Novel mutations in the MNX1 gene in two families with Currarino syndrome and variable phenotype.

The Currarino syndrome (CS) consists of a sacral defect, an anorectal malformation and a pre-sacral mass. It manifests as an autosomal dominant congenital malformation in familial settings, with varying penetrance. The disease-causing gene, Motor neuron and pancreas homeobox-1 (MNX1), is known to be mutated in almost all familial cases, but due to the lack of genotype-phenotype correlation, there is a need for better clinical and molecular genetic characterization of the CS. Here, we report two novel mutations in the MNX1 gene in two cases. Each case was found to be familial upon further investigation of the other members of each family. The first affected case (a one year old boy) exhibited a missense mutation, p.Phe289Ser, in exon 3 in the highly conserved third helix of the homeodomain, which is considered to affect the DNA binding property and transcription regulation of the protein. The mutation seemed to display full penetrance of the disease in this family, but with different time of on-set. The second affected case (a 5 months old boy) displayed a 13 basepair insertion in exon 1, creating a complex frameshift mutation which results in a premature truncation of the protein that lacks the third helix homeodomain. Other members of the boy's family, who harbored the same mutation, were found to be completely asymptomatic. In conclusion, we detected two novel mutations in the MNX1 gene in cases with CS, which supports mutational analysis in the diagnosis of CS, even though the variability in the genotype and phenotype correlation maintains.