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Case Reports
.2017 Jun 2;18(1):62.
doi: 10.1186/s12881-017-0425-4.

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

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Case Reports

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

Darina Prchalova et al. BMC Med Genet..

Abstract

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.

Keywords: Epilepsy; Intellectual disability; SYNGAP1 gene; Splice mutation; Splice region; Whole exome sequencing.

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Figures

Fig. 1
Fig. 1
Facial photographs of the patient at the age of 1 month (a), 1 year (b), 3 years (c), 5 years (d), 7 years (e), 10 years (f), 16 years (g), and 31 years (h)
Fig. 2
Fig. 2
Electropherograms of Sanger sequences ofSYNGAP1 genomic DNA (gDNA) (a) and lymphocyte cDNA (b) of a representative normal control and the patient, and schematics of splicing of the exon 10 - exon 11 region in mRNA from the normal and mutatedSYNGAP1 alleles (c). The variant in intron 10 is marked by athick red arrow. The regular exon 10 - intron 10 boundary and the new splice donor site in exon 10 are indicated by asolid black vertical line and adashed red vertical line, respectively.Black,red,green andblue lettering in (b) andthick lines in (c) correspond to regular splicing of exon 10, aberrant splicing of exon 10, regular splicing of exon 11 and alternative splicing of exon 11, respectively.Asterisks indicate premature stop codons
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References

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

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