Journal article

Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly

Meng-Han Tsai, Alison M Muir, Won-Jing Wang, Yi-Ning Kang, Kun-Chuan Yang, Nian-Hsin Chao, Mei-Feng Wu, Ying-Chao Chang, Brenda E Porter, Laura A Jansen, Guillaume Sebire, Nicolas Deconinck, Wen-Lang Fan, Shih-Chi Su, Wen-Hung Chung, Edith P Almanza Fuerte, Michele G Mehaffey, Ching-Ching Ng, Chung-Kin Chan, Kheng-Seang Lim Show all

Neuron | CELL PRESS | Published : 2020

Abstract

Lissencephaly (LIS), denoting a "smooth brain," is characterized by the absence of normal cerebral convolutions with abnormalities of cortical thickness. Pathogenic variants in over 20 genes are associated with LIS. The majority of posterior predominant LIS is caused by pathogenic variants in LIS1 (also known as PAFAH1B1), although a significant fraction remains without a known genetic etiology. We now implicate CEP85L as an important cause of posterior predominant LIS, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance. We show that CEP85L is a centrosome protein localizing to the pericentriolar material, and knockdow..

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Grants

Awarded by University of Washington Birth Defects Research Laboratory (NIH)


Awarded by University of Washington Intellectual and Developmental Disabilities Research Center (IDDRC; NIH) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development


Awarded by NHLBI


Awarded by National Institutes of Health (NIH)


Awarded by Chang Gung Medical Foundation (CGMF)


Awarded by Ministry of Science and Technology (MOST), Taiwan


Awarded by MOST


Awarded by NYMU School of Medicine, Taiwan


Awarded by National Institute of Neurological Disorders and Stroke (NINDS)


Awarded by National Health and Medical Research Council (NHMRC) of Australia


Awarded by NHMRC Senior Practitioner Fellowship


Awarded by NHMRC Career Development Fellowship


Awarded by Australian Genomics Health Alliance - NHMRC


Funding Acknowledgements

We thank the patients and their families for participating in this study. We thank Dr. Sarah Barton for assistance with MRI image processing. This work was supported by the University of Washington Birth Defects Research Laboratory (NIH 5R24HD000836) and the University of Washington Intellectual and Developmental Disabilities Research Center (IDDRC; NIH U54HD083091) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Sequencing was provided by the University of Washington Center for Mendelian Genomics (UW-CMG) and was funded by NHGRI and NHLBI grants UM1 HG006493 and U24 HG008956. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. A.M.M. received support from the American Epilepsy Society. H.C.M. received support from the National Institutes of Health (NIH R01 NS069605). M.-H.T. received support from Chang Gung Medical Foundation (CGMF grant CMRPG8G0252), Whole-Genome Research Core Laboratory of Human Diseases at CGMF, and Ministry of Science and Technology (MOST grants 106-2314-B-182A-077 and 107-2314-B-182A057-MY3), Taiwan. J.-W.T. received support from MOST (103-2628-B-010002-MY3, 106-2628-B-010-002-MY3, 107-2633-B-009-003, 107-2221-E010-014, 108-2638-B-010-001-MY2, and 108-2321-B-010-011-MY2), the National Health Research Institute (NHRI), the Brain Research Center, NYMU through the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education, and NYMU School of Medicine (107F-M01-0502), Taiwan. W.-J.W. received support from MOST (108-2628-B-010-007 and 107-2313-B-010-001). G.M.M. received support from the National Institute of Neurological Disorders and Stroke (NINDS) under award number K08NS092898, Jordan's Guardian Angels, and the Brotman Baty Institute. I.E.S. and S.F.B. were supported by National Health and Medical Research Council (NHMRC) of Australia (program grant 628952, 2011-2015; 1091593, 2016-2020); I.E.S. has a NHMRC Senior Practitioner Fellowship (1006110, 2011-2015; 1104831 2016-2020). M.S.H. was supported by a NHMRC Career Development Fellowship (1063799) and project grant (1079058). R.J.L. is supported by a Melbourne Children's Clinician Scientist Fellowship. Support was received from the Australian Genomics Health Alliance, funded by NHMRC grant 1113531 and the Australian Government's Medical Research Future Fund.