Publication Q&A: ANKLE2-related Microcephaly: A Variable Microcephaly Syndrome Resembling Zika Infection

August 2022 – Dr. Ghayda Mirzaa, principal investigator in Seattle Children’s Center for Integrative Brain Research and assistant professor of pediatrics and genetics at the University of Washington School of Medicine, and colleagues share their discovery that genetic variants in ANKLE2 cause small brain size in children that overlap with the Zika virus and provide links between genetic and acquired causes for microcephaly. 

Ajay Thomas, Nichole Link, Laurie Robak, Gail Demmler-Harrison, Emily Pao*, Audrey Squire*, Savannah Michels, Julie Cohen, Anne Comi, Paolo Prontera, Alberto Verrotti di Pianella, Giuseppe Di Cara, Livia Garavelli, Stefano Giuseppe Caraffi, Carlo Fusco, Roberta Zuntini, Kendall Parks, Elliott Sherr, Mais Hashem, Sateesh Maddirevula, Fowzan Alkuraya, Isphana Contractar, Jennifer Neil, Christopher Walsh, Hugo Bellen, Hsiao-Tuan Chao, Robin Clark, Ghayda Mirzaa*

First published July 24, 2022

Read this article in the Annals of Clinical and Translational Neurology.

What are the significant findings in this paper?

Changes in the ANKLE2 gene cause a unique syndrome where children have microcephaly (small brain size) apparent either at birth or shortly after birth, with a broad range of other structural brain abnormalities. This study also identified shared mechanisms between ANKLE2 and congenital Zika virus infection, a well-known cause of microcephaly in affected areas.

What does this research tell us that we didn’t know before?

This is the first study to report on the clinical spectrum of ANKLE2, a rare disorder causing small brain size in children, and shows that children can have variable microcephaly and other neurodevelopmental issues. This research allowed us to also better understand links between ANKLE2, a genetic insult, and congenital Zika infection, a viral insult causing microcephaly.

What are the broad implications of this research?

This study highlights the importance of a thorough diagnostic evaluation, including molecular diagnostic testing, in children presenting with microcephaly whether at birth or later, with consideration for both genetic and acquired causes.

What are the next steps and long-term goals for this research?

This research has helped us better understand causes of microcephaly in children. Long-term goals include using comprehensive genetic tools (e.g., whole genome sequencing) to identify underlying genetic causes more globally to facilitate earlier diagnosis for families.

Any other specific information about this paper?

This was a highly collaborative and multidisciplinary initiative.

Learn more about Dr. Mirzaa’s research.

*Seattle Children’s contributing authors