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 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, ZIC2) and GLI3, a gene associated with polydactyly and 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 in which to study other affected children and delineate the molecular etiology of this disorder.

Pseudotrisomy 13 syndrome: Use of homozygosity mapping to target candidate genes

“…There are limited data available, however, on the significance of these genes in the context of Pseudotrisomy 13 syndrome. The published literature suggests that a mutation in these HPE genes may not be as prevalent in Pseudotrisomy 13 syndrome compared to isolated (or non-syndromic) HPE (Cordero et al, 2008;Schulz et al, 2005). It appears, too, that even in cases of isolated HPE, the frequency of point mutations in these and other HPE candidate genes is much higher in live-born infants than in stillborn foetuses, while the opposite is true for submicroscopic deletions (Bendavid et al, 2009).…”

“…The FOXA2 gene has no reported point mutations (Bendavid et al, 2006), and while microdeletions have been described in association with microforms of HPE, none have been detected in any patients with severe HPE or with Pseudotrisomy 13 (Cordero et al, 2008;Rosenfeld et al, 2010). The decision was made not to analyse this gene.…”

“…Although multiple regions of homozygosity were identified it does not necessarily follow, however, that the causative mutations are in a gene located in one of these areas. It is also possible that Pseudotrisomy 13 syndrome is digenic, rather than monogenic, in which case our approach was not tailored to find the causative mutations (Cordero et al, 2008;Ming and Muenke, 2002).…”

“…It has also been suggested that Pseudotrisomy 13 syndrome is due to submicroscopic deletions in a range of holoprosencephaly (HPE) genes, but this remains unsubstantiated (Cordero et al, 2008). We present here a case in which Pseudotrisomy 13 syndrome was diagnosed prenatally, and describe an approach based on identifying regions of homozygosity in an attempt to establish a molecular diagnosis.…”

“…Pseudotrisomy 13 syndrome is thought to be an autosomal recessive condition due to its recurrence in multiple children of normal parents, frequently in the context of consanguinity (Cohen and Gorlin, 1991;Lurie and Wulfsberg, 1993;Ramos-Arroyo et al, 1994;Schulz et al, 2005;Seller et al, 1993;Utine et al, 2008;Verloes et al, 1991); however a causative gene has yet to be mapped (Cordero et al, 2008;Utine et al, 2008). It has also been suggested that Pseudotrisomy 13 syndrome is due to submicroscopic deletions in a range of holoprosencephaly (HPE) genes, but this remains unsubstantiated (Cordero et al, 2008).…”