Analysis of 31-year-old patient with SYNGAP1 gene defect points to importance of variants in broader splice regions and reveals developmental trajectory of SYNGAP1-associated phenotype: case report

Abstract

BackgroundWhole exome sequencing is a powerful tool for the analysis of genetically heterogeneous conditions. The prioritization of variants identified often focuses on nonsense, frameshift and canonical splice site mutations, and highly deleterious missense variants, although other defects can also play a role. The definition of the phenotype range and course of rare genetic conditions requires long-term clinical follow-up of patients.Case presentationWe report an adult female patient with severe intellectual disability, severe speech delay, epilepsy, autistic features, aggressiveness, sleep problems, broad-based clumsy gait and constipation. Whole exome sequencing identified a de novo mutation in the SYNGAP1 gene. The variant was located in the broader splice donor region of intron 10 and replaced G by A at position +5 of the splice site. The variant was predicted in silico and shown experimentally to abolish the regular splice site and to activate a cryptic donor site within exon 10, causing frameshift and premature termination. The overall clinical picture of the patient corresponded well with the characteristic SYNGAP1-associated phenotype observed in previously reported patients. However, our patient was 31 years old which contrasted with most other published SYNGAP1 cases who were much younger. Our patient had a significant growth delay and microcephaly. Both features normalised later, although the head circumference stayed only slightly above the lower limit of the norm. The patient had a delayed puberty. Her cognitive and language performance remained at the level of a one-year-old child even in adulthood and showed a slow decline. Myopathic facial features and facial dysmorphism became more pronounced with age. Although the gait of the patient was unsteady in childhood, more severe gait problems developed in her teens. While the seizures remained well-controlled, her aggressive behaviour worsened with age and required extensive medication.ConclusionsThe finding in our patient underscores the notion that the interpretation of variants identified using whole exome sequencing should focus not only on variants in the canonical splice dinucleotides GT and AG, but also on broader splice regions. The long-term clinical follow-up of our patient contributes to the knowledge of the developmental trajectory in individuals with SYNGAP1 gene defects.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-017-0425-4) contains supplementary material, which is available to authorized users.

Comprehensive behavioral analysis of heterozygous Syngap1 knockout mice

“…De novo SYNGAP1 mutations have been found in patients with ID, epilepsy, or ASD [11][12][13][14][15][16][17][18][19][20] . In a large-scale developmental disorders study, seven SYNGAP1 mutations were identified in 940 patients with ID; therefore, the frequency of SYNGAP1 mutations is suggested to be ∼0.74% in patients with ID 19 .…”

Low-Dose Perampanel Rescues Cortical Gamma Dysregulation Associated With Parvalbumin Interneuron GluA2 Upregulation in Epileptic Syngap1+/− Mice

“…encephalopathies have a slow developmental regression that is primarily due to seizures, interictal spikes (IISs), or cortical dysrhythmia identified on EEG (19,20). Case reports indicate that adult patients demonstrate gradual decline in cognitive abilities (21). Perampanel (PMP), an AMPA receptor (AMPAR) antagonist recently approved by the Food and Drug Administration, has shown significant promise for multiple seizure types in idiopathic generalized epilepsies, including absence seizures (22).…”

Novel SYNGAP1 variant in a patient with intellectual disability and distinctive dysmorphisms

“…Parker et al () suggested discriminative dysmorphic features, and seizure and behavioral types in SYNGAP1 ‐mutated individuals. Recent report also showed that myopathic facial features became more significant overtime (Prchalova et al ). Table shows the phenotypic comparison between previously identified SYNGAP1 variants and our present patient, who contributes to an expansion of the disease phenotype.…”