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Whole-Exome Sequencing Study Reveals New Monogenetic Causes of Polymicrogyria

NEW YORK — Researchers have found six novel genetic causes for a typical brain malformation called polymicrogyria, which could help increase the rates of gene diagnosis and inform treatment options. 

In a study published in JAMA Neurology on Monday, a team led by researchers at Harvard University described their findings on the new germline mutations associated with the condition. 

Patients with polymicrogyria have excessive folding of the cortex, resulting in a malformation that an MRI identifies. It usually presents in infancy or childhood with epilepsy attacks and intellectual disabilities.

While the condition can be caused by genetic and nongenetic events such as uterine infections, the authors believe that the identifiable genetic causes of polymicrogyria are underestimated. "Prior efforts to catalog polymicrogyria-associated genes were limited by small case numbers, a focused set of considered etiologies, and use of targeted gene sequencing panels," they wrote.

For this study, the researchers resorted to exome sequencing and panel sequencing of blood DNA samples from a retrospective cohort of 275 families from 15 countries with genetically unconfirmed polymicrogyria. These samples were accrued over more than 20 years, from 1994 to 2020.

The researchers started with a targeted next-generation sequencing panel comprising 155 manually curated genes associated with polymicrogyria in 219 families. Of these, 13 families were found to have known genetic causes of the condition and were considered solved, with no further sequencing done. However, for the remaining 262 families, the authors performed exome sequencing and unraveled new genetic variants associated with the condition.

They found genetic variants with satisfactory molecular explanations in 32.7 percent or 90 of 275 polymicrogyria-affected families. This included genetic variants in six candidate novel polymicrogyria genes: de novo missense variants in PANX1, QRICH1, and SCN2A; and compound heterozygous variants in TMEM161B, KIF26A, and MAN2C1. The results, the authors noted, reveal that polymicrogyria's monogenetic causes are more common than previously documented and support clinical exome sequencing of affected individuals.

Next, the researchers generated a protein-protein interaction network map using the STRING database to organize the genetic causes of polymicrogyria according to biological mechanisms. Although most of the genes were related to previously recognized polymicrogyria-associated categories (tubulins, mTOR pathway), the findings revealed some new ones, such as ion-conducting proteins. The authors found that nearly 20 percent of polymicrogyria-associated variants were linked to genes encoding ion-conducting proteins, suggesting channelopathies are a more common cause of polymicrogyria than previously appreciated. 

The authors emphasized that their results make a strong case for using exome sequencing over panel sequencing for a genetic diagnosis of polymicrogyria. "While our paper provides strong evidence for that, I don't think that these results alone are enough to make a consensus recommendation since this study was carried out in a retrospective cohort," said lead author Shyam Akula, a medical and research student at Harvard Medical School.

However, Akula said that exome sequencing results could open doors to individualized therapies and help clinicians decide if surgery is the way to go. "I would be less likely to do an epilepsy surgery in someone with a germline mutation," he added.

The researchers also wanted to understand if head size predicted polymicrogyria etiology, as the condition frequently co-occurs with either macrocephaly or microcephaly. They analyzed the proportions of 68 affected individuals whose genetic etiologies were microcephalic, normocephalic, and macrocephalic. The results showed that most individuals with polymicrogyria had normocephaly or microcephaly. However, individuals with polymicrogyria and documented macrocephaly had variants only in genes encoding components of or related to the mTOR pathway. "This suggests that polymicrogyria co-occurring with macrocephaly should specifically prompt consideration of mTORopathies," they wrote.

The authors highlighted several limitations of the study, noting that sequencing depth precluded reliable assessment of mosaic variants, which may cause a fraction of polymicrogyria cases. The study also did not consider the cost-effectiveness of exome sequencing relative to other diagnostic strategies.

As next steps, Akula said he is interested in follow-up studies to understand the functional effects of the newly discovered genes linked to the condition, which he hopes could lead to new drugs for treating the symptoms.