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

BMC Medical Genetics

Case Report

Darina Prchalova¹  Marketa Havlovicova¹  Miroslava Hancarova¹  Zdenek Sedlacek¹  Katalin Sterbova²  Viktor Stranecky³ 

[1] 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;

关键词: SYNGAP1;    Intellectual disability;    Epilepsy;    Splice mutation;    Splice region;    Whole exome sequencing;   

DOI  :  10.1186/s12881-017-0425-4

 received in 2017-01-23, accepted in 2017-05-22,  发布年份 2017

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s). 2017