Major genomic rearrangements without loss of genetic material — balanced translocations — are infrequently found in patients with neurodevelopmental disorders but also in unaffected individuals. Genome sequencing and break point analysis of 38 patients now show a fine-grained view of the implication of such chromosomal abnormalities in neurodevelopmental disorders.
Most balanced translocations in patients with autism or ID are non-recurrent and leave the geneticists who want to understand cause and effect scratching their heads as the overall genomic content appears normal as all genes are present at first glance.
The frequency in patients with autism and neurodevelopmental disorders appears to be elevated by the factor of 6, which indicates that some rearrangements might add to the phenotype. Another famous example, FOXP2, a gene involved in developmental language disorders, was identified through a proband with a gene-disrupting balanced translocation. Single patients with epilepsy have been described whose balanced translocations helped identifying the responsible gene. Laura Klitten and coworkers from Denmark could recently identify a disruption of the SYNGAP1 gene in a patient with Myoclonic Absences. SYNGAP1 had been identified mainly in patients with intellectual disability and the balanced translocation now helped extending the phenotype to a rare epilepsy subtype. Balanced translocations might disrupt genes and the loss of function of the affected gene might result in disease. Hence, balanced translocations are an additional possibility to identify monogenic disorders.
The publication by Talkowski et al. in Cell used a massive parallel sequencing approach to identify disrupted genes in patients with autism and related disorders and balanced translocations. The authors could identify 33 loci with potentially pathogenic gene disruptions. Given that the interpretation of these findings has to approached with caution given that balanced translocations are also found in unaffected individuals, they followed up there findings in both a large set of patients genotyped for microdeletions and in results from Genome-Wide Association studies in schizophrenia and autism. Overall, they could identify an enrichment of these 33 loci in both follow-up strategies, which suggests that the identified genes are candidate genes for neurodevelopmental disorders.
Some genes identified by the authors deserve particular mention for the EuroEPINOMICS community. First, they identify a female patient with a disruption of the CDKL5 gene. CDKL5 mutations or deletions are known to cause a severe, early-onset epileptic encephalopathy that some members of the consortium are actively working on. It is therefore interesting to find this gene in a patient with autism. In the Supplemental Material, the authors state that the patient was referred for a “suspicion of seizure”. Unfortunately, the epileptology in the phenotypic description is relatively poor and no information on the EEG is given. Secondly, the authors identify a patient with a disruption of AUTS2. AUTS2 is a known autism gene assumed to be involved in brain development, which was also found to be deleted in a patient with JME, suggesting yet another phenotypic overlap between IGE/GGE and other neurodevelopmental disorders including autism.
The follow-up studies performed by the authors are interesting and strengthen their argument that these variants are pathogenic, but add little further information for the epilepsy community. The analysis of GWAS data and the interpretation that both rare and common variations in the candidate loci contribute to the phenotype should be regarded with a bit of caution and should be studied in more detail.
Balanced translocations in patients with epilepsies are extremely rare. The study by Talkowski et al. confirms that the methodology for analyzing these translocations down to the base pair level are ready to confirm existing candidate genes and find novel risk loci.