Currarino Syndrome via the MNX1 Gene

Currarino syndrome is an autosomal dominant disorder characterized by a triad of a presacral mass, anorectal malformation, and sacral agenesis (Köchling et al. 2001. PubMed ID: 11528505; Hagan et al. 2000. PubMed ID: 10749657; Lynch et al. 2000. PubMed ID: 10922380). The distinct feature of this syndrome is sacral anomaly and hence this disease is also known as hereditary sacral agenesis (HSA). There is a considerable variability of disease penetrance and expressivity. The complete triad was found in only about 30-40% of patients.

Currarino syndrome is an autosomal dominant disorder due to defects in the MNX1 gene (also known as HLXB9) (Köchling et al. 2001. PubMed ID: 11528505; Hagan et al. 2000. PubMed ID: 10749657; Ross et al. 1998. PubMed ID: 9843207). This disease is caused by defective dorsal-ventral patterning during embryonic development. As mentioned above, there is a considerable variability of disease penetrance. An obvious genotype-phenotype correlation is lacking.

The MNX1 gene (three coding exons) encodes motor neuron and pancreas homeobox protein 1. To date, documented genetic defects of MNX1 include both missense and truncating variants (nonsense, splicing variants and small indels) (Human Gene Mutation Database). Large deletions and complex rearrangements have also been reported (Human Gene Mutation Database).

In a study of 28 patients with familial or sporadic Currarino syndrome, pathogenic variants in MNX1 were detected in 20 of 21 patients with familial Currarino syndrome and in 2 of 7 patients with sporadic Currarino syndrome (Hagan et al. 2000. PubMed ID: 10749657).

In another study of 9 families with Currarino syndrome, pathogenic variants in MNX1 were detected in 4 of 4 patients with familial Currarino syndrome and in 1 of 5 simplex families (sporadic cases) (Köchling et al. 2001. PubMed ID: 11528505).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides almost full coverage of all coding exons of the MNX1 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).

This test does not include variants within c.310 to c.400 (NM_005515) due to sequence complexity.

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).