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男孩有呼吸道症状和生长发育迟缓，携带 CFTR 基因纯合突变 M348K。致病突变还是良性变异？

Homozygous CFTR mutation M348K in a boy with respiratory symptoms and failure to thrive. Disease-causing mutation or benign alteration?

机构信息

Institute of Human Genetics, Jena University Hospital, Kollegiengasse 10, 07743, Jena, Germany.

出版信息

Eur J Pediatr. 2012 Jul;171(7):1039-46. doi: 10.1007/s00431-012-1672-1. Epub 2012 Jan 25.

DOI:10.1007/s00431-012-1672-1
PMID:22274833
Abstract

UNLABELLED

We report on a 6-month-old premature boy from consanguineous parents. He presented with respiratory distress, necrotizing enterocolitis and hyperbilirubinemia shortly after birth. Persisting respiratory symptoms and failure to thrive prompted cystic fibrosis diagnostics, which showed the lack of wild-type signal for the mutation R347P suggesting a homozygous deletion or an alteration different from the known mutation at this position. Sequencing of this region revealed the homozygous substitution 1175 T > A (HGVS: c.1043 T > A) in exon 7 resulting in the homozygous amino acid change M348K. This mutation has never been reported in homozygosity before. Computational analysis tools classified M348K as 'presumably disease causing.' In our patient, sweat testing and electrophysiological assessment of CFTR function in native rectal epithelium demonstrated normal Cl(-) secretion.

CONCLUSION

We assume that the homozygous alteration M348K is a harmless variant rather than a CF-causing mutation.

摘要

目的

我们报道了一例来自近亲的 6 个月大的早产儿。他出生后不久即出现呼吸窘迫、坏死性小肠结肠炎和高胆红素血症。持续的呼吸系统症状和生长不良促使进行囊性纤维化的诊断，该诊断显示突变 R347P 的野生型信号缺失，提示该位置存在纯合缺失或不同于已知突变的改变。对该区域的测序显示，第 7 外显子的纯合替代 1175T>A（HGVS：c.1043T>A）导致了 M348K 的纯合氨基酸变化。该突变以前从未在纯合子中报道过。计算分析工具将 M348K 归类为“可能致病”。在我们的患者中，汗液测试和对天然直肠上皮 CFTR 功能的电生理评估显示正常的 Cl(-)分泌。

结论

我们假设纯合改变 M348K 是一种无害的变体，而不是导致 CF 的突变。

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本文引用的文献

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The K+ channel opener 1-EBIO potentiates residual function of mutant CFTR in rectal biopsies from cystic fibrosis patients.K+ 通道 opener 1-EBIO 可增强囊性纤维化患者直肠活检组织中突变 CFTR 的残留功能。
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Segregation analysis in cystic fibrosis at-risk family demonstrates that the M348K CFTR mutation is a rare innocuous polymorphism.对囊性纤维化高危家庭进行的分离分析表明，M348K囊性纤维化跨膜传导调节因子突变是一种罕见的无害多态性。
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