MNX1 – Currarino Syndrome

Currarino syndrome (CS) is an autosomal dominant congenital disorder defined by the triad of partial sacral agenesis, anorectal malformation, and presacral mass. MNX1 encodes a homeobox transcription factor essential for caudal embryonic development. Pathogenic variants in MNX1 associate with CS, guiding diagnostic evaluation in individuals presenting with one or more triad features (PMID:10749657).

Extensive mutation surveys identified intragenic MNX1 mutations in 20 of 21 familial CS index patients and in 2 of 7 sporadic cases (PMID:10749657). A multicentre study of 50 CS probands reported 23 novel MNX1 heterozygous mutations in 26 patients, yielding a detection rate of ~90% in familial settings (PMID:18449898). These data support a Definitive gene–disease relationship.

Inheritance is autosomal dominant with variable penetrance. Segregation analysis in a Swedish family revealed that 3 additional brothers carrying a frameshift MNX1 variant developed presacral tumors—two asymptomatic—underscoring intrafamilial variability (PMID:21763840).

The MNX1 variant spectrum includes frameshift (e.g., c.196_211del (p.Pro66fs)), nonsense (e.g., c.863G>A (p.Trp288Ter)), missense, polyalanine expansions, and whole-gene deletions. A GCC12 polyalanine allele (c.373_375[12]) represents a benign variant, highlighting the need for dosage analysis when sequencing is uninformative (PMID:23370340).

Functional and expression studies corroborate haploinsufficiency as the pathogenic mechanism. MNX1 is expressed in the human basal spinal cord and pancreas during Carnegie stages 12–21. Homeodomain mutations alter DNA-binding and nuclear localization, matching the clinical spectrum (PMID:10749657).

In summary, the evidence meets ClinGen Definitive criteria. MNX1 testing is recommended for patients with anorectal anomalies, hemisacrum, or presacral masses to confirm CS, inform surveillance strategies, and enable genetic counseling.

References

• American Journal of Human Genetics • 2000 • Mutation analysis and embryonic expression of the HLXB9 Currarino syndrome gene PMID:10749657
• Human Mutation • 2008 • Spectrum of HLXB9 gene mutations in Currarino syndrome and genotype-phenotype correlation PMID:18449898
• Journal of Pediatric Surgery • 2011 • Mutation analysis of the motor neuron and pancreas homeobox 1 (MNX1) gene in Swedish patients with Currarino syndrome PMID:21763840

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