Autosomal Dominant, Non-Syndromic Holoprosencephaly via the GAS1 Gene

Holoprosencephaly (HPE, OMIM 236100) is the most common developmental anomaly of the human forebrain and midface affecting 1 in 16,000 live births (Solomon et al. GeneReviews, 2011) and approximately 1 in 200 spontaneous abortions (Orioli et al. Hum Genet 109:1-6, 2001). HPE results from failure of the developing forebrain to divide into two hemispheres and causes a continuum of structural brain malformations ranging from alobar HPE to semilobar HPE to lobar HPE. In addition to the structural brain abnormality, patients with HPE may exhibit variable craniofacial anomalies, including cyclopia, ocular hypotelorism, structurally and positionally abnormal proboscis, bilateral cleft lip, anophthalmia or microophthalmia, absent nasal septum, flat nose, or single central incisor. Because incomplete penetrance is a feature of dominantly inherited HPE, relatively normal facial appearance can be seen in individuals who have causative gene variants and affected first degree relatives. Developmental delay is a nearly constant clinical manifestation of HPE. Severely affected newborns with alobar HPE, cyclopia, and ethmocephaly usually do not live beyond the first week of life (Croen et al. Am J Med Genet 64:465-472, 1996), but survival is greater in those cases with less severe craniofacial anomalies (Barr and Cohen Am J Med Genet 89:116-120, 1999). Clinical signs present in patients with GAS1 variants range from classic HPE to HPE-like signs (Ribeiro et al. Am J Med Genet A. 152A:1688-1694, 2010; Pineda-Alvarez et al. Hum Genet, DOI 10.1007/s00439-011-1078-6, 2011).

Holoprosencephaly (HPE) 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 variants (Solomon et al. GeneReviews, 2011). Nonsyndromic HPE is inherited as an autosomal dominant disorder with incomplete penetrance and intrafamilial variable expression. The GAS1 protein is a positive regulator of sonic hedgehog (SHH; Martinelli et al. Genes Dev 21:1231-1243, 2007), and it has been established that sequence variants in GAS1 impair its physical interaction with SHH (Pineda-Alvarez et al. 2011). Thus far, a small number of GAS1 variants have been reported, and all are amino acid substitutions (Ribeiro et al. Am J Med Genet A. 152A:1688-1694, 2010; Pineda-Alvarez et al. 2011). Most of the variants have been correlated with decreased GAS1-SHH binding affinity (Pineda-Alvarez et al. 2011).

Among 394 unrelated patients referred for HPE spectrum clinical findings, Pineda-Alvarez et al. (2011) identified five novel variants in the GAS1 gene.

This test provides full coverage of all coding exons of the GAS1 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).