DNA variants in coding region of EFHC1: SNPs do not associate with juvenile myoclonic epilepsy

Abstract

Summary Purpose Juvenile myoclonic epilepsy (JME) accounts for 3 to 12% of all epilepsies. In 2004, we identified a mutation-harboring Mendelian gene that encodes a protein with one EF-hand motif (EFHC1) in chromosome 6p12. We observed one doubly heterozygous and three heterozygous missense mutations in EFHC1 segregating as an autosomal dominant gene with 21 affected members of six Hispanic JME families from California and Mexico. In 2006, similar and three novel missense mutations were reported in sporadic and familial Caucasian JME from Italy and Austria. In this study, we asked if coding single nucleotide polymorphisms (SNPs) of EFHC1 also contribute as susceptibility alleles to JME with complex genetics. Methods We screened using denaturing high-performance liquid chromatography (DHPLC) and then directly sequenced the 11 exons of EFHC1 in 130 unrelated JME probands, their 352 family members, and seven exons of EFHC1 in 400–614 ethnically matched controls. We carried out case-control association studies between 124 unrelated Hispanic JME probands and 552–614 ethnically matched controls using four SNPs, rs3804506, rs3804505, rs1266787, and rs17851770. We also performed family-based association on SNPs rs3804506 and rs3804505 in 84 complete JME families using the Family-Based Association Test (FBAT) program. Results We found no statistically significant differences between JME probands and controls in case-control association and no genetic transmission disequilibria in family-based association for the tested SNPs. In addition, we identified four new DNA variants in the coding region of EFHC1. Conclusion The four coding SNPs, rs3804506, rs3804505, rs1266787, and rs17851770, of EFHC1 may not be susceptibility alleles for JME.

Genetic evaluation and counseling for epilepsy

“…similarly, mutations in the eF-hand domain-containing 1 (EFHC1) gene (and EFHC2), 86 offered on multiple platforms, have only been connected with Jme in rare Central american pedigrees and not in the general population. 87 unlike in Jme, no convincing susceptibility variants for common forms of Cae have yet been reported. 3 some GaBa receptor subunit gene variants have been mapped in atypical forms of Cae but, to date, no evidence exists that these variants have any role in the common form of this condition.…”

EFHC1 variants in juvenile myoclonic epilepsy: reanalysis according to NHGRI and ACMG guidelines for assigning disease causality

“…14), were not available in 2004 when variants of the EF-hand domain (C-terminal) containing 1 gene (EFHC1) were reported as disease-causing mutations in myoclonic and grand mal clonic-tonic-clonic (CTC) convulsions produced by juvenile myoclonic epilepsy (JME). Consequently, all EFHC1 variants discovered in the first decade of this millennium and reported with respect to epilepsy or not [15][16][17][18][19][20][21][22][23][24][25][26][27][28] have not been "vetted" through NHGRI and ACMG guidelines. More importantly, both NHGRI and ACMG guidelines advise that "with evidence on variants evolving" and the "content of sequencing tests expanding, " "rigorous evaluation" and "reanalysis of variants are encouraged" to prevent misannotation of the pathogenicity of variants in public databases.…”

Association Between Idiopathic Generalized Epilepsy and EFHC1 Gene Mutations of 662 G>A and 685 T>C

“…25 Honduras, Amerika ve Meksika'lı 130 JME'li ailede yapılmış bir diğer çalışmada da 685T>C (F229L) mutasyonunun JME'li ailelerde bulunduğu, fakat kontrol grubunda bulunmadığı belirtilmektedir. 24 Bu çalış-mada ise hem hasta hem de kontrol grubunda az sayıda ve yakın frekansta mutasyon olduğu belirlenmiş ve yukarıda anılan iki çalışmaya zıt bir bulgu elde edilmiştir.…”

“…22 Sonraki yıllarda Alman toplumunda, İtalyan toplumunda, Avusturyalı İJE olgularında ve Avrupa kökenli JME'li hastalarda gerçekleştirilen çalışmalar, EFHC1 genindeki patojenik olabilecek mutasyonlar hakkında farklı sonuçlar ortaya çıkarmıştır. [23][24][25][26][27] Bu çalışmalarda, EFHC1 geni ile İJE sendromları arasındaki ilişkinin, toplumdan topluma farklı-lık gösterdiği ve özellikle genin 4. ekzonunda rastlanan 685 T>C ve 662G>A mutasyonlarının patojenik etkilerinin kimi toplumlarda gözlenirken, kimilerinde gözlenmediği saptanmıştır. Bu nedenler dikkate alınarak gendeki bu iki mutasyonun, Türk toplumunda hastalıkla ilişkisi bakımından araştırılması amaçlanmıştır.…”