Acrofacial Dysostosis 1, Nagar Type via the SF3B4 Gene

Acrofacial dysostosis, Nager type is characterized by malformation of the craniofacial area and the limbs. The major craniofacial features are: downslanted palpebral fissures, midface retrusion, and micrognathia. The upper limb defects consist of small or absent thumbs, triphalangeal thumbs, radial hypoplasia or aplasia, and radioulnar synostosis. Some other features include, but are not limited to, cleft palate, tracheotomy and hearing loss. Acrofacial dysostosis, Nager type shares some features with Miller syndrome (Bernier et al. 2012).

SF3B4-related Acrofacial dysostosis, Nager type is inherited in an autosomal dominant manner. One SF3B4 de novo pathogenic variant was found in a patient affected with Rodriguez syndrome, a severe acrofacial dysostosis, phocomelia with pre- and post-axial limb defects, fibular agenesis, rib, and shoulder girdle anomalies (McPherson et al. 2014). In a study of 14 families, at least five of the sporadic cases were de novo, suggesting complete penetrance (Petit et al. 2014). The SF3B4 protein is a component of the U2 pre-mRNA spliceosomal complex involving RNA-binding activity. To date, ~30 unique pathogenic variants have been documented in HGMD (Human Gene Mutation Database): missense (6%); nonsense (20%), splicing (13%), small deletion/insertion (61%). No large deletions/insertions have been reported (Bernier et al. 2012; Petit et al. 2014; Castori et al. 2014; HGMD).

Bernier et al. (2012) identified 18 different heterozygous SF3B4 pathogenic variants in 20 (57%) of 35 families affected by Acrofacial dysostosis, Nager type. Analytical sensitivity should be high because almost all of the documented SF3B4 pathogenic variants are point mutations, and small deletion/insertions which are expected to be detected by direct sequencing of genomic DNA.

This test provides full coverage of all coding exons of the SF3B4 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).