BACKGROUND: Whole 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 PRESENTATION: We 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. CONCLUSIONS: The 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.

Department of Biology and Medical Genetics Charles University 2nd Faculty of Medicine and University Hospital Motol Plzenska 130 221 15000 Prague 5 Czech Republic

Department of Child Neurology Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Institute of Inherited Metabolic Disorders Charles University 1st Faculty of Medicine and General University Hospital Prague Czech Republic

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Jeyabalan N, Clement JP. SYNGAP1: mind the gap. Front Cell Neurosci. 2016;10:1–16. doi: 10.3389/fncel.2016.00032. PubMed DOI PMC

Komiyama NH, Watabe AM, Carlisle HJ, Porter K, Charlesworth P, Monti J, et al. SynGAP regulates ERK/MAPK signaling, synaptic plasticity, and learning in the complex with postsynaptic density 95 and NMDA receptor. J Neurosci. 2002;22:9721–32. PubMed PMC

Kim JH, Lee H-K, Takamiya K, Huganir RL. The role of synaptic GTPase-activating protein in neuronal development and synaptic plasticity. J Neurosci. 2003;23:1119–24. PubMed PMC

Hamdan FF, Gauthier J, Spiegelman D, Noreau A, Yang Y, Pellerin S, et al. Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. N Engl J Med. 2009;360:599–605. doi: 10.1056/NEJMoa0805392. PubMed DOI PMC

Mignot C, Stülpnagel C Von, Nava C, Ville D, Sanlaville D, Lesca G, et al. Genetic and neurodevelopmental spectrum of SYNGAP1 -associated intellectual disability and epilepsy. J Med Genet. 2016;53:511–22. PubMed

Berryer MH, Hamdan FF, Klitten LL, Møller RS, Carmant L, Schwartzentruber J, et al. Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency. Hum Mutat. 2013;34:385–94. doi: 10.1002/humu.22248. PubMed DOI

Sibley CR, Blazquez L, Ule J. Lessons from non-canonical splicing. Nat Rev Genet. 2016;17:407–21. doi: 10.1038/nrg.2016.46. PubMed DOI PMC

Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, et al. Landscape of transcription in human cells. Nature. 2012;489:101–8. doi: 10.1038/nature11233. PubMed DOI PMC

Musova Z, Kaiserova M, Kriegova E, Fillerova R, Vasovcak P, Santava A, et al. A novel frameshift mutation in the AFG3L2 gene in a patient with spinocerebellar ataxia. Cerebellum. 2014;13:331–7. doi: 10.1007/s12311-013-0538-z. PubMed DOI

Magyar I, Colman D, Arnold E, Baumgartner D, Bottani A, Fokstuen S, et al. Quantitative sequence analysis of FBN1 premature termination codons provides evidence for incomplete NMD in leukocytes. Hum Mutat. 2009;30:1355–64. doi: 10.1002/humu.21058. PubMed DOI

Parker MJ, Fryer AE, Shears DJ, Lachlan KL, McKee SA, Magee AC, et al. De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromic form of intellectual disability. Am J Med Genet A. 2015;167:2231–7. doi: 10.1002/ajmg.a.37189. PubMed DOI PMC

A novel variant of C12orf4 in a consanguineous Armenian family confirms the etiology of autosomal recessive intellectual disability type 66 with delineation of the phenotype