Michal Gafner1,2, Marina Michelson2,3,4, Emanuela Argilli5,6, Keren Yosovich2,3,7, Elliott H Sherr5,6, Kendall C Parks5,6, Eleina M England8, Ronen Hady-Cohen2,3,9, Zvi Leibovitz10,11, Dorit Lev2,3,4, Yael Michaeli-Yosef2,3,9, Tally Lerman-Sagie2,3,9, Lubov Blumkin12,13,14,15. 1. Department of Pediatrics B, Schneider Children's Medical Center of Israel, Petach Tikva, Israel. 2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 3. Magen Center for Rare Diseases, Wolfson Medical Center, Holon, Israel. 4. The Rina Mor Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel. 5. Department of Neurology, University of California, San Francisco, San Francisco, CA, USA. 6. Institute of Human Genetics and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. 7. Molecular Genetics Laboratory, Wolfson Medical Center, Holon, Israel. 8. Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 9. Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel. 10. Fetal Neurology Clinic, Wolfson Medical Center, Holon, Israel. 11. Obstetrics-Gynecology Ultrasound Unit, Rappaport Faculty of Medicine, Bnai-Zion Medical Center, The Technion, Haifa, Israel. 12. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. luba.blumkin@gmail.com. 13. Magen Center for Rare Diseases, Wolfson Medical Center, Holon, Israel. luba.blumkin@gmail.com. 14. Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel. luba.blumkin@gmail.com. 15. Pediatric Movement Disorders Service, Wolfson Medical Center, Holon, Israel. luba.blumkin@gmail.com.
Abstract
OBJECTIVE: BCORL1, a transcriptional co-repressor, has a role in cortical migration, neuronal differentiation, maturation, and cerebellar development. We describe BCORL1 as a new genetic cause for major brain malformations. METHODS AND RESULTS: We report three patients from two unrelated families with neonatal onset intractable epilepsy and profound global developmental delay. Brain MRI of two siblings from the first family depicted hypoplastic corpus callosum and septal agenesis (ASP) in the older brother and unilateral perisylvian polymicrogyria (PMG) in the younger one. MRI of the patient from the second family demonstrated complete agenesis of corpus callosum (CC). Whole Exome Sequencing revealed a novel hemizygous variant in NM_021946.5 (BCORL1):c.796C>T (p.Pro266Ser) in the two siblings from the first family and the NM_021946.5 (BCORL1): c.3376G>A; p.Asp1126Asn variant in the patient from the second family, both variants inherited from healthy mothers. We reviewed the patients' charts and MRIs and compared the phenotype to the other published BCORL1-related cases. Brain malformations have not been previously described in association with the BCORL1 phenotype. We discuss the potential influence of BCORL1 on brain development. CONCLUSIONS: We suggest that BCORL1 variants present with a spectrum of neurodevelopmental disorders and can lead to major brain malformations originating at different stages of fetal development. We suggest adding BCORL1 to the genetic causes of PMG, ASP, and CC dysgenesis.
OBJECTIVE: BCORL1, a transcriptional co-repressor, has a role in cortical migration, neuronal differentiation, maturation, and cerebellar development. We describe BCORL1 as a new genetic cause for major brain malformations. METHODS AND RESULTS: We report three patients from two unrelated families with neonatal onset intractable epilepsy and profound global developmental delay. Brain MRI of two siblings from the first family depicted hypoplastic corpus callosum and septal agenesis (ASP) in the older brother and unilateral perisylvian polymicrogyria (PMG) in the younger one. MRI of the patient from the second family demonstrated complete agenesis of corpus callosum (CC). Whole Exome Sequencing revealed a novel hemizygous variant in NM_021946.5 (BCORL1):c.796C>T (p.Pro266Ser) in the two siblings from the first family and the NM_021946.5 (BCORL1): c.3376G>A; p.Asp1126Asn variant in the patient from the second family, both variants inherited from healthy mothers. We reviewed the patients' charts and MRIs and compared the phenotype to the other published BCORL1-related cases. Brain malformations have not been previously described in association with the BCORL1 phenotype. We discuss the potential influence of BCORL1 on brain development. CONCLUSIONS: We suggest that BCORL1 variants present with a spectrum of neurodevelopmental disorders and can lead to major brain malformations originating at different stages of fetal development. We suggest adding BCORL1 to the genetic causes of PMG, ASP, and CC dysgenesis.
Authors: Janneke H M Schuurs-Hoeijmakers; Anneke T Vulto-van Silfhout; Lisenka E L M Vissers; Ilse I G M van de Vondervoort; Bregje W M van Bon; Joep de Ligt; Christian Gilissen; Jayne Y Hehir-Kwa; Kornelia Neveling; Marisol del Rosario; Gausiya Hira; Santina Reitano; Aurelio Vitello; Pinella Failla; Donatella Greco; Marco Fichera; Ornella Galesi; Tjitske Kleefstra; Marie T Greally; Charlotte W Ockeloen; Marjolein H Willemsen; Ernie M H F Bongers; Irene M Janssen; Rolph Pfundt; Joris A Veltman; Corrado Romano; Michèl A Willemsen; Hans van Bokhoven; Han G Brunner; Bert B A de Vries; Arjan P M de Brouwer Journal: J Med Genet Date: 2013-10-11 Impact factor: 6.318
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Authors: Yong-hui Jiang; Ryan K C Yuen; Xin Jin; Mingbang Wang; Nong Chen; Xueli Wu; Jia Ju; Junpu Mei; Yujian Shi; Mingze He; Guangbiao Wang; Jieqin Liang; Zhe Wang; Dandan Cao; Melissa T Carter; Christina Chrysler; Irene E Drmic; Jennifer L Howe; Lynette Lau; Christian R Marshall; Daniele Merico; Thomas Nalpathamkalam; Bhooma Thiruvahindrapuram; Ann Thompson; Mohammed Uddin; Susan Walker; Jun Luo; Evdokia Anagnostou; Lonnie Zwaigenbaum; Robert H Ring; Jian Wang; Clara Lajonchere; Jun Wang; Andy Shih; Peter Szatmari; Huanming Yang; Geraldine Dawson; Yingrui Li; Stephen W Scherer Journal: Am J Hum Genet Date: 2013-07-11 Impact factor: 11.025