Agnathia-Otocephaly Complex Panel

Agnathia-otocephaly complex is a lethal malformation disorder that probably occurs early in embryogenesis (Schiffer et al. 2002). Mandibular hypoplasia or agnathia and abnormal ear position or ear fusion are the hallmark findings. Other findings include cleft palate, hypotelorism, microstomia, and the tongue can be small or absent. Variable findings include pulmonary hypoplasia and genitourinary and cardiovascular anomalies. Holoprosencephaly and situs inversus are commonly found in affected infants. Prenatal ultrasound has detected an affected fetus with polyhydramnios, micrognathia, low-set ears, and malformed feet (Akiyama et al. 2013). Affected babies have been reported to die in utero or shortly after birth.

Agnathia-otocephaly complex is inherited in an autosomal dominant manner and is caused by pathogenic variants in the PRRX1 or OTX2 genes. However, the PRRX1 gene also has been reported to be responsible for an autosomal recessive form of otocephaly (Çelik et al. 2011).

This Agnathia-otocephaly complex panel includes the PRRX1 and OTX2 genes.

PRRX1: encodes the paired-related homeobox 1 protein. It is expressed in specific temporal and spatial patterns and functions as a transcriptional regulator of developmental processes. One case of familial recurrence due to paternal gonadal mosaicism has been reported (Dasouki et al. 2013). A de novo pathogenic variant in PRRX1 has also been reported in an infant with Agnathia-otocephaly (Donnelly et al. 2012).

OTX2 (Orthodenticle homeobox 2): encodes a bicoid class homeobox family transcription factor that is required for normal development of the forebrain, eye, and pituitary gland. The reported pathogenic variants in OTX2 in Agnathia-otocephaly are variants with complete loss of function of the protein, such as nonsense, frame-shift mutation, as well as large deletions (Sergouniotis et al. 2015). De novo pathogenic variants are common in Agnathia-otocephaly complex patients. Extreme variable expression has been seen (Patat et al. 2013).

Less than 15% of otocephalic infants tested were found to have pathogenic variants in the PRRX1 gene (Donnelly et al. 2012). The clinical and analytical sensitivity are unknown for the OTX2 gene due to the rarity of this disorder.

This panel provides full coverage of coding exons of the genes 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 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).