Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2010 Feb 15;154C(1):93-101.
doi: 10.1002/ajmg.c.30253.

Current recommendations for the molecular evaluation of newly diagnosed holoprosencephaly patients

Daniel E Pineda-Alvarez  1 , Christèle Dubourg, Véronique David, Erich Roessler, Maximilian Muenke
Affiliations
Review

Current recommendations for the molecular evaluation of newly diagnosed holoprosencephaly patients

Daniel E Pineda-Alvarez et al. Am J Med Genet C Semin Med Genet. .

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Algorithm for the genetic study of new holoprosencephaly patients
Bold lines refer to medically indicated tests; thin lines are optional tests depending on a specific clinical indication or the capabilities of the diagnostic laboratory; dotted lines refer to tests available in research labs that will contribute to a better understanding of HPE. For further details, see the following references: a: [Hahn et al., this issue; [Hahn and Plawner, 2004] b: [Dubourg et al., 2007] c: [Roessler and Muenke, this issue] d: [Bendavid et al., this issue] e: Refers to High-Resolution DNA Melting (HRM) f: Multiplex Ligation-dependent Probe Amplification (MLPA) g: gene specific phenotype, h: [Bullen et al., 2001; Ong et al., 2007]. i: recruit parental samples for better test interpretation in case of a positive result. +: positive diagnostic test results.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Bejjani BA, Shaffer LG. Application of array-based comparative genomic hybridization to clinical diagnostics. J Mol Diagn. 2006;8:528–533. - PMC - PubMed
    1. Bendavid C, Rochard L, Dubourg C, Seguin J, Gicquel I, Pasquier L, Vigneron J, Laquerriere A, Marcorelles P, Jeanne-Pasquier C, Rouleau C, Jaillard S, Mosser J, Odent S, David V. Array-CGH analysis indicates a high prevalence of genomic rearrangements in holoprosencephaly: an updated map of candidate loci. Hum Mutat. 2009;30:1175–1182. - PubMed
    1. Brown SA, Warburton D, Brown LY, Yu CY, Roeder ER, Stengel-Rutkowski S, Hennekam RC, Muenke M. Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired. Nat Genet. 1998;20:180–183. - PubMed
    1. Bullen PJ, Rankin JM, Robson SC. Investigation of the epidemiology and prenatal diagnosis of holoprosencephaly in the North of England. Am J Obstet Gynecol. 2001;184:1256–1262. - PubMed
    1. Cohen MM., Jr Holoprosencephaly: clinical, anatomic, and molecular dimensions. Birth Defects Res A Clin Mol Teratol. 2006;76(9):658–673. - PubMed

Publication types