Myoclonic Epilepsy, Juvenile, Susceptibility To, 3

For general phenotypic information and a discussion of genetic heterogeneity of juvenile myoclonic epilepsy, see 254770.

Mapping

Greenberg et al. (1987) studied 24 families with JME. Segregation analysis allowed them to reject fully penetrant dominant and recessive models. For the linkage analysis, they assumed a fully penetrant recessive model or a recessive model with 60% penetrance. Using either clinical phenotype or EEG changes to score persons as affected with JME, Greenberg et al. (1987, 1988) found evidence for linkage to BF (138470) and HLA (142800) on chromosome 6p21; the lod score exceeded 3.0 when HLA and BF were used together. Greenberg et al. (1989) and Delgado-Escueta et al. (1989) presented additional evidence for linkage to HLA and BF. Delgado-Escueta et al. (1989) stated in an addendum that linkage with HLA serologic and DNA markers had been confirmed by 2 other groups.

In a study of 23 families ascertained through a JME proband, Weissbecker et al. (1991) found evidence for linkage to HLA on 6p (maximum lod score of 3.11 at a male recombination distance of 0.001 and a female recombination distance of 0.2). The results assumed autosomal dominant inheritance with 90% penetrance.

Durner et al. (1991) studied 21 families of JME patients and obtained a lod score of 3.9 for linkage to HLA-DQ (146880) assuming a dominant mode of inheritance and 70% penetrance when family members with JME, absence epilepsy, or epilepsy with generalized tonic-clonic seizures were considered affected. The lod score increased to 4.1 when family members with generalized spike-wave discharges on EEG were considered affected. Durner et al. (1991) concluded that a gene locus for several types of generalized idiopathic epilepsy map to 6p.

Sander et al. (1995) ascertained 44 families with 452 individuals through patients with either childhood absence epilepsy (ECA1; 600131) or juvenile absence epilepsy (JAE; 607631), both of which are subsets of idiopathic generalized epilepsy. Strong negative lod scores excluded a major susceptibility locus for these disorders in the HLA region on chromosome 6p21. However, suggestive evidence for linkage to HLA was found for a subgroup of 14 families with JME patients (lod score of 1.92 at theta (max) = 0.053) when family members with idiopathic generalized epilepsy or idiopathic generalized tonic-clonic seizures were included as being affected. The authors used a single locus approximation model that assumed either autosomal dominant or recessive inheritance with penetrance of 70%. Sander et al. (1997) reported significant evidence of linkage of JME to a candidate region of 10.1 cM on chromosome 6p21 between the flanking loci HLA-DQ and D6S1019 in a sample of German families. However, JME families they collected elsewhere in the world gave evidence against linkage, suggesting that linkage of JME to HLA may represent a European phenomenon.

Greenberg et al. (2000) found evidence of genetic heterogeneity within JME. Their data suggested that JME may be predominantly maternally inherited and that the HLA-linked form is more likely to occur in families of European origin.

Molecular Genetics

Pal et al. (2003) noted that the critical region of the major JME susceptibility locus that maps to 6p21 is delimited by obligate recombinants at HLA-DQ (146880) and HLA-DP (142858), and that association between JME and a microsatellite marker in the 6p21 region had been reported (Greenberg et al., 2000). They found highly significant linkage disequilibrium (LD) between JME and a core haplotype of 5 SNP and microsatellite markers in this critical region, with LD peaking in the BRD2 gene (601540). In 20 probands from families linked to 6p21, DNA sequencing revealed 2 JME-associated SNP variants in the BRD2 promoter region, but no other potentially causative coding mutations. Pal et al. (2003) suggested that JME at the 6p21 locus may be caused by mutation in the BRD2 gene, a putative nuclear transcriptional regulator and a member of a family of genes that are expressed during development. The authors noted that reported abnormal cerebral microanatomy in JME (Woermann et al., 1999) would be consistent with BRD2 involvement.

Nomenclature

A locus for juvenile myoclonic epilepsy linked to HLA on chromosome 6p21.3 was originally termed 'EJM1' (Sander et al., 1995). Since then, EJM1 has been used to refer to a different JME phenotype (254770) caused by mutation in the EFHC1 gene (608815) on chromosome 6p12-p11. The locus at 6p21 is symbolized EJM3.