title: Holoprosencephaly-Polydactyly syndrome: in search of an etiology.
abstract: Holoprosencephaly-Polydactyly (HPS) or Pseudotrisomy 13 syndrome are names conferred to clinically categorize patients whose phenotype is congruent with Trisomy 13 in the context of a normal karyotype. The literature suggests that this entity may be secondary to submicroscopic deletions in holoprosencephaly (HPE) genes; however, a limited number of investigations have been undertaken to evaluate this hypothesis. To test this hypothesis we studied a patient with HPE, polydactyly, and craniofacial dysmorphologies consistent with the diagnosis of Trisomy 13 whose karyotype was normal. We performed mutational analysis in the four main HPE causing genes (SHH, SIX3, TGIF, and ZIC2) and GLI3, a gene associated with polydactyly as well as fluorescent in situ hybridization (FISH) to search for microdeletions in these genes and two candidate HPE genes (DISP1 and FOXA2). No mutations or deletions were detected. A whole genome approach utilizing array Comparative Genomic Hybridization (aCGH) to screen for copy number abnormalities was then taken. No loss or gain of DNA was noted. Although a single case, our results suggest that coding mutations in these HPE genes and copy number anomalies may not be causative in this disorder. Instead, HPS likely involves mutations in other genes integral in embryonic development of the forebrain, face and limbs. Our systematic analysis sets the framework to study other affected children and delineate the molecular etiology of this disorder.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Dwight R
authors.initials: DR
authors.lastname: Cordero
authors.forename: Claude
authors.initials: C
authors.lastname: Bendavid
authors.forename: Alan L
authors.initials: AL
authors.lastname: Shanske
authors.forename: Bassem R
authors.initials: BR
authors.lastname: Haddad
authors.forename: Maximilian
authors.initials: M
authors.lastname: Muenke
mesh_terms: D005136:Eye Proteins / Q000235:genetics; D017353:Gene Deletion; D018628:Gene Dosage; D053823:Hedgehog Proteins / Q000235:genetics; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics; D016142:Holoprosencephaly / Q000235:genetics* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D009693:Nucleic Acid Hybridization; D017689:Polydactyly / Q000235:genetics* / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D000074290:Zinc Finger Protein Gli3; D000097607:Homeobox Protein SIX3
chemical_list: D005136:Eye Proteins; D053823:Hedgehog Proteins; D051542:Hepatocyte Nuclear Factor 3-beta; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D012697:Serine Endopeptidases; D014157:Transcription Factors; D000074290:Zinc Finger Protein Gli3; D000097607:Homeobox Protein SIX3; C496502:FOXA2 protein, human; C065683:GLI3 protein, human; C509239:SHH protein, human; C097504:TGIF1 protein, human; C491812:ZIC2 protein, human; C408085:distal intestinal serine protease