title: Current recommendations for the molecular evaluation of newly diagnosed holoprosencephaly patients.
abstract: Holoprosencephaly (HPE) is the most common structural malformation of the developing forebrain in humans and is typically characterized by different degrees of hemispheric separation that are often accompanied by similarly variable degrees of craniofacial and midline anomalies. HPE is a classic example of a complex genetic trait with "pseudo"-autosomal dominant transmission showing incomplete penetrance and variable expressivity. Clinical suspicion of HPE is typically based upon compatible craniofacial findings, the presence of developmental delay or seizures, or specific endocrinological abnormalities, and is then followed up by confirmation with brain imaging. Once a clinical diagnosis is made, a thorough genetic evaluation is necessary. This usually includes analysis of chromosomes by high-resolution karyotyping, clinical assessment to rule-out well recognized syndromes that are associated with HPE (e.g., Pallister-Hall syndrome, Smith-Lemli-Opitz syndrome and others), and molecular studies of the most common HPE associated genes (e.g., SHH, ZIC2 and SIX3). In this review, we provide current step-by-step recommendations that are medically indicated for the genetic evaluation of patients with newly diagnosed HPE. Moreover, we provide a brief review of several available methods used in molecular diagnostics of HPE and describe the advantages and limitations of both currently available and future tests as they relate to high throughput screening, cost, and the results that they may provide.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-3717, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Pineda-Alvarez
authors.forename: Christèle
authors.initials: C
authors.lastname: Dubourg
authors.forename: Véronique
authors.initials: V
authors.lastname: David
authors.forename: Erich
authors.initials: E
authors.lastname: Roessler
authors.forename: Maximilian
authors.initials: M
authors.lastname: Muenke
mesh_terms: D000465:Algorithms; D002869:Chromosome Aberrations; D005136:Eye Proteins / Q000235:genetics; D006287:Health Planning Guidelines; D053823:Hedgehog Proteins / Q000235:genetics; D016142:Holoprosencephaly / Q000175:diagnosis* / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D019082:Smith-Lemli-Opitz Syndrome / Q000235:genetics; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics; D000097607:Homeobox Protein SIX3
chemical_list: D005136:Eye Proteins; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D000097607:Homeobox Protein SIX3; C509239:SHH protein, human; C491812:ZIC2 protein, human