title: Clinical characterization of individuals with deletions of genes in holoprosencephaly pathways by aCGH refines the phenotypic spectrum of HPE.
abstract: Holoprosencephaly (HPE) is the most common developmental forebrain anomaly in humans. Both environmental and genetic factors have been identified to play a role in the HPE phenotype. Previous studies of the genetic bases of HPE have taken a phenotype-first approach by examining groups of patients with HPE for specific mutations or deletions in known or candidate HPE genes. In this study, we characterized the presence or absence of HPE or a microform in 136 individuals in which microarray-based comparative genomic hybridization (aCGH) identified a deletion of one of 35 HPE loci. Frank holoprosencephaly was present in 11 individuals with deletions of one of the common HPE genes SHH, ZIC2, SIX3, and TGIF1, in one individual with a deletion of the HPE8 locus at 14q13, and in one individual with a deletion of FGF8, whereas deletions of other HPE loci and candidate genes (FOXA2 and LRP2) expressed microforms of HPE. Although individuals with deletions of other HPE candidates (DISP1, LSS, HHIP, SMO, BMP4, CDON, CDC42, ACVR2A, OTX2, and WIF1) had clinically significant features, none had frank HPE or a microform. A search for significant aCGH findings in individuals referred for testing for HPE revealed a novel association of a duplication involving GSK3B at 3q13.33 with HPE or a microform, seen in two unrelated individuals.
authors.affiliation: Signature Genomic Laboratories, Spokane, WA 99207, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.forename: Blake C
authors.initials: BC
authors.lastname: Ballif
authors.forename: Donna M
authors.initials: DM
authors.lastname: Martin
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Aylsworth
authors.forename: Bassem A
authors.initials: BA
authors.lastname: Bejjani
authors.forename: Beth S
authors.initials: BS
authors.lastname: Torchia
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Shaffer
mesh_terms: D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D003616:Dandy-Walker Syndrome / Q000150:complications / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D051524:Fibroblast Growth Factor 8 / Q000235:genetics; D017353:Gene Deletion; D020440:Gene Duplication; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D057895:Haploinsufficiency; D053823:Hedgehog Proteins / Q000235:genetics; D016142:Holoprosencephaly / Q000145:classification / Q000150:complications / Q000235:genetics* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008957:Models, Genetic; D009419:Nerve Tissue Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D000097607:Homeobox Protein SIX3
chemical_list: D005136:Eye Proteins; D051524:Fibroblast Growth Factor 8; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000097607:Homeobox Protein SIX3; C496456:FGF8 protein, human; C509239:SHH protein, human; C000605506:GSK3B protein, human