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De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromic form of intellectual disability.
- Source :
-
American journal of medical genetics. Part A [Am J Med Genet A] 2015 Oct; Vol. 167A (10), pp. 2231-7. Date of Electronic Publication: 2015 Jun 15. - Publication Year :
- 2015
-
Abstract
- De novo mutations (DNM) in SYNGAP1, encoding Ras/Rap GTPase-activating protein SynGAP, have been reported in individuals with nonsyndromic intellectual disability (ID). We identified 10 previously unreported individuals with SYNGAP1 DNM; seven via the Deciphering Developmental Disorders (DDD) Study, one through clinical analysis for copy number variation and the remaining two (monozygotic twins) via a research multi-gene panel analysis. Seven of the nine heterozygous mutations are likely to result in loss-of-function (3 nonsense; 3 frameshift; 1 whole gene deletion). The remaining two mutations, one of which affected the monozygotic twins, were missense variants. Each individual carrying a DNM in SYNGAP1 had moderate-to-severe ID and 7/10 had epilepsy; typically myoclonic seizures, absences or drop attacks. 8/10 had hypotonia, 5/10 had significant constipation, 7/10 had wide-based/unsteady gait, 3/10 had strabismus, and 2/10 had significant hip dysplasia. A proportion of the affected individuals had a similar, myopathic facial appearance, with broad nasal bridge, relatively long nose and full lower lip vermilion. A distinctive behavioral phenotype was also observed with aggressive/challenging behavior and significant sleep problems being common. 7/10 individuals had MR imaging of the brain each of which was reported as normal. The clinical features of the individuals reported here show significant overlap with those associated with 6p21.3 microdeletions, confirming that haploinsufficiency for SYNGAP1 is responsible for both disorders. © 2015 Wiley Periodicals, Inc.<br /> (© 2015 Wiley Periodicals, Inc.)
- Subjects :
- Adolescent
Child
Child, Preschool
Constipation diagnosis
Constipation genetics
Constipation pathology
DNA Mutational Analysis
Epilepsies, Myoclonic diagnosis
Epilepsies, Myoclonic genetics
Epilepsies, Myoclonic pathology
Female
Gait Disorders, Neurologic diagnosis
Gait Disorders, Neurologic genetics
Gait Disorders, Neurologic pathology
Gene Expression
Haploinsufficiency
Hip Dislocation diagnosis
Hip Dislocation genetics
Hip Dislocation pathology
Humans
Intellectual Disability diagnosis
Intellectual Disability pathology
Male
Muscle Hypotonia diagnosis
Muscle Hypotonia genetics
Muscle Hypotonia pathology
Phenotype
Strabismus diagnosis
Strabismus genetics
Strabismus pathology
Twins, Monozygotic
Heterozygote
Intellectual Disability genetics
Mutation
ras GTPase-Activating Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1552-4833
- Volume :
- 167A
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- American journal of medical genetics. Part A
- Publication Type :
- Academic Journal
- Accession number :
- 26079862
- Full Text :
- https://doi.org/10.1002/ajmg.a.37189