New findings for phenotype-genotype correlations in a large European series of holoprosencephaly cases

Abstract

An algorithm is proposed based on these new phenotype-genotype correlations, to facilitate molecular analysis and genetic counselling for HPE.

Currarino Syndrome and HPE Microform Associated with a 2.7-Mb Deletion in 7q36.3 Excluding SHH Gene

“…SHH mutations are most often associated with a microform or mild HPE, in contrast to mutations in other common HPE-related genes [Mercier et al, 2011;Solomon et al, 2012]. In the same way, it seems that a HPE phenotype associated with cytogenetic rearrangements occurring in the upstream portion of SHH gene is more often mild with predominantly HPE microforms ( table 1 ).…”

“…However, a broad clinical spectrum is observed, and no precise correlation between the phenotype and the genotype can be currently established. The variable HPE phenotype could be explained in different ways such as the extent of the deletion, an effect of an additional chromosomal imbalance, a possible position effect of the juxtaposed chromosomal regions which could modulate the expression of SHH [Lettice et al, 2011], mutations or deletion in another gene [Mercier et al, 2011], or additional environmental effects. Another explanation could be a possible imprinting effect at the SHH locus with disruption of an imprinting domain leading to an abnormal phenotype in some individuals, but not in some others [Lukusa et al, 2005].…”

“…In the clinical subtypes of HPE, microforms are characterized by facial midline defects (e.g. solitary maxillary central incisor, hypotelorism, flat nasal bridge, midface hypoplasia, and congenital nasal pyriform aperture stenosis) without neurologic findings [Mercier et al, 2011]. The etiology of HPE is heterogeneous and may result from environmental, metabolic factors, prenatal exposures to drugs or infections.…”

“…SHH is the most frequently mutated gene in HPE accounting for approximately 12% of cases [Roessler et al, 2009]. Despite of no clear phenotype-genotype correlation, the mutations of this gene are more related to milder forms of HPE such as microforms than those in other common HPE-related genes [Mercier et al, 2011;Solomon et al, 2012].The Currarino triad associates partial sacral agenesis with presacral mass and anorectal malformations. Mutations in the gene MNX1 (HLXB9) (MIM 142994), located in 7q36.3, were identified in nearly all patients with a familial form of Currarino syndrome and in 30% of those with a sporadic form [Lynch et al, 2000].…”

Array-CGH Analysis Suggests Genetic Heterogeneity in Rhombencephalosynapsis

“…Complete autopsy allows pure neurological phenotypes and those associated with extraneural anomalies to be distinguished from syndromic forms: Gomez-Lopez-Hernandez (GLH) syndrome (MIM 601853) [Lopez-Hernandez, 1982;Poretti et al, 2008] and VACTERL-H syndrome (MIM 276950) [Michaud et al, 1982;Pasquier et al, 2009]. In foetal cases, isolated RS without fusion of the colliculi (also named mesencephalosynapsis) or aqueductal anomalies are never observed; various associated supratentorial abnormalities, such as agenesis of the corpus callosum, atresia of the third ventricle and holoprosencephaly, have been described [Pasquier et al, 2009;Mercier et al, 2011;Ishak et al, 2012]. In the postnatal period, there is impaired neurological function in most cases [Romanengo et al, 1997;Danon et al, 2000], although in some cases of RS cognitive functions are normal [Obersteiner, 1914;Bell et al, 2005;Poretti et al, 2009].…”