Recommended testing for this condition at Breda Genetics:
- Single gene testing based on exome sequencing (SYNGAP1 gene). If negative: upgrade to full exome data analysis.
SYNGAP1 gene mutations have been associated with autism or autism spectrum disorders, nonsyndromic intellectual disability, delay of psychomotor development, acquired microcephaly, and several forms of idiopathic generalized epilepsy. The condition caused by SYNGAP1 gene mutations is called MRD5 (Mental Retardation, autosomal Dominant 5) and is often improperly called SYNGAP1 syndrome.
Detailed clinical description
Onset is in the first year of life and the clinical features may be found in different combinations. A majority (but not all) of patients show epilepsy (myoclonic, clonic and clonic-tonic seizures, also during sleep, absences or drop attacks, which may be responsive to valproic acid treatment). Other observed clinical characteristics include hypotonia, unsteady gait, strabismus, hip dysplasia and some dysmorphic features (myopathic facial appearance, broad nasal bridge, long nose and full lower lip vermilion).
Loss-of-function mutations causing haploinsufficiency of the SYNGAP1 gene (and likely damaging the development of the forebrain glutamatergic neurons) are causative of the disorder. Almost all reported cases have occurred de novo. Most mutations are protein truncating (nonsense, frame shifting, splice mutations), although a minority of missense mutations has also been reported. Mutations reported thus far include the following: c.412A>T (p.Lys138*); c.1735C>T (p.Arg579*); and c.2438delT (p.Leu813Argfs*23) (PMID: 21376300), c.501-1G>A, c.2294+1G>A (causing the skipping of exon 13 and the premature termination Glu706LeufsTer38), c.1084T>C (p.Trp362Arg), c.1685C>T (p.Pro562Leu) (PMID: 23161826) c.2212_2213del (p.Ser738*) (possibly disease-causing according to the authors, PMID: 25852444); Trp267* and Arg143* (PMID: 23708187), c.348C>A (p.Y116*) (PMID: 26110312).
One whole gene deletion has also been mentioned (PMID: 26079862). Indeed, MRD5 may clinically overlap with 6p21.3 microdeletions (which causes the deletion of several genes including SYNGAP1), confirming that gene loss may also be expected as cause of haploinsufficiency. Even patients with deletions that include SYNGAP1 and several other genes may show autism spectrum disorders (PMID: 21480541).
SYNGAP1 gene testing methods
SYNGAP1 should be analyzed by full sequencing of the entire coding region (by Sanger sequencing or NGS). If negative, deletion/duplication testing (MLPA/qPCR) should be performed. If negative again, upgrade to exome sequencing may be considered to screen for mutations in genes associated with overlapping phenotypes with mental retardation and epilepsy.
Recommended testing workflow
Recommended testing for this condition at Breda Genetics:
- EXOME 15MB (6,000 genes) or
- EXOME GENE (SYNGAP1 gene). If negative: UPGRADE TO EXOME 15MB (6,000 genes)
SYNGAP1 Mutation in Focal and Generalized Epilepsy: A Literature Overview and A Case Report with Special Aspects of the EEG. von Stülpnagel C, Funke C, Haberl C, Hörtnagel K, Jüngling J, Weber YG, Staudt M1, Kluger G. Neuropediatrics. 2015 Aug;46(4):287-91. PMID: 26110312
Reduced cognition in Syngap1 mutants is caused by isolated damage within developing forebrain excitatory neurons. Ozkan ED, Creson TK, Kramár EA, Rojas C1, Seese RR, Babyan AH2, Shi Y, Lucero R, Xu X, Noebels JL, Miller CA, Lynch G, Rumbaugh G. PMID: 24945774
Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Hamdan FF, Gauthier J, Araki Y, Lin DT, Yoshizawa Y, Higashi K, Park AR, Spiegelman D, Dobrzeniecka S, Piton A, Tomitori H, Daoud H, Massicotte C, Henrion E, Diallo O; S2D Group, Shekarabi M, Marineau C, Shevell M, Maranda B, Mitchell G, Nadeau A, D’Anjou G, Vanasse M, Srour M, Lafrenière RG, Drapeau P, Lacaille JC, Kim E, Lee JR, Igarashi K, Huganir RL, Rouleau GA, Michaud JL. Am J Hum Genet. 2011 Mar 11;88(3):306-16. PMID: 21376300,
Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency. Berryer MH, Hamdan FF, Klitten LL, Møller RS, Carmant L, Schwartzentruber J, Patry L, Dobrzeniecka S, Rochefort D, Neugnot-Cerioli M, Lacaille JC, Niu Z, Eng CM, Yang Y, Palardy S, Belhumeur C, Rouleau GA, Tommerup N, Immken L, Beauchamp MH, Patel GS, Majewski J, Tarnopolsky MA, Scheffzek K, Hjalgrim H, Michaud JL, Di Cristo G. Hum Mutat. 2013 Feb;34(2):385-94. PMID: 23161826
Whole-Exome Sequencing in the Clinic: Lessons from Six Consecutive Cases from the Clinician’s Perspective. Volk A, Conboy E, Wical B, Patterson M, Kirmani S. Mol Syndromol. 2015 Feb;6(1):23-31. PMID: 25852444
Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Carvill GL, Heavin SB, Yendle SC, McMahon JM, O’Roak BJ, Cook J, Khan A, Dorschner MO, Weaver M, Calvert S, Malone S, Wallace G, Stanley T, Bye AM, Bleasel A, Howell KB, Kivity S, Mackay MT, Rodriguez-Casero V, Webster R, Korczyn A, Afawi Z, Zelnick N, Lerman-Sagie T, Lev D, Møller RS, Gill D, Andrade DM, Freeman JL, Sadleir LG, Shendure J, Berkovic SF, Scheffer IE, Mefford HC. Nat Genet. 2013 Jul;45(7):825-30. PMID: 23708187
De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromic form of intellectual disability. Parker MJ, Fryer AE, Shears DJ, Lachlan KL, McKee SA, Magee AC, Mohammed S, Vasudevan PC, Park SM, Benoit V, Lederer D, Maystadt I, Study D, FitzPatrick DR. Am J Med Genet A. 2015 Oct;167A(10):2231-7. PMID: 26079862
De novo autosomal dominant mutation in SYNGAP1. Cook EH Jr. Autism Res. 2011 Apr;4(2):155-6. PMID: 21480541