6p21.3 microdeletion involving the SYNGAP1 gene in a patient with intellectual disability, seizures, and severe speech impairment

Abstract

The chromosome 6p21.3 microdeletion phenotype was recently identified through array comparative genomic hybridization. The main features are developmental delay with severe speech impairment, seizures, and behavioral abnormalities. Three patients have been reported with deletion sizes ranging from 100 to 800 kb. We report on a 9-year-old boy with an apparently de novo, 50 kb deletion, and global developmental delay, severe speech impairment, and generalized epilepsy well-controlled by medication. There were four genes identified in this deletion, of which SYNGAP1 is considered to be responsible for speech impairment and epilepsy. We compared the clinical features of this patient with previously reported patients with 6p21.3 and patients with SYNGAP1 mutations. © 2013 Wiley Periodicals, Inc.

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“…A number of newly identified disease mutations were also located in the "hotspots" previously reported in epilepsy related phenotypes, such as 6p21.3 microdeletions, where a Leu308Phe mutation in the CYP21A2 gene identified in the current study, were observed in more than four patients in different studies, including a most recent report [26]. The main feature of 6p21.3 deletion occurs in patients with developmental delay with severe speech impairment, seizures and behavioral abnormalities.…”

De novo, heterozygous, loss‐of‐function mutations in SYNGAP1 cause a syndromic form of intellectual disability

“…Supplementary Table I summarizes the available clinical data on the 26 individuals who have been reported to date with presumed causative mutations in SYNGAP1 or deletions or translocations involving this gene [Hamdan et al, 2009, 2011a, b; Krepischi et al, 2010; Pinto et al, 2010; Vissers et al, 2010; Cook, 2011; Klitten et al, 2011; Zollino et al, 2011; Clement et al, 2012; de Ligt et al, 2012; Rauch et al, 2012; Berryer et al, 2013; Carvill et al, 2013; Writzl and Knegt, 2013; Dyment et al, 2014; O'Roak et al, 2014; Redin et al, 2014]. De novo mutations in this gene are undoubtedly a significant cause of intellectual disability, accounting for 0.62% of all the patients in the DDD Study [Wright et al, 2014] and major contributors to other cohorts that have been studied (Supplementary Table II).…”

“…Heterozygous, de novo loss‐of‐function mutations in SYNGAP1 have been described in 26 individuals to date [Hamdan et al, 2009, 2011a, b; Krepischi et al, 2010; Pinto et al, 2010; Vissers et al, 2010; Zollino et al, 2011; de Ligt et al, 2012; Rauch et al, 2012; Berryer et al, 2013; Carvill et al, 2013; Writzl and Knegt, 2013; Redin et al, 2014]. SYNGAP1 encodes Ras/Rap GTPase‐activating protein SynGAP, which is a major component of the post‐synaptic density that regulates synaptic plasticity and ERK/MAPK signaling probably via N‐methyl‐d‐aspartate (NMDA) receptor activation [Komiyama et al, 2002; Muhia et al, 2010].…”

“…In addition, there have been four individuals with genomic deletions of 6p23.1 involving SYNGAP1 , and one with a de novo apparently balanced reciprocal translocation in which one of the breakpoints disrupts SYNGAP1 [Krepischi et al, 2010; Pinto et al, 2010; Klitten et al, 2011; Zollino et al, 2011; Writzl and Knegt, 2013]. Thus the 26 individuals reported to date consist of 21 intragenic mutations, four whole gene deletions, and one translocation.…”

“…Thus the 26 individuals reported to date consist of 21 intragenic mutations, four whole gene deletions, and one translocation. To date, facial images have only been published in six individuals: three in the seminal Hamdan et al paper, plus three single patients in subsequent papers [Hamdan et al, 2009; Zollino et al, 2011; Rauch et al, 2012; Writzl and Knegt, 2013]. …”