behavioral phenotype.
摘要：
15q11.2BP1-BP2缺失（Burnside-Butler）综合征正在成为神经发育或自闭症谱系障碍（ASD）患者中最常见的细胞遗传学发现，用于微阵列遗传测试。伯恩赛德-巴特勒综合征的临床发现包括发育和运动迟缓，先天性异常,学习和行为问题，和异常的大脑发现。为了更好地定义症状表现，我们进行了全面的认知和行为测试，收集医疗和家族史，并进行了临床遗传评估。15q11.2BP1-BP2区域包括TUBGCP5、CYFIP1、NIPA1和NIPA2基因。为了确定15q11.2区域之外的其他基因组变异是否会影响Burnside-Butler综合征的症状表达，在至少有一个父母和孩子缺失15q1l.2BP1-BP2的5个家庭中,首次对父母和受影响儿童进行了全外显子组测序.总的来说,在所有受影响的儿童中，有453个基因具有可能的破坏性变异。其中,99个基因仅具有从头变异体，而107个基因仅具有从亲本遗传而没有缺失的变异体。有三个基因(APBB1、GOLGA2和MEOX1)具有从头变体,其编码被证明与CYFIP1相互作用的蛋白质。此外,另一个目的基因（FAT3）具有从亲本遗传而没有缺失的变体，并编码与CYFIP1相互作用的蛋白质。受影响的个体通常表现出神经发育表型，包括ASD，说话延迟,异常反射,和协调问题以及颅面发现和骨科相关的结缔组织问题。在453个有变异的基因中，35例与ASD相关。平均而言,每个受影响的儿童在6个不同的ASD相关基因中都有变异(xé=6.33,sd=3.01).此外,32个具有变体的基因被包括在来自临床实验室改进修正案(CLIA)批准和认可的商业实验室的反映其他观察到的表型的临床测试面板上。值得注意的是,本研究中分析的数据集很小,报告的结果需要在更大的样本中进行验证以及功能随访.无论如何,我们预计，我们的研究结果将为未来的研究提供信息，以了解影响Burnside-Butler综合征患者不同症状的遗传因素，一种具有神经发育行为表型的新兴疾病。
