title: Minimal evidence for a direct involvement of twisted gastrulation homolog 1 (TWSG1) gene in human holoprosencephaly.
abstract: Holoprosencephaly (HPE) is the most common disorder of human forebrain and facial development. Presently understood etiologies include both genetic and environmental factors, acting either alone, or more likely, in combination. The majority of patients without overt chromosomal abnormalities or recognizable associated syndromes have unidentified etiologies. A potential candidate gene, Twisted Gastrulation Homolog 1 (TWSG1), was previously suggested as a contributor to the complex genetics of human HPE based on (1) cytogenetic studies of patients with 18p deletions, (2) animal studies of TWSG1 deficient mice, and (3) the relationship of TWSG1 to bone morphogenetic protein (BMP) signaling, which modulates the primary pathway implicated in HPE, Sonic Hedgehog (SHH) signaling. Here we present the first analysis of a large cohort of patients with HPE for coding sequence variations in TWSG1. We also performed fine mapping of 18p for a subset of patients with partial 18p deletions. Surprisingly, minimal evidence for alterations of TWSG1 was found, suggesting that sequence alterations of TWSG1 are neither a common direct cause nor a frequent modifying factor for human HPE pathologies.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Emily F
authors.initials: EF
authors.lastname: Kauvar
authors.forename: Ping
authors.initials: P
authors.lastname: Hu
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Pineda-Alvarez
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Solomon
authors.forename: Amalia
authors.initials: A
authors.lastname: Dutra
authors.forename: Evgenia
authors.initials: E
authors.lastname: Pak
authors.forename: Brooke
authors.initials: B
authors.lastname: Blessing
authors.forename: Virginia
authors.initials: V
authors.lastname: Proud
authors.forename: Alan L
authors.initials: AL
authors.lastname: Shanske
authors.forename: Cathy A
authors.initials: CA
authors.lastname: Stevens
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Shaffer
authors.forename: Erich
authors.initials: E
authors.lastname: Roessler
authors.forename: Maximilian
authors.initials: M
authors.lastname: Muenke
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000328:Adult; D000818:Animals; D001483:Base Sequence; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002887:Chromosomes, Human, Pair 18; D055028:Comparative Genomic Hybridization; D005260:Female; D056726:Genetic Association Studies; D016142:Holoprosencephaly / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009691:Nucleic Acid Denaturation; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics
chemical_list: D019485:Bone Morphogenetic Proteins