SHANK Mutations May Disorder Brain Development

ferent nature, are caused by either loss or duplication of SHANK3. Thus, mutations of SHANK3 , provoking haploinsufficiency or triplosufficiency, are sufficient to elicit a clinical phenotype. Such a dominant effect of mutations suggests that SHANK3 may be a node in a combinatorial genetic network, as for instance CNTNAP2 [Poot et al., 2011; Poot, 2015]. It remains conceivable, however, that some mutations of SHANK3 may alone be sufficient to elicit a clinical disorder. To shed light on these issues and to derive possible phenotype-genotype relationships, a closer examination of a large number of mutations may be a promising approach [Leblond et al., 2014]. Leblond et al. [2014] analyzed copy-number variants (CNVs) in 5,657 ASD patients and 19,163 healthy controls, and ascertained single nucleotide variants (SNVs) in coding sequences of the SHANK genes in 760–2,147 ASD patients and 492–1,090 controls (depending on the gene examined) by performing classical dideoxy sequencing of the 3 SHANK genes. In approximately 1% of patients with ASD, CNVs and gene-truncating mutations were found. SNVs in SHANK1 (0.04%) were only found in male patients with normal IQ and ASD, while SNVs in SHANK2 were detected in 0.17% of patients with ASD and mild intellectual disability. In contrast, SNVs in SHANK3 were found in 0.69% of patients with ASD and in up to 2.12% of the ASD cases, moderate to profound intellectual disability was found. The frequencies of CNVs and SNVs of SHANK2 and SHANK3 were significantly higher than in healthy controls. In previous exome-sequencing efforts, only 1 de novo SNV in SHANK2 and no truncating coding-sequence variants in SHANK1 and SHANK3 have been found [Neale et al., 2012; O’Roak et al., 2012; Sanders et al., 2012]. This may be due to the poor mutation detection rate in stretches of GC base pairs by the current exome-sequencing technology. SNVs were Late Breaking Chromosomes