William B Dobyns

Research in our laboratory involves the field of developmental neurogenetics, especially the molecular characterization of human brain malformations. Specifically, we ascertain children and some adults with brain malformations, obtain appropriate brain imaging studies and other clinical data, obtain DNA and other samples for our laboratory, identify and delineate new malformation syndromes, map and clone genes responsible for human malformation syndromes, and study the role of these genes in normal brain development and function. Lissencephaly (smooth brain, agyria-pachygyria) is a severe brain malformation caused by incomplete neuronal migration to the cerebral cortex. We identified the first human lissencephaly gene, LIS1. Hemizygous deletion or mutation of this gene results in haploinsufficiency of the LIS1 protein and causes lissencephaly. A second gene causing lissencephaly has been identified on the X chromosome (XLIS or DCX), and mutations in this gene causes lissencephaly in hemizygous males and subcortical band heterotopia in carrier females.

While this program began with the study of lissencephaly (smooth brain), it has expanded to include several malformations of brain organogenesis and cortical development. Examples of the former include (1) holoprosencephaly, (2) agenesis of the corpus callosum, (3) Dandy-Walker malformation (DWM), and (4) other hindbrain anomalies such as cerebellar vermis hypoplasia and the "molar tooth" malformation. In collaboration with Dr. Kathleen Millen, we identified the first (and should soon have the second) gene associated with DWM. Malformations of cortical development consist of (5) congenital or "primary" microcephaly; (6) periventricular heterotopia, (7) lissencephaly and subcortical band heterotopia, and (8) polymicrogyria and schizencephaly.

Research in our laboratory involves the field of developmental neurogenetics, especially the molecular characterization of human brain malformations. Specifically, we ascertain children and some adults with brain malformations, obtain appropriate brain imaging studies and other clinical data, obtain DNA and other samples for our laboratory, identify and delineate new malformation syndromes, map and clone genes responsible for human malformation syndromes, and study the role of these genes in normal brain development and function. Lissencephaly (smooth brain, agyria-pachygyria) is a severe brain malformation caused by incomplete neuronal migration to the cerebral cortex. We identified the first human lissencephaly gene, LIS1. Hemizygous deletion or mutation of this gene results in haploinsufficiency of the LIS1 protein and causes lissencephaly. A second gene causing lissencephaly has been identified on the X chromosome (XLIS or DCX), and mutations in this gene causes lissencephaly in hemizygous males and subcortical band heterotopia in carrier females.

While this program began with the study of lissencephaly (smooth brain), it has expanded to include several malformations of brain organogenesis and cortical development. Examples of the former include (1) holoprosencephaly, (2) agenesis of the corpus callosum, (3) Dandy-Walker...

Cardoso C, Leventer RJ, Ward HL, Toyo-oka K, Chung J, Gross A, Martin CL, Allanson J, Pilz DT, Olney AH, Mutchinick OM, Hirotsune S, Wynshaw-Boris A, Dobyns WB, Ledbetter DH. Refinement of a 400kb critical region allows genotypic differentiation between isolated lissencephaly, Miller-Dieker syndrome and other phenotypes secondary to deletions of 17p13.3. Am J Hum Genet 2003;72:918-930. 

Descipio C, Schneider L, Young TL, Wasserman N, Yaeger D, Lu F, Wheeler PG, Williams MS, Bason L, Jukofsky L, Menon A, Geschwindt R, Chudley AE, Saraiva J, Schinzel AA, Guichet, A, Dobyns WB, Toutain A, Spinner NB, Krantz ID. Subtelomeric deletions of chromosome 6p: molecular and cytogenetic characterization of three new cases with phenotypic overlap with Ritscher-Schinzel (3C) syndrome. Am J Med Genet A 2005;134(1):3-11. 

Dobyns WB, Filauro A, Tomson BN, Chan AS, Ho AW, Ting NT, Oosterwijk JC, Ober C. Inheritance of most X linked traits is not dominant or recessive, just X linked. Am J Med Genet A 2004;129A:136-143. 

Gilbert SL, Dobyns WB, Lahn BT. Genetic links between brain development and brain evolution. Nat Rev Genet 2005; 6: 581-90. 

Grinberg I, Northrup H, Ardinger H, Dobyns WB, Millen KJ. Heterozygous deletion of the linked ZIC1 and ZIC4 genes and Dandy-Walker malformation. Nat Genet 36:1053-1055. 

Kato M, Das S, Petras K, Kitamura K, Morohashi K, Abuelo DN, Barr M, Bonneau D, Brady A, Carpenter NJ, Frisone F, Fukuda T, Guerrini R, Iida E, Itoh M, Lewanda AF, Nanba Y, Oka A, Proud VK, Russel KL, Saugier-Veber P, Schelley SL, Selicorni A, Shaner R, Silengo M, Stewart F, Sugiyami N, Toyama J, Toutain A, Vargas AL, Yanazawa M, Zackai EH, Dobyns WB. Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. Hum Mutation, 2004;23:147-159. 

Cardoso C, Leventer RJ, Ward HL, Toyo-oka K, Chung J, Gross A, Martin CL, Allanson J, Pilz DT, Olney AH, Mutchinick OM, Hirotsune S, Wynshaw-Boris A, Dobyns WB, Ledbetter DH. Refinement of a 400kb critical region allows genotypic differentiation between isolated lissencephaly, Miller-Dieker syndrome and other phenotypes secondary to deletions of 17p13.3. Am J Hum Genet 2003;72:918-930. 

Descipio C, Schneider L, Young TL, Wasserman N, Yaeger D, Lu F, Wheeler PG, Williams MS, Bason L, Jukofsky L, Menon A, Geschwindt R, Chudley AE, Saraiva J, Schinzel AA, Guichet, A, Dobyns WB, Toutain A, Spinner NB, Krantz ID. Subtelomeric deletions of chromosome 6p: molecular and cytogenetic characterization of three new cases with phenotypic overlap with Ritscher-Schinzel (3C) syndrome. Am J Med Genet A 2005;134(1):3-11. 

Dobyns WB, Filauro A, Tomson BN, Chan AS, Ho AW, Ting NT, Oosterwijk JC, Ober C. Inheritance of most X linked traits is not dominant or recessive, just X linked. Am J Med Genet A 2004;129A:136-143. 

Gilbert SL, Dobyns WB, Lahn BT. Genetic links between brain development and brain evolution. Nat Rev Genet 2005; 6: 581-90. 

Grinberg I, Northrup H, Ardinger H, Dobyns WB, Millen KJ. Heterozygous deletion of the linked ZIC1 and ZIC4 genes and Dandy-Walker malformation. Nat Genet 36:1053-1055.