Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance

Abstract

Microdeletion at chromosomal position 15q13.3 has been described in intellectual disability, autism spectrum disorders, schizophrenia and recently in idiopathic generalized epilepsy (IGE). Using independent IGE cohorts, we first aimed to confirm the association of 15q13.3 deletions and IGE. We then set out to determine the relative occurrence of sporadic and familial cases and to examine the likelihood of having seizures for individuals with the microdeletion in familial cases. The 15q13.3 microdeletion was identified in 7 of 539 (1.3%) unrelated cases of IGE using quantitative PCR or SNP arrays and confirmed by array comparative genomic hybridization analysis using probes specific to the 15q13.3 region. The inheritance of this lesion was tracked using family studies. Of the seven microdeletions identified in probands, three were de novo, two were transmitted from an unaffected parent and in two cases the parents were unavailable. Non-penetrance of the microdeletion was identified in 4/7 pedigrees and three pedigrees included other family members with IGE who lacked the 15q13.3 deletion. The odds ratio is 68 (95% confidence interval 29-181), indicating a pathogenic lesion predisposing to epilepsy with complex inheritance and incomplete penetrance for the IGE component of the phenotype in multiplex families.

Figure 1.

High-density oligonucleotide array CGH analysis of 15q13.3 microdeletions in patients with idiopathic generalized epilepsy. The 15q13.3 microdeletions were confirmed using high-density oligonucelotide array CGH (NCBI Build 36, chr15: 28 200 000–30 700 000 shown). The minimal deletion region lies between the segmental duplication clusters at breakpoints 4 (BP4) and 5 (BP5) and contains six RefSeq genes, shown in blue. Segmental duplications of increasing similarity (90–98%, 98–99% and >99%) are represented by grey/yellow/orange bars, respectively. For each individual, deviations of probe log₂ ratios from zero are depicted by grey/black lines, with those exceeding a threshold of 1.5 standard deviations from the mean probe ratio colored green and red to represent relative gains and losses, respectively.

Figure 2.

Family pedigrees of probands with 15q13.3 microdeletions showing only partial segregation with affected status. Family 1 is Turkish and Families 2–7 are Australian. Three microdeletions arose de novo in the proband in three families (1, 2 and 5), two were inherited (4 and 7) and in two families the parents of the proband were not available for study (3 and 6). Transmission of the microdeletion occurred in four families (3, 4, 6 and 7) and in all cases at least one unaffected individual carries the microdeletion. Four families have multiple individuals affected with IGE (2, 3, 4 and 5) and in one family (4) the microdeletion is present in all affected members of the family. Overall 8/12 subjects with the deletion are affected while 8/12 of those affected with IGE have the microdeletion. nl: signifies subjects who have been tested and who do not have the 15q13.3 microdeletion.