Pinto Anna Maria, Bianciardi Laura, Mencarelli Maria Antonietta, Imperatore Valentina, Di Marco Chiara, Furini Simone, Suppiej Agnese, Salviati Leonardo, Tenconi Romano, Ariani Francesca, Mari Francesca, Renieri Alessandra
Medical Genetics, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
Medical Genetics, University of Siena, Siena, Italy.
Brain Dev. 2016 Jun;38(6):590-6. doi: 10.1016/j.braindev.2015.12.006. Epub 2016 Jan 2.
Neurodevelopmental disorders include a broad spectrum of conditions, which are characterized by delayed motor and/or cognitive milestones and by a variable range of intellectual disability with or without an autistic behavior. Several genetic factors have been implicated in intellectual disability onset and exome sequencing studies have recently identified new inherited or de novo mutations in patients with neurodevelopmental disorders.
We report the case of two monozygotic twins who came for the first time to our attention at the age of 20months for a global neurodevelopmental delay associated with an autism spectrum disorder, hypotonia, postnatal microcephaly, stereotypic movements and circadian rhythm alterations in association with late-onset epilepsy. MECP2 sequence was normal. A CGH-array analysis revealed in both twins two maternally inherited duplications on chromosomes 8p22 and 16p13.11. The latter has been previously associated with neurodevelopmental disorders. We performed an exome sequencing analysis on one twin and her parents and identified a CHD2 mutation, previously described in association with a phenotypic spectrum overlapping our patients' phenotype.
This work underlines the importance to consider a CHD2 involvement in children with intellectual disability and autism spectrum disorder even in the absence of epilepsy at an early age. It also highlights the necessity to re-evaluate inherited copy number variants with low penetrance and/or high phenotypic variability because an underlying de novo molecular event can be the major cause of the phenotype. This is essential in order to reach a correct diagnosis and provide the couple with a proper recurrence risk.
神经发育障碍包括一系列广泛的病症，其特征为运动和/或认知发育里程碑延迟，伴有不同程度的智力残疾，有或没有自闭症行为。多种遗传因素与智力残疾的发病有关，外显子组测序研究最近在神经发育障碍患者中发现了新的遗传或新生突变。
我们报告了一对同卵双胞胎的病例，他们在20个月大时首次引起我们的注意，患有与自闭症谱系障碍相关的全面神经发育迟缓、肌张力减退、出生后小头畸形、刻板动作和昼夜节律改变，并伴有迟发性癫痫。MECP2序列正常。比较基因组杂交芯片分析显示，这对双胞胎在染色体8p22和16p13.11上均有两个母系遗传的重复。后者此前已与神经发育障碍相关。我们对其中一名双胞胎及其父母进行了外显子组测序分析，发现了一个CHD2突变，此前曾报道该突变与一系列与我们患者表型重叠的表型相关。
这项工作强调了即使在儿童早期没有癫痫的情况下，也应考虑CHD2参与智力残疾和自闭症谱系障碍患儿的发病。它还强调了重新评估低 penetrance 和/或高表型变异性的遗传拷贝数变异的必要性，因为潜在的新生分子事件可能是表型的主要原因。这对于做出正确诊断并为夫妇提供适当的复发风险至关重要。
