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LIS1 missense mutations cause milder lissencephaly phenotypes including a child with normal IQ

* Drs. Leventer and Cardoso contributed equally to this article., From the Departments of Human Genetics (Drs. Leventer, Cardoso, Ledbetter, and Dobyns), Neurology (Drs. Leventer and Dobyns) and Pediatrics (Drs. Ledbetter and Dobyns), The University of Chicago, IL.

Address correspondence and reprint requests to Dr. William B. Dobyns, University of Chicago Department of Human Genetics, 5841 S. Maryland Ave., Rm. L163, MC 2050, Chicago, IL 60637; e-mail: wbd{at}genetics.bsd.uchicago.edu

Background:— Classical lissencephaly is a disorder of neuroblast migration with most patients having mutations of either the LIS1 or DCX genes. Most patients with lissencephaly secondary to LIS1 mutations have a severe malformation consisting of generalized agyria and pachygyria. However, increasing experience suggests that the phenotypic spectrum is wider than previously thought.

Methods:— The authors describe the clinical and imaging features and mutation data of the five known patients with missense mutations of the LIS1 gene and emphasize one patient with normal intelligence.

Results:— Patients with a missense mutation of the LIS1 gene have a wider and milder spectrum of cortical malformations and clinical sequelae compared with patients with other mutation types.

Conclusion:— Milder and more variable phenotypes seen in patients with missense mutations of LIS1 are likely a consequence of suboptimal function of the mutant LIS1 protein, rather than complete loss of function of this protein. The authors suggest that the few patients found thus far with missense mutations of LIS1 results from an underascertainment of patients with more subtle malformations and that abnormalities of the LIS1 gene may account for a greater spectrum of neurologic problems in childhood than has previously been appreciated.

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