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.

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.