Holoprosencephaly-7 (Autosomal Dominant, Nonsyndromic) via the PTCH1 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 that 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 loci, including five documented genes and one candidate gene (TMEM1), have been identified as causes of autosomal dominant nonsyndromic HPE. The five HPE genes are SHH, ZIC2, SIX3, TGIF1, and PTCH1. Another gene, GLI2, is associated with facial features typical of HPE but does not cause typical CNS findings. In addition to HPE, PTCH1 variants cause Gorlin syndrome and sporadic basal cell carcinoma (Bale and Yu Hum Mol Genet 10:757-762, 2001). All HPE7 cases have been found to harbor PTCH1 missense variants.

PTCH1 variants are a rare cause of HPE. Thus far, five unrelated individuals with HPE have been found to have PTCH1 variants (Ming et al. Hum Genet 110:297-301, 2002).

This test provides full coverage of all coding exons of the PTCH1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.