BACKGROUND α1-Antitrypsin (A1AT) deficiency predisposes patients to pulmonary disease due to inadequate protection against human neutrophil elastase released during inflammatory responses. A1AT deficiency is caused by homozygosity or compound heterozygosity for A1AT variants; individuals with A1AT deficiency most commonly have at least one Z variant allele (c.1096G > A (Glu366Lys)). Null variants that result in complete absence of A1AT in the plasma are much rarer. With one recent exception, all reported A1AT variants are characterized by a single pathogenic variant. CASE An 8 years old patient from Edmonton, Alberta, Canada, was investigated for A1AT deficiency. His A1AT phenotype was determined to be M (wild type)/Null by isoelectric focusing (IEF) but M/Z by targeted genotyping. Gene sequencing revealed two heterozygous variants: Z and Ile100Asn (c.299 T > A). The Ile100Asn substitution is predicted to disrupt the secondary structure of an α-helix in which it resides and the neighbouring tertiary structure, resulting in intracellular degradation of A1AT prior to hepatocyte secretion. METHODS Family testing was conducted to verify potential inheritance of an A1AT allele carrying the two mutations in cis, as this arrangement of the mutations would explain "Z" detection by genotyping but not by IEF. Molecular modeling was used to assess the effect of the variants on A1AT structure and stability. DISCUSSION Carrier status for a novel variant NullCanada with in cis mutations (c.[299 T > A;1096G > A], p.[(Ileu100Asn;Glu366Lys)]) was confirmed. A sibling was identified as having A1AT deficiency on the basis of compound heterozygosity for two alleles: NullCanada and the common Z allele. A separate pedigree from the Maritimes was subsequently recognized as carrying NullCanada. CONCLUSION In cis mutations such as NullCanada may be more common than previously described due to failure to detect such mutations using historical testing methods. Combined approaches that include gene sequencing and segregation studies allow recognition of rare A1AT variants, including in cis mutations.

中文翻译：

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NullCana​​da：具有顺式变体Glu366Lys和Ile100Asn的新型α1-抗胰蛋白酶等位基因。

背景技术α1-抗胰蛋白酶（A1AT）缺乏使患者易患肺部疾病，原因是对炎症反应期间释放的人嗜中性粒细胞弹性蛋白酶的保护作用不足。A1AT缺乏症是由A1AT变体的纯合或复合杂合引起的；患有A1AT缺乏症的个体最常见的是至少有一个Z变异等位基因（c.1096G> A（Glu366Lys））。导致血浆中完全不存在A1AT的无效变体要少得多。除了一个最近的例外，所有报道的A1AT变异体均以单个病原体变异体为特征。案例对来自加拿大艾伯塔省埃德蒙顿的一名8岁患者进行了A1AT缺乏症调查。通过等电聚焦（IEF）将他的A1AT表型确定为M（野生型）/无效，但通过有针对性的基因分型将其确定为M / Z。基因测序揭示了两个杂合变体：Z和Ile100Asn（c.299 T> A）。预计Ile100Asn取代会破坏它所驻留的α-螺旋的二级结构和邻近的三级结构，从而导致A1AT在细胞内降解，然后再分泌肝细胞。方法进行家庭测试以验证携带两个顺式突变的A1AT等位基因的潜在遗传，因为这种突变排列将通过基因分型而不是通过IEF解释“ Z”检测。使用分子建模来评估变体对A1AT结构和稳定性的影响。讨论证实了具有顺式突变（c。[299 T> A; 1096G> A]，p。[（Ileu100Asn; Glu366Lys）]）的新型NullCana​​da的携带者状态。根据两个等位基因的复合杂合性，将同胞鉴定为A1AT缺乏症：NullCana​​da和常见的Z等位基因。随后从海事处分离出一个谱系携带NullCana​​da。结论在NullCana​​da等顺式突变中，由于未能使用历史测试方法检测到此类突变，因此可能比以前描述的更常见。包括基因测序和分离研究在内的组合方法可以识别罕见的A1AT变体，包括顺式突变。