To date, mutations in 15 actin- or microtubule-associated genes have been associated with the cortical malformation lissencephaly and variable brainstem hypoplasia. During a multicenter review, we recognized a rare lissencephaly variant with a complex brainstem malformation in three unrelated children. We searched our large brain-malformation databases and found another five children with this malformation (as well as one with a less severe variant), analyzed available whole-exome or -genome sequencing data, and tested ciliogenesis in two affected individuals. The brain malformation comprised posterior predominant lissencephaly and midline crossing defects consisting of absent anterior commissure and a striking W-shaped brainstem malformation caused by small or absent pontine crossing fibers. We discovered heterozygous de novo missense variants or an in-frame deletion involving highly conserved zinc-binding residues within the GAR domain of MACF1 in the first eight subjects. We studied cilium formation and found a higher proportion of mutant cells with short cilia than of control cells with short cilia. A ninth child had similar lissencephaly but only subtle brainstem dysplasia associated with a heterozygous de novo missense variant in the spectrin repeat domain of MACF1. Thus, we report variants of the microtubule-binding GAR domain of MACF1 as the cause of a distinctive and most likely pathognomonic brain malformation. A gain-of-function or dominant-negative mechanism appears likely given that many heterozygous mutations leading to protein truncation are included in the ExAC Browser. However, three de novo variants in MACF1 have been observed in large schizophrenia cohorts.
Bibliographical noteFunding Information:
We thank the families and their referring physicians for their important contributions to our ongoing work on these disorders. This study was funded by the US National Institutes of Health under National Institute of Neurological Disorders and Stroke grants 5R01NS050375 and 1R01NS058721 to W.B.D. and K08NS092898 to G.M.M., National Eye Institute (NEI) grant R01EY027421 , and National Heart, Lung, and Blood Institute (NHLBI) grant X01HL132377 to E.C.E. and by Netherlands ErasmusMC Mrace grant 104673 to G.M.S.M. Sequencing and/or data analysis was provided by the University of Washington Center for Mendelian Genomics with support from National Human Genome Research Institute (NHGRI) grant U54HG006493 to D.A.N. and M.J.B., the Center for Mendelian Genomics at the Broad Institute of MIT and Harvard with support from NHGRI, NEI, and NHLBI grant UM1HG008900 to Daniel MacArthur and Heidi Rehm, and the University of Washington IDDRC Genetics Core with support from NHGRI grant U54HG006493 to D.D. Additional funding came from private donations to W.B.D. and D.D. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding sources. Please note that the authors cite OMIM according to journal editorial policy but do not endorse the referenced OMIM data.
- axonal pathfinding
- brainstem hypoplasia
- midline crossing