Holoprosencephaly-2 (Autosomal Dominant, Nonsyndromic) via the SIX3 Gene

Holoprosencephaly (HPE; OMIM 236100) is a common developmental anomaly of the human forebrain and midface affecting 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 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, 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).

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 Pediat. 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 not typical CNS findings. HPE2 (OMIM 157170) results from SIX3 variants, the majority of which are missense variants.

SIX3 variants are a rare cause of HPE. In a study of 200 HPE probands, Dubourg et al. (Hum Mut 24:43- 51, 2004) found eight causative SIX3 variants.

This test provides full coverage of all coding exons of the SIX3 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).