Spectrum of MNX1 Pathogenic Variants and Associated Clinical Features in Korean Patients with Currarino Syndrome
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Background: The major genetic cause of Currarino syndrome (CS), a congenital malformation syndrome typically characterized by sacral agenesis, anorectal malformation, and presence of a pre-sacral mass, is known to be pathogenic variants in motor neuron and pancreas homeobox 1 (MNX1), which exist in almost all familial cases and 30% of sporadic cases. Less commonly, a large deletion or a complex rearrangement involving the 7q36 region is associated with CS. We investigated the spectrum of MNX1 pathogenic variants and associated clinical features in the Korean patients with CS. Methods: We enrolled 25 patients with CS, including 24 sporadic cases and one familial case. Direct sequencing of MNX1 and multiplex ligation-dependent probe amplification were performed. We also analyzed clinical phenotypes and evaluated genotype-phenotype correlations. Results: We identified six novel variants amongst a total of six null variants, one missense variant, and one large deletion. The null variants included four frameshift variants (p.Gly98Alafs* 124, p.Gly145Alafs*77, p.Gly151Leufs*67, and p.Ala216Profs*5) and two nonsense variants (p.Tyr186* and p.Gln212*). The missense variant, p.Lys295Gln, was located in the highly-conserved homeobox domain and was predicted to be deleterious. A large deletion involving the 7q36 region was detected in one patient. Pathogenic variants in MNX1 were detected in 28% of all CS cases and 25% of sporadic cases. The clinical phenotype was variable in patients with and without pathogenic variants; no significant genotype-phenotype correlation was observed. Conclusions: This study revealed the spectrum and phenotypic variability of MNX1 pathogenic variants in the Korean population.
Abstract
Background: The major genetic cause of Currarino syndrome (CS), a congenital malformation syndrome typically characterized by sacral agenesis, anorectal malformation, and presence of a pre-sacral mass, is known to be pathogenic variants in motor neuron and pancreas homeobox 1 (MNX1), which exist in almost all familial cases and 30% of sporadic cases. Less commonly, a large deletion or a complex rearrangement involving the 7q36 region is associated with CS. We investigated the spectrum of MNX1 pathogenic variants and associated clinical features in the Korean patients with CS. Methods: We enrolled 25 patients with CS, including 24 sporadic cases and one familial case. Direct sequencing of MNX1 and multiplex ligation-dependent probe amplification were performed. We also analyzed clinical phenotypes and evaluated genotype-phenotype correlations. Results: We identified six novel variants amongst a total of six null variants, one missense variant, and one large deletion. The null variants included four frameshift variants (p.Gly98Alafs* 124, p.Gly145Alafs*77, p.Gly151Leufs*67, and p.Ala216Profs*5) and two nonsense variants (p.Tyr186* and p.Gln212*). The missense variant, p.Lys295Gln, was located in the highly-conserved homeobox domain and was predicted to be deleterious. A large deletion involving the 7q36 region was detected in one patient. Pathogenic variants in MNX1 were detected in 28% of all CS cases and 25% of sporadic cases. The clinical phenotype was variable in patients with and without pathogenic variants; no significant genotype-phenotype correlation was observed. Conclusions: This study revealed the spectrum and phenotypic variability of MNX1 pathogenic variants in the Korean population.
참고문헌 (38)
- Currarino G, "Triad of anorectal, sacral, and presacral anomalies", AJR Am J Roentgenol, 137, pp.395~398 (1981)[DOI]
- Horn D, "Minimal clinical expression of the holoprosencephaly spectrum and of Currarino syndrome due to different cytogenetic rearrangements deleting the Sonic Hedgehog gene and the HLXB9 gene at 7q36.3", Am J Med Genet A, 128A, pp.85~92 (2004)[DOI]
- Pavone P, "Microcephaly, sensorineural deafness and Currarino triad with duplication-deletion of distal 7q", Eur J Pediatr, 169, pp.475~481 (2010)[DOI]
- Cuturilo G, "Phenotype analysis impacts testing strategy in patients with Currarino syndrome", Clin Genet, 89, pp.109~114 (2016)[DOI]
- Hagan DM, "Mutation analysis and embryonic expression of the HLXB9 Currarino syndrome gene", Am J Hum Genet, 66, pp.1504~1515 (2000)[DOI]
- Kochling J, "Spectrum of mutations and genotypephenotype analysis in Currarino syndrome", Eur J Hum Genet, 9, pp.599~605 (2001)[DOI]
- Wang RY, "A previously unreported mutation in a Currarino syndrome kindred", Am J Med Genet A, 140, pp.1923~1930 (2006)
- Cretolle C, "Currarino syndrome shown by prenatal onset ventriculomegaly and spinal dysraphism", Am J Med Genet A, 143A, pp.871~874 (2007)[DOI]
- Kim IS, "Clinical and genetic analysis of HLXB9 gene in Korean patients with Currarino syndrome", J Hum Genet, 52, pp.698~701 (2007)[DOI]
- Zu S, "Mutation analysis of the motor neuron and pancreas homeobox 1 (MNX1, former HLXB9) gene in Swedish patients with Currarino syndrome", J Pediatr Surg, 46, pp.1390~1395 (2011)[DOI]
- Markljung E, "Novel mutations in the MNX1 gene in two families with Currarino syndrome and variable phenotype", Gene, 507, pp.50~53 (2012)[DOI]
- Wang Y, "A novel HLXB9 mutation in a Chinese family with Currarino syndrome", Eur J Pediatr Surg, 22, pp.243~245 (2012)[DOI]
- Yates VD, "Anterior sacral defects: an autosomal dominantly inherited condition", J Pediatr, 102, pp.239~242 (1983)[DOI]
- Lynch SA, "A gene for autosomal dominant sacral agenesis maps to the holoprosencephaly region at 7q36", Nat Genet, 11, pp.93~95 (1995)[DOI]
- Ross AJ, "A homeobox gene, HLXB9, is the major locus for dominantly inherited sacral agenesis", Nat Genet, 20, pp.358~361 (1998)[DOI]
- Belloni E, "Involvement of the HLXB9 homeobox gene in Currarino syndrome", Am J Hum Genet, 66, pp.312~319 (2000)[DOI]
- Cretolle C, "Spectrum of HLXB9 gene mutations in Currarino syndrome and genotypephenotype correlation", Hum Mutat, 29, pp.903~910 (2008)[DOI]
- Merello E, "Novel MNX1 mutations and clinical analysis of familial and sporadic Currarino cases", Eur J Med Genet, 56, pp.648~654 (2013)[DOI]
- Kim AY, "Currarino syndrome: variable imaging features in three siblings with HLXB9 gene mutation", Clin Imaging, 37, pp.398~402 (2013)[DOI]
- Adzhubei IA, "A method and server for predicting damaging missense mutations", Nat Methods, 7, pp.248~249 (2010)[DOI]
- Kumar P, "Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm", Nat Protoc, 4, pp.1073~1081 (2009)[DOI]
- Schwarz JM, "MutationTaster2: mutation prediction for the deep-sequencing age", Nat Methods, 11, pp.361~362 (2014)[DOI]
- Desmet FO, "Human Splicing Finder: an online bioinformatics tool to predict splicing signals", Nucleic Acids Res, 37, pp.e67~ (2009)[DOI]
- Richards S, "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology", Genet Med, 17, pp.405~424 (2015)[DOI]
- Garcia-Barcelo M, "Population differences in the polyalanine domain and 6 new mutations in HLXB9 in patients with Currarino syndrome", Clin Chem, 52, pp.46~52 (2006)[DOI]
- Garcia-Barcelo MM, "MNX1 (HLXB9) mutations in Currarino patients", J Pediatr Surg, 44, pp.1892~1898 (2009)[DOI]
- Benzacken B, "Different proximal and distal rearrangements of chromosome 7q associated with holoprosencephaly", J Med Genet, 34, pp.899~903 (1997)[DOI]
- Coutton C, "Currarino syndrome and HPE microform associated with a 2.7-Mb deletion in 7q36.3 excluding SHH gene", Mol Syndromol, 5, pp.25~31 (2014)
- Frints SG, "De novo 7q36 deletion: breakpoint analysis and types of holoprosencephaly", Am J Med Genet, 75, pp.153~158 (1998)[DOI]
- Frints SG, "Strong variable clinical presentation in 3 patients with 7q terminal deletion", Genet Couns, 9, pp.5~14 (1998)
- Holm I, "A 5.8 kb deletion removing the entire MNX1 gene in a Norwegian family with Currarino syndrome", Gene, 518, pp.457~460 (2013)[DOI]
- Masuno M, "Two unrelated cases of single maxillary central incisor with 7q terminal deletion", Jinrui Idengaku Zasshi, 35, pp.311~317 (1990)[DOI]
- Rodriguez L, "Terminal deletion of the chromosome 7(q36-qter) in an infant with sacral agenesis and anterior myelomeningocele", Am J Med Genet, 110, pp.73~77 (2002)[DOI]
- Roessler E, "Cytogenetic rearrangements involving the loss of the Sonic Hedgehog gene at 7q36 cause holoprosencephaly", Hum Genet, 100, pp.172~181 (1997)[DOI]
- Lee SK, "Synchronization of neurogenesis and motor neuron specification by direct coupling of bHLH and homeodomain transcription factors", Neuron, 38, pp.731~745 (2003)[DOI]
- Lee SK, "Analysis of embryonic motoneuron gene regulation: derepression of general activators function in concert with enhancer factors", Development, 131, pp.3295~3306 (2004)[DOI]
- Nakano T, "Identification of a conserved 125 base-pair Hb9 enhancer that specifies gene expression to spinal motor neurons", Dev Biol, 283, pp.474~485 (2005)[DOI]
- Holm I, "Whole exome sequencing of sporadic patients with Currarino Syndrome: a report of three trios", Gene, 624, pp.50~55 (2017)[DOI]