Holoprosencephaly-9 (Autosomal Dominant, Nonsyndromic) via the GLI2 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 2010) 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 ventricles causing 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. Other findings include short stature, failure to thrive, seizures, feeding problems, and hypothalamic and brain stem dysfunction. Severely affected newborns with alobar HPE and 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). 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. Am J Med Genet 73:217-226, 1997; Barr and Cohen, 1999). GLI2 loss of function variants have been associated with abnormal pituitary gland formation or function and variable presentation of craniofacial findings typical of HPE (Roessler et al. Proc Natl Acad Sci 100:13424-13429, 2003; Rahimov et al. Am J Med Genet A 140, 2571-2576, 2006). Other clinical features of GLI2 HPE include isolated cleft lip/palate with polydactyly and branchial arch anomalies (Bertolacini et al. Clin Genet DOI 10.1111, 1-6, 2011). The branchial arch anomalies included hemifacial hypoplasia and preauricular skin tags.

Holoprosencephaly has both genetic and non-genetic causes. The most common non-genetic cause is maternal diabetes, which confers a risk of 1% to infants of diabetic mothers (Barr et al. J Pediatr 102:565-568, 1983). Chromosome aneuploidy and structural abnormality is the overall single most common cause accounting for 25%-50% of all cases, while another 18%-25% of all cases occur as part of syndromes resulting from single gene variants (Solomon et al. 2010). Both autosomal recessive and dominant syndromes are known with HPE as a feature. 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, Teratology 40:211-235, 1989). GLI2 loss of function variants have been associated with abnormal pituitary gland formation or function and variable presentation of craniofacial findings typical of HPE (Roessler et al. Proc Natl Acad Sci 100:13424-13429, 2003; Rahimov et al. Am J Med Genet A 140, 2571-2576, 2006). Other clinical features of GLI2 HPE include isolated cleft lip/palate with polydactyly and branchial arch anomalies (Bertolacini et al. Clin Genet DOI 10.1111, 1-6, 2011). The branchial arch anomalies included hemifacial hypoplasia and preauricular skin tags. Five other genes (SHH, ZIC2, SIX3, TGIF, and PTCH1) are also known to cause autosomal dominant nonsyndromic HPE.

GLI2 is one of the rarest causes of HPE Solomon et al. (2010). Roessler et al. (2003) found four families with GLI2 variants among 390 HPE patients. In two of the four families HPE-like craniofacial features were present.

This test provides full coverage of all coding exons of the GLI2 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).