Holoprosencephaly, Autosomal Dominant, Nonsyndromic, Panel

Holoprosencephaly (HPE) is a relatively common developmental anomaly of the human forebrain affecting 1 in 10,000 live births and approximately 1 in 250 spontaneous abortions (Orioli and Castilla 2010). HPE results from failure of the developing forebrain to divide into two hemispheres and ventricles causing a continuum of structural brain malformations ranging from (in order of decreasing severity): alobar HPE to semilobar HPE to lobar HPE. In addition to the structural brain abnormality, patients with HPE may exhibit variable craniofacial anomalies including microcephaly, hypotelorism, cyclopia, proboscis, cleft lip/palate, anophthalmia or microophthalmia, absent nasal septum, flat nose, or single central incisor (Solomon et al. 2010). Because incomplete penetrance is a feature of dominantly inherited HPE, relatively normal facial appearance can be seen in individuals who have pathogenic variants and affected first degree relatives. Developmental delay is a nearly constant clinical manifestation of HPE. Severely affected newborns with alobar HPE and cyclopia and ethmocephaly usually do not live beyond the first week of life (Croen et al. 1996), but survival is greater in those cases with less severe craniofacial anomalies (Barr and Cohen 1999; Levey et al. 2010). Greater than half of all infants with semilobar or lobar HPE and no other major organ system involvement survive the first year of life (Olsen et al. 1997; Barr and Cohen 1999).

Holoprosencephaly has both genetic and non-genetic causes. Chromosome aneuploidy and structural abnormality are the overall most common cause accounting for 25%-50% of all cases; another 18%-25% of all cases occur as part of syndromes resulting from single gene pathogenic variants (Solomon et al. 2013). Both autosomal recessive and dominant syndromes with HPE as a feature exist. Nonsyndromic HPE is inherited as an autosomal dominant disorder with incomplete penetrance and intrafamilial variable expression. It is estimated that approximately one-third of obligate carriers of autosomal dominant forms of HPE are asymptomatic with normal cognitive function (Cohen 1989). Fourteen genes have been identified as causes of autosomal dominant nonsyndromic HPE. The fourteen HPE genes are CDON, CRIPTO/TDGF1, DISP1, DLL1, FGF8, FOXH1, GAS1, GLI2, NODAL, PTCH1, SHH, SIX3, TGIF1, and ZIC2 (Solomon et al. 2013). Pathogenic variants in these genes are thought to be inherited in an autosomal dominant manner. Pathogenic variants in the SHH gene are the most common cause of HPE (Roessler et al. 2009), followed by ZIC2, SIX3 and TGIF1. The prevalence of pathogenic variants in the other genes is unknown/rare (Solomon et al. 2013).

See individual gene test descriptions for information on molecular biology of gene products.

The clinical sensitivity depends on whether the affected individual has a positive family history or is a simplex case. Clinical sensitivity for pathogenic variants in the SHH, ZIC2, SIX3 and TGIF1 genes in individuals with a family history are 30-40%, 5%, 1.3% and 1.3%, respectively. For simplex cases the clinical sensitivity for pathogenic variants in the SHH and ZIC2 genes are <5% and 2%, respectively. For all other genes the clinical sensitivity is expected to be very low (Solomon et al. 2013).

The clinical sensitivity of large deletions from most genes on this panel is expected to low. Deletions in only the DLL1, GLI2, SHH, SIX3, TGIF1, and ZIC2 genes have infrequently been reported in association with holoprosencephaly (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.8% coverage of all coding exons of the genes 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 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).