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

Tuncer, Feyza Nur; Gormez, Zeliha; Çalık, Mustafa; Uzun, Güneş Altıokka; Sağıroğlu, Mahmut Şamil; Yücetürk, Betül; Yüksel, Bayram; Baykan, Betül; Bebek, Nerses; İşcan, Akın; İşeri, Sibel Aylin Uğur; Özbek, Uğur

doi:10.1016/j.eplepsyres.2015.02.020

Cited by 8 publications

(5 citation statements)

References 17 publications

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“…In both families, the heterozygouscarrier parents remained unaffected while their homozygous children developed SCN1A-related epilepsies, including DS and GEFS + (14). Since then, six more patients have been published (16)(17)(18)(19)(20). Here, we report two siblings, sons of a family with high consanguinity, with GEFS+ associated with the homozygous c.4513A > C variant in the SCN1A gene.…”

Section: Recessive Mutations In Scn1a Genementioning

confidence: 87%

“…In 2015, Brunklaus et al published for the first time two novel homozygous missense mutations of the SCN1A gene in four children. Then, Tuncer et al published two brothers with compound heterozygosity in SCN1A with symptoms compatible with DS ( 17 ). Subsequently, Aslan et al and Van et al have published two more cases with homozygous variants in patients with DS ( 18 , 19 ), and Moretti et al published two novel homozygous missense variations of the SCN1A gene in two individuals from two different families from consanguineous pedigrees.…”

Section: Discussionmentioning

confidence: 99%

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Case Report: Novel Homozygous Likely Pathogenic SCN1A Variant With Autosomal Recessive Inheritance and Review of the Literature

et al. 2021

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Dominant pathogenic variations in the SCN1A gene are associated with several neuro developmental disorders with or without epilepsy, including Dravet syndrome (DS). Conversely, there are few published cases with homozygous or compound heterozygous variations in the SCN1A gene. Here, we describe two siblings from a consanguineous pedigree with epilepsy phenotype compatible with genetic epilepsy with febrile seizures plus (GEFS+) associated with the homozygous likely pathogenic variant (NM_001165963.1): c.4513A > C (p.Lys1505Gln). Clinical and genetic data were compared to those of other 10 previously published patients with epilepsy and variants in compound heterozygosity or homozygosity in the SCN1A gene. Most patients (11/12) had missense variants. Patients in whom the variants were located at the cytoplasmic or the extracellular domains frequently presented a less severe phenotype than those in whom they are located at the pore-forming domains. Five of the patients (41.7%) meet clinical criteria for Dravet syndrome (DS), one of them associated acute encephalopathy. Other five patients (41.7%) had a phenotype of epilepsy with febrile seizures plus familial origin, while the two remaining (17%) presented focal epileptic seizures. SCN1A-related epilepsies present in most cases an autosomal dominant inheritance; however, there is growing evidence that some genetic variants only manifest clinical symptoms when they are present in both alleles, following an autosomal recessive inheritance.

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Section: Recessive Mutations In Scn1a Genementioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Case Report: Novel Homozygous Likely Pathogenic SCN1A Variant With Autosomal Recessive Inheritance and Review of the Literature

et al. 2021

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“…Actually, somatic and germline SCN1A mosaicism has been reported in a small number of cases. [20,21] Somatic mosaicism may account for variable expressivity of SCN1A mutations in SMEI families.…”

Section: Discussionmentioning

confidence: 99%

Clinical and molecular analysis of epilepsy-related genes in patients with Dravet syndrome

et al. 2018

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“…The Djallonke genome was designated as the index case and compared against the Sahelian as the unaffected case for input settings for the HomSI analysis. Analysis of runs of homozygosity in Djallonke and Sahelian using HomSI, with the stringent settings of 5 Mb window size and 10 kb sliding size, allowed the capturing of a wide spectrum of different lengths of homozygosity throughout the genome [26–29]. Integrative Genomics Viewer (IGV 2.3.46, www.BroadInstitute.org) was used to view vcf and BAM file tracks aligned to the sheep reference genome Oar v3.1, selecting regions based on genomic coordinates of regions of contrasting reduced heterozygosity identified by HomSI in order to identify candidate genes.…”

Section: Methodsmentioning

confidence: 99%

Analysis of pooled genome sequences from Djallonke and Sahelian sheep of Ghana reveals co-localisation of regions of reduced heterozygosity with candidate genes for disease resistance and adaptation to a tropical environment

et al. 2019

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BackgroundThe Djallonke sheep is well adapted to harsh environmental conditions, and is relatively resistant to Haemonchosis and resilient to animal trypanosomiasis. The larger Sahelian sheep, which cohabit the same region, is less well adapted to these disease challenges. Haemonchosis and Trypanosomiasis collectively cost the worldwide animal industry billions of dollars in production losses annually.ResultsHere, we separately sequenced and then pooled according to breed the genomes from five unrelated individuals from each of the Djallonke and Sahelian sheep breeds (sourced from Ghana), at greater than 22-fold combined coverage for each breed. A total of approximately 404 million (97%) and 343 million (97%) sequence reads from the Djallonke and Sahelian breeds respectively, were successfully mapped to the sheep reference genome Oar v3.1. We identified approximately 11.1 million and 10.9 million single nucleotide polymorphisms (SNPs) in the Djallonke and Sahelian breeds, with approximately 15 and 16% respectively of these not previously reported in sheep. Multiple regions of reduced heterozygosity were also found; 70 co-localised within genomic regions harbouring genes that mediate disease resistance, immune response and adaptation in sheep or cattle. Thirty- three of the regions of reduced heterozygosity co-localised with previously reported genes for resistance to haemonchosis and trypanosomiasis.ConclusionsOur analyses suggest that these regions of reduced heterozygosity may be signatures of selection for these economically important diseases.

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

Cited by 8 publications

References 17 publications

Case Report: Novel Homozygous Likely Pathogenic SCN1A Variant With Autosomal Recessive Inheritance and Review of the Literature

Case Report: Novel Homozygous Likely Pathogenic SCN1A Variant With Autosomal Recessive Inheritance and Review of the Literature

Clinical and molecular analysis of epilepsy-related genes in patients with Dravet syndrome

Analysis of pooled genome sequences from Djallonke and Sahelian sheep of Ghana reveals co-localisation of regions of reduced heterozygosity with candidate genes for disease resistance and adaptation to a tropical environment

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