Microform Holoprosencephaly (HPE10) via the DISP1 Gene

Holoprosencephaly (HPE, OMIM 236100) is a common developmental anomaly of the human forebrain and midface affecting 1 in 16,000 live births (Solomon et al. GeneReviews, 2008) and approximately 1 in 200 spontaneous abortions (Orioli et al. 2001. PubMed ID: 11479728). Disruption of the sonic hedgehog (SHH) signaling pathway, and specifically variants of the SHH ligand encoded by the SHH gene, is the most common underlying cause of HPE (Roessler et al. 2009. PubMed ID: 19603532). Other proteins involved with the SHH pathway are also known to be involved in the HPE spectrum. Those proteins include the receptor of the SHH ligand, encoded by the PTCH1 gene; the GLI2 gene product, which is involved in transduction of SHH ligand; and the SIX3 gene product, which acts as a regulator of SHH gene transcription. Another protein, termed "homolog of Drosophila dispatched 1’" is encoded by the DISP1 gene (OMIM 607502), and is required for secretion of SHH ligand. Experimental evidence indicates that DISP1-mediated release of soluble SHH ligand is negatively affected by alteration in functionally important residues of the PTCH1 gene product (Ma et al. 2002. PubMed ID: 12372301). Consequently, DISP1 was considered an HPE candidate gene because of its functional role in SHH signaling and its location at chromosome 1q41 where the HPE10 locus (OMIM 612530) was previously mapped (Roessler and Muenke. 1998. PubMed ID: 9728329). In a study of a large HPE cohort consisting of patients with mild to severe clinical presentations,  two unrelated children with microform HPE and truncating variants of the DISP1 gene were found (Roessler et al. 2009. PubMed ID: 19184110). One child had a history of seizures, developmental delay including speech, and cleftlip/palate. She was diagnosed as having HPE sequence with a normal head CT scan. The second case had clear signs of microform HPE with a repaired bilateral cleft-lip/palate, hypotelorism, upslanting palpebral fissures, and a solitary maxillary central incisor. She was of normal intelligence and had a normal brain MRI. Previously, (Shaffer et al. 2007. PubMed ID: 17873649) reported seven de novo cases of chromosome 1q41-q42 deletion syndrome with features of developmental delay, seizures, craniofacial dysmorphisms, microcephaly, cleft palate, clubfeet, and short stature. As a result of the phenotypic similarity of these seven patients to the two cases described above, and because DISP1 is located within the 1q41-q42 region, Roessler et al. suggested that haploinsufficiency for DISP1 may confer susceptibility to the craniofacial and neurodevelopmental disorders at the mild end of the HPE spectrum (Roessler et al. 2009. PubMed ID: 19184110).

The two reported DISP1 variants predict heterozygous loss of function, and both were inherited from a clinically unaffected parent. Roessler et al. commented that incomplete penetrance is not inconsistent with microforms of HPE (Roessler et al. 2009. PubMed ID: 19184110).

The DISP1 gene is composed of 7 coding exons and is located on chromosome 1q41.

Two cases with DISP1 variants were found among a cohort of 520 HPE patients (Roessler et al. 2009. PubMed ID: 19184110).

This test provides full coverage of all coding exons of the DISP1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).