Holoprosencephaly-3 (Autosomal Dominant Nonsyndromic) via the SHH Gene

Holoprosencephaly (HPE; OMIM 236100) is a common developmental anomaly of the human forebrain and midface that affects 1 in 16,000 live births (Muenke and Gropman. GeneReviews 2008) 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 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. Other findings include short stature, failure to thrive, seizures, feeding problems, and hypothalamic and brain stem dysfunction. 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). More 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).

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 (Muenke and Gropman; GeneReviews, 2008). Both autosomal recessive and dominant syndromes with HPE as a feature are known. 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 40:211-35, 1989). Seven causative loci, including five proven genes and one candidate gene (TMEM1), have been identified as causes of autosomal dominant nonsyndromic HPE. The five HPE genes are SHH, ZIC2, SIX3, TGIF, and PTCH1. Another gene, GLI2, is associated with facial features typical of HPE but does not cause typical CNS findings. Over 50 SHH variants, mostly missense, have been documented as causative for HPE3 (OMIM 142945).

SHH variants have been reported to account for 30%-40% of autosomal dominant nonsyndromic HPE and <5% of simplex cases (Nanni et al., Hum Mol Genet 8:2479-2488, 1999; Muenke and Gropman; GeneReviews, 2008).

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