A clinical variant in SCN1A inherited from a mosaic father cosegregates with a novel variant to cause Dravet syndrome in a consanguineous family

doi:10.1016/j.eplepsyres.2015.02.020

Epilepsy Research

Volume 113, July 2015, Pages 5-10

https://doi.org/10.1016/j.eplepsyres.2015.02.020 Get rights and content

Highlights

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A consanguineous family from Turkey with two children resembling Dravet syndrome.
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Implementation of a combined analysis of exome sequencing and SNP genotyping.
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Two SCN1A variants detected; a mosaic clinical variant coinherited with a novel one.
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Presence of both consanguinity and mosaicism complicate inheritance pattern.
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Heterozygous variants spotted in the family aid diagnosis and genetic counseling.

Summary

A consanguineous family from Turkey having two children with intellectual disability exhibiting myoclonic, febrile and other generalized seizures was recruited to identify the genetic origin of these phenotypes. A combined approach of SNP genotyping and exome sequencing was employed both to screen genes associated with Dravet syndrome and to detect homozygous variants. Analysis of exome data was extended further to identify compound heterozygosity. Herein, we report identification of two paternally inherited genetic variants in SCN1A (rs121917918; p.R101Q and p.I1576T), one of which was previously implicated in Dravet syndrome. Interestingly, the previously reported clinical variant (rs121917918; p.R101Q) displayed mosaicism in the blood and saliva of the father. The study supported the genetic diagnosis of affected children as Dravet syndrome possibly due to the combined effect of one clinically associated (rs121917918; p.R101Q) and one novel (p.I1576T) variants in SCN1A gene. This finding is important given that heterozygous variants may be overlooked in standard exome scans of consanguineous families. Thus, we are presenting an interesting example, where the inheritance of the condition may be misinterpreted as recessive and identical by descent due to consanguinity and mosaicism in one of the parents.

Introduction

Dravet syndrome (DS) or severe myoclonic epilepsy of infancy (SMEI) is an epileptic encephalopathy characterized by prolonged, recurrent generalized seizures and hemiconvulsions that might be induced by fever, where frequent refractory episodes of status epilepticus usually take place (Striano et al., 2013). Heterozygous mutations in the voltage-gated sodium channel type I alpha subunit (SCN1A) gene are a major cause of DS explaining up to 80% of cases (Depienne et al., 2009). Almost 95% of these mutations have been presumed as de novo due to their absence in parents (Mulley et al., 2005). Nevertheless, this percentage may be an overestimation, since detection of mosaicism requires further analyses in which inheritance from mildly affected or asymptomatic mosaic parents has well been documented only in rare cases (Shi et al., 2012).

Herein, we report genetic and clinical findings in a consanguineous family from Turkey with two affected children resembling DS phenotypes, with the ultimate aim of delineating the associated genetic variations.

Section snippets

Subjects

A consanguineous family from Turkey having two affected siblings along with four healthy members (Fig. 1) has been followed-up for 3 years. Physical and neurological examinations were performed for all available family members and detailed information on family history was collected. Magnetic resonance imaging (MRI) of the brain and electroencephalography (EEG) recordings were performed on the affected siblings and their asymptomatic father. Informed consents were obtained from all family

Results and discussion

WES data was initially screened for six DS related genes (Table 1, Supplementary Table 1 for non-filtered exome variants in these genes). Two heterozygous variants were common to both affected siblings within SCN1A gene (NM_001165963.1), making them strong candidates for compound heterozygosity: a reportedly clinical variant (rs121917918: p.R101Q; c.302G>A) and a novel variant (p.I1576T; c.4727T>C) (Fig. 2a, Supplementary Table 1). These variants were also identified using a parallel approach

Conclusion

Our in-depth genetic analyses of this family confirmed the diagnosis of affected individuals as DS, where presence of the novel p.I1576T SCN1A gene variant may have augmented the clinical effect in individuals already carrying the clinical p.R101Q variant in full heterozygous form. We highlighted the importance of parental mosaicism in DS diagnosis and genetic counseling. This study as well identified a novel variant that could be relevant in SCN1A screens especially when coinherited with a

Conflict of interest

None of the authors has any conflicts of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Acknowledgments

The authors are grateful to the patients and their relatives for their participation in this study. This work was supported by the grants of Scientific Research Projects Coordination Unit of Istanbul University, ÖNAP Project Number: 11021; The Scientific and Technology Research Council of Turkey (TUBITAK) Project Numbers: 113S331, 109S218 and UEKAE, BILGEM T439000 and The Republic of Turkey Ministry of Development Infrastructure Grant, Grant Number: 2011K120020.

We highly appreciate the efforts

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A novel homozygous missense mutation in POC1A, which is a causative gene of SOFT syndrome, was detected using by FMFilter. Compound heterozygous model: First sample is a consanguineous family from Turkey having two children with Drave syndrome [7]. In this case because of consanguinity, first the recessive model second the compound model have been considered.
The availability of whole exome and genome sequencing has completely changed the structure of genetic disease studies. It is now possible to solve the disease causing mechanisms within shorter time and budgets. For this reason, mining out the valuable information from the huge amount of data produced by next generation techniques becomes a challenging task. Current tools analyze sequencing data in various methods. However, there is still need for fast, easy to use and efficacious tools. Considering genetic disease studies, there is a lack of publicly available tools which support compound heterozygous and de novo models. Also, existing tools either require advanced IT expertise or are inefficient for handling large variant files. In this work, we provide FMFilter, an efficient sieving tool for next generation sequencing data produced by genetic disease studies. We develop a software which allows to choose the inheritance model (recessive, dominant, compound heterozygous and de novo), the affected and control individuals. The program provides a user friendly Graphical User Interface which eliminates the requirement of advanced computer techniques. It has various filtering options which enable to eliminate the majority of the false alarms. FMFilter requires negligible memory, therefore it can easily handle very large variant files like multiple whole genomes with ordinary computers. We demonstrate the variant reduction capability and effectiveness of the proposed tool with public and in-house data for different inheritance models. We also compare FMFilter with the existing filtering software. We conclude that FMFilter provides an effective and easy to use environment for analyzing next generation sequencing data from Mendelian diseases.
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Short CommunicationA clinical variant in SCN1A inherited from a mosaic father cosegregates with a novel variant to cause Dravet syndrome in a consanguineous family

Highlights

Summary

Introduction

Section snippets

Subjects

Results and discussion

Conclusion

Conflict of interest

Acknowledgments

Lancet Neurol.

Am. J. Hum. Genet.

Epilepsy Res.

Lancet Neurol.

Brain Dev.

GABRA1 and STXBP1: novel genetic causes of Dravet syndrome

Neurology

Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients

J. Med. Genet.

Mutations of neuronal voltage-gated Na+ channel alpha 1 subunit gene SCN1A in core severe myoclonic epilepsy in infancy (SMEI) and in borderline SMEI (SMEB)

Epilepsia

Short Communication
A clinical variant in SCN1A inherited from a mosaic father cosegregates with a novel variant to cause Dravet syndrome in a consanguineous family