De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism.
BACKGROUND
Little is known about the genetics of nonsyndromic intellectual disability (NSID). Recently, we reported de novo truncating mutations in the SYNGAP1 gene of 3 of 94 NSID cases, suggesting that its disruption represents a common cause of autosomal dominant NSID.


METHODS
To further explore the involvement of SYNGAP1 in NSID, we sequenced its exons and intronic boundaries in 60 additional sporadic cases of NSID, including 30 patients with autism spectrum disorders (ASD) and 9 with epilepsy, and in 380 control individuals.


RESULTS
We identified de novo out-of-frame deletions in two patients with NSID and mild generalized epilepsy (c.2677delC/p.Q893RfsX184 and c.321_324delGAAG/p. K108VfsX25) and a de novo splicing mutation (c.2294 + 1G>A), which results in the creation of a premature stop codon, in a patient with NSID and autism. No splicing or truncating mutations were found in control subjects.


CONCLUSIONS
We provide evidence that truncating mutations in SYNGAP1 are common in NSID and can be also associated with autism.
Centre of Excellence in Neuromics of Université de Montréal and Synapse to Disease, S2D, Group, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, Canada.
Fadi F
FF
Hamdan
Hussein
H
Daoud
Amélie
A
Piton
Julie
J
Gauthier
Sylvia
S
Dobrzeniecka
Marie-Odile
MO
Krebs
Ridha
R
Joober
Jean-Claude
JC
Lacaille
Amélie
A
Nadeau
Jeff M
JM
Milunsky
Zhenyuan
Z
Wang
Lionel
L
Carmant
Laurent
L
Mottron
Miriam H
MH
Beauchamp
Guy A
GA
Rouleau
Jacques L
JL
Michaud
D000328:Adult; D001321:Autistic Disorder / Q000235:genetics*; D018389:Codon, Nonsense; D004827:Epilepsy / Q000235:genetics; D005091:Exons; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D009154:Mutation; D020703:ras GTPase-Activating Proteins / Q000235:genetics*
D018389:Codon, Nonsense; C484739:SYNGAP1 protein, human; D020703:ras GTPase-Activating Proteins