Department of Laboratory Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea.
Ann Lab Med. 2018 May;38(3):242-248. doi: 10.3343/alm.2018.38.3.242.
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.
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.
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.Gly145Alafs77, p.Gly151Leufs67, and p.Ala216Profs5) 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.
This study revealed the spectrum and phenotypic variability of MNX1 pathogenic variants in the Korean population.
Currarino 综合征（CS）是一种先天性畸形综合征，其主要遗传病因是运动神经元和胰腺同源盒 1（MNX1）的致病性变异，该综合征的特征通常为骶骨发育不全、直肠肛门畸形和骶前肿块，这些变异几乎存在于所有家族性病例和 30%的散发性病例中。较少见的是，7q36 区域的大片段缺失或复杂重排也与 CS 相关。我们研究了韩国 CS 患者中 MNX1 致病性变异的谱及其相关临床特征。
我们纳入了 25 名 CS 患者，包括 24 例散发性病例和 1 例家族性病例。对 MNX1 进行直接测序和多重连接依赖性探针扩增。我们还分析了临床表型，并评估了基因型-表型相关性。
我们在总共 6 个无义变异、1 个错义变异和 1 个大片段缺失中发现了 6 个新变异。无义变异包括 4 个移码变异（p.Gly98Alafs124、p.Gly145Alafs77、p.Gly151Leufs67 和 p.Ala216Profs5）和 2 个无义变异（p.Tyr186和 p.Gln212）。错义变异 p.Lys295Gln 位于高度保守的同源盒结构域，预计具有致病变异。在 1 名患者中检测到涉及 7q36 区域的大片段缺失。MNX1 中的致病性变异在所有 CS 病例中的检出率为 28%，在散发性病例中的检出率为 25%。有和没有致病性变异的患者的临床表型存在差异，但未观察到显著的基因型-表型相关性。
本研究揭示了韩国人群中 MNX1 致病性变异的谱和表型变异性。
