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

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.

Keywords: 6p21.3 microdeletion; DDD study; SYNGAP1; behavioral phenotype; epilepsy; hip dysplasia; hypertrichosis; intellectual disability; strabismus; syndrome.

Figure 1

Faces of individuals with SYNGAP1 haploinsufficiency. Facial photographs of Patient 1 at 7 years, 3 months (a); Patient 2 at 8 years, 2 months (b); Patient 3 at 7 years, 9 months (c); Patient 4 at 3 years, 2 months (d); Patient 5 at 8 years, 4 months (e); Patient 6 at 12 years, 10 months (f); Patient 7 at 5 years, 7 months (g); Patient 8 at 8 years, 7 months (h); and Patients 9 and 10 at 8 years, 3 months (i and j). The most common shared facial characteristics are almond‐shaped palpebral fissures, which slant downwards slightly. With the exception of Patient 5 (e), the others have a mildly myopathic appearance, with an open mouth and relatively full lower lip. Patients 1 (a), 3 (c), 4 (d), 6 (f), 7 (g) and 9 (i) and 10 (j) have relatively long noses; Patients 2 (b), 4 (d), 5 (e), 6 (f), 7 (g) and 8 (h) have relatively long ears with protuberant lobes. Patients 1 (a), 6 (f) and 9 (i) and 10 (j) were thought to have relatively deep‐set eyes and Patient 8 (h) has a degree of ptosis. Patient 6 (f) has a missing central incisor due to trauma. We do not believe that Patient 7 (g), the only deletion patient in this series, differs significantly in appearance from the others.