MRD5 is characterized by moderate to severe intellectual disability with delayed psychomotor development apparent in the first years of life. Some patients develop variable types of seizures, some have autism or autism spectrum disorder (see 209850), and some ... MRD5 is characterized by moderate to severe intellectual disability with delayed psychomotor development apparent in the first years of life. Some patients develop variable types of seizures, some have autism or autism spectrum disorder (see 209850), and some have acquired microcephaly (summary by Berryer et al., 2013).
In 3 of 94 patients with nonsyndromic mental retardation, Hamdan et al. (2009) identified 3 different de novo heterozygous truncating mutations in the SYNGAP1 gene (603384.0001-603384.0003). All patients showed global developmental delay with delayed motor development, hypotonia, moderate ... In 3 of 94 patients with nonsyndromic mental retardation, Hamdan et al. (2009) identified 3 different de novo heterozygous truncating mutations in the SYNGAP1 gene (603384.0001-603384.0003). All patients showed global developmental delay with delayed motor development, hypotonia, moderate to severe mental retardation, and severe language impairment. One patient had strabismus, and 2 had epilepsy. There were no other dysmorphic features. Hamdan et al. (2011) reported 3 unrelated patients with MRD5. In addition to moderate to severe intellectual disability, the children also showed behavioral abnormalities, such as avoidance of other children and impulsivity, and mood problems, such as sullenness and rigidity. Two had well-controlled epilepsy and acquired microcephaly, and 1 had autism, thus expanding the phenotypic spectrum associated with SYNGAP1 mutations. Berryer et al. (2013) reported 5 unrelated patients with MRD5. All presented with delayed development in the first years of life and all but 1 showed moderate to severe intellectual disability. Four patients had epilepsy, 3 had autism, and 3 had behavioral abnormalities. There were no notable dysmorphic features or structural brain abnormalities. Carvill et al. (2013) reported 2 unrelated patients with epileptic encephalopathy, severe mental retardation, and autism spectrum disorder. One patient had onset of atypical absence seizures at age 3 years, followed by atonic seizures, focal dyscognitive seizures, and myoclonic jerks associated with EEG abnormalities. The other had onset of absence seizures at age 10 months, followed by myoclonic jerks. Both had delayed development and showed cognitive regression after seizure onset. Each patient carried a de novo heterozygous truncating mutation in the SYNGAP1 gene (603384.0009 and 603384.0010). Three additional unrelated patients with a similar phenotype, mental retardation associated with onset of multiple seizure types in the first years of life and developmental regression, also carried heterozygous truncating SYNGAP1 mutations, but DNA from one or both parents was not available to confirm that the mutations occurred de novo. Carvill et al. (2013) concluded that epileptic encephalopathy should be part of the phenotypic spectrum associated with SYNGAP1 mutations. These patients were identified from a large cohort of 500 patients with epileptic encephalopathy who underwent targeted sequencing of candidate genes. SYNGAP1 mutations accounted for 1% of cases.
In 3 of 94 patients with nonsyndromic mental retardation, Hamdan et al. (2009) identified 3 different de novo heterozygous truncating mutations in the SYNGAP1 gene (603384.0001-603384.0003).
In 3 of 60 patients with nonsyndromic intellectual disability, including ... In 3 of 94 patients with nonsyndromic mental retardation, Hamdan et al. (2009) identified 3 different de novo heterozygous truncating mutations in the SYNGAP1 gene (603384.0001-603384.0003). In 3 of 60 patients with nonsyndromic intellectual disability, including 30 with autism spectrum disorder and 9 with epilepsy, Hamdan et al. (2011) identified de novo heterozygous truncating mutations in the SYNGAP1 gene (see, e.g., 603384.0005 and 603384.0006). Berryer et al. (2013) identified 5 different SYNGAP1 mutations (see, e.g., 603384.0007 and 603384.0008) in 5 unrelated patients with nonsyndromic intellectual disability. There were 3 truncating mutations and 2 missense mutations. These patients were identified by targeted sequencing of the SYNGAP1 gene in several cohorts including a total of 34 patients with nonsyndromic intellectual disability. Four of the mutations occurred de novo; 1 was inherited from a mildly affected parent who was mosaic for the mutation. None of the mutant proteins were detected in neuronal cells transfected with the mutations, suggesting decreased stability, even of the missense mutations. Studies in cortical pyramidal neurons showed that the missense mutations were unable to suppress activity-mediated ERK (176872), consistent with a loss of protein function.