AT AES 2016

HOUSTON (FRONTLINE MEDICAL NEWS) – The rate of parental mosaicism in children with sporadic cases of epileptic encephalopathy and an apparent de novo mutation is believed to be at least 10%, which is much higher than previously thought.

The discovery, which was revealed with advanced genetic testing methods, underscores the need to rethink how parents of children with epileptic encephalopathy are counseled with regard to family planning, lead study author Candace T. Myers, PhD, said in an interview in advance of the annual meeting of the American Epilepsy Society. “Generally, families are counseled with a recurrence risk of 1%-3%, but we found that in 10% of our families their recurrence risk is much higher because we’re able to see the genetic mutation in either blood or saliva of an unaffected parent,” said Dr. Myers of the division of genetic medicine in the department of pediatrics at the University of Washington, Seattle. “If we’re able to detect it in either of those tissues that means that the level in their gametes is much higher than just a single cell or a handful of cells, which is usually how people think about de novo mutations. What we’re finding is that in 10% of cases these mutations happen during embryonic development of the parent.”

The researchers used a highly sensitive, improved version of the molecular inversion probe (MIP) technology called single molecule MIPs to investigate the frequency of somatic and germline mosaicism in parents of children with epileptic encephalopathies associated with heterozygous de novo mutations. They screened 109 families where the affected child’s epileptic encephalopathy was attributed to a substitution or small indel in 1 of 31 established epilepsy genes and reported as “de novo” by either clinical or research analysis of parental DNA. They screened for the causative variant in DNA isolated from parental blood or saliva.

Dr. Myers reported that of the 109 families screened, 10 cases of low-level somatic mosaicism were identified: 6 in fathers and 4 in mothers. The fraction of mutant alleles identified ranged from 3%-25%, which are levels that would pass undetected by traditional Sanger sequencing methods. In three families where a mosaic parent was identified, there were multiple affected children. The finding “opens up more questions for families that are thinking about future pregnancies,” she said. “I think we should have more genetic counselors working with pediatric neurologists to facilitate those discussions.”

She acknowledged certain limitations of the study, including the fact that DNA samples were extracted only from blood and saliva. “If the mutation is not present or detected in those particular tissues, it is still possible for the parent to be a germline carrier,” Dr. Myers said. “The most relevant tissue type for us to be testing would be the sex cells. We’ll have to look for families to see if they’re willing to donate [those cells] for future studies.”

The study was funded by the National Institute of Neurological Disorders and Stroke. Dr. Myers is supported by a postdoctoral fellowship provided by the Lennox-Gastaut Syndrome Foundation and by the American Epilepsy Society. She reported having no financial disclosures.


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