Novel MNX1 mutations and genotype–phenotype analysis of patients with Currarino syndrome

• Main Authors: Lu Han, Zhen Zhang, Hui Wang, Hui Song, Qing Gao, Yuchun Yan, Ran Tao, Ping Xiao, Long Li, Qian Jiang, Qi Li
• Format: Article
• Language: English
• Published: BMC 2020-06-01
• Series: Orphanet Journal of Rare Diseases
• Subjects: Currarino syndrome; MNX1; Genotype–phenotype analysis; Recurrent; Noncanonical splice site variant
• Online Access: http://link.springer.com/article/10.1186/s13023-020-01442-4

Abstract Background Currarino syndrome (CS) is a specific complex of congenital caudal anomalies, including anorectal malformations, presacral mass and sacral anomalies. Mutations in the MNX1 gene are closely related to CS and occur in almost all familial cases and less than half of sporadic patients. We investigated the spectrum of MNX1 pathogenic variants and associated clinical features in Chinese patients with CS. Results Seventeen index patients from 16 families were recruited from 2015 to 2018. All patients were diagnosed with CS and treated at the Capital Institute of Pediatrics Affiliated Children’s Hospital. Genetic testing was applied to identify mutations in CS patients and their relatives by whole-exome sequencing and Sanger sequencing. Functional verification was performed for a recurrent noncanonical splice site variant in MNX1 with a minigene splicing assay. In 17 CS patients, 14 were complete CS and 3 were mild CS. Nine variants in MNX1 were identified in 11 patients, and these included two frameshift mutations (p.Leu223Leufs*61, p.X402Serfs*70), four nonsense mutations (p.Gly42X, p.Cys88X, p.Gln24X, p.Cys241X), one missense mutation (p.Trp288Leu), one splice region variant (c.691 + 3G > T) and one polyalanine polymorphism (p.Ala135insAlaAla). Seven of these nine variants have never been reported. Pathogenic MNX1 mutations were found in 100% (4/4) of familial and 46% (6/13) of sporadic patients. Conclusion Our study expanded the mutation spectrum of MNX1 and provided clinical and genetic analyses of seventeen CS patients from mainland China.