Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, Texas 77030, USA;
J Med Genet. 2010 May;47(5):332-41. doi: 10.1136/jmg.2009.073015. Epub 2009 Nov 12.
Deletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay.
We indentified 27 deletions and 18 duplications of 16p11.2 were identified in 0.6% of all samples submitted for clinical array-CGH (comparative genomic hybridisation) analysis. Detailed molecular and phenotypic characterisations were performed on 17 deletion subjects and ten subjects with the duplication.
The most common clinical manifestations in 17 deletion and 10 duplication subjects were speech/language delay and cognitive impairment. Other phenotypes in the deletion patients included motor delay (50%), seizures ( approximately 40%), behavioural problems ( approximately 40%), congenital anomalies ( approximately 30%), and autism ( approximately 20%). The phenotypes among duplication patients included motor delay (6/10), behavioural problems (especially attention deficit hyperactivity disorder (ADHD)) (6/10), congenital anomalies (5/10), and seizures (3/10). Patients with the 16p11.2 deletion had statistically significant macrocephaly (p<0.0017) and 6 of the 10 patients with the duplication had microcephaly. One subject with the deletion was asymptomatic and another with the duplication had a normal cognitive and behavioural phenotype. Genomic analyses revealed additional complexity to the 16p11.2 region with mechanistic implications. The chromosomal rearrangement was de novo in all but 2 of the 10 deletion cases in which parental studies were available. Additionally, 2 de novo cases were apparently mosaic for the deletion in the analysed blood sample. Three de novo and 2 inherited cases were observed in the 5 of 10 duplication patients where data were available.
Recurrent reciprocal 16p11.2 deletion and duplication are characterised by a spectrum of primarily neurocognitive phenotypes that are subject to incomplete penetrance and variable expressivity. The autism and macrocephaly observed with deletion and ADHD and microcephaly seen in duplication patients support a diametric model of autism spectrum and psychotic spectrum behavioural phenotypes in genomic sister disorders.
16p11.2 的缺失和相互重复最近与自闭症和发育迟缓有关。
我们在提交进行临床阵列-CGH（比较基因组杂交）分析的所有样本中，发现了 0.6%的 16p11.2 缺失和 18 个重复。对 17 个缺失和 10 个重复的受试者进行了详细的分子和表型特征分析。
17 个缺失和 10 个重复的受试者中最常见的临床表现是语言延迟和认知障碍。缺失患者的其他表型包括运动延迟（50%）、癫痫发作（约 40%）、行为问题（约 40%）、先天性异常（约 30%）和自闭症（约 20%）。在重复的患者中，表型包括运动延迟（10/10）、行为问题（尤其是注意力缺陷多动障碍（ADHD））（10/10）、先天性异常（10/10）和癫痫发作（10/10）。16p11.2 缺失的患者有统计学意义上的大头（p<0.0017），而 10 名重复患者中有 6 名患者头小畸形。1 名缺失患者无症状，而另 1 名重复患者的认知和行为表型正常。基因组分析显示 16p11.2 区域的结构更为复杂，具有机制意义。除了 10 个缺失病例中有 2 个为父母研究外，所有病例均为新发缺失。此外，在分析的血样中，2 个新发病例显然为缺失的镶嵌体。在可获得数据的 10 个重复患者中的 5 个患者中，观察到 3 个新发和 2 个遗传病例。
反复发生的 16p11.2 缺失和重复表现为一系列主要的神经认知表型，其表现为不完全外显和可变表达。缺失患者中观察到的自闭症和大头畸形以及重复患者中看到的 ADHD 和小头畸形支持基因组姐妹疾病的自闭症和精神病谱系行为表型的对立模型。
