CNNM2-Related Disorders: Phenotype and Its Severity Were Associated With the Mode of Inheritance.
CNNM2-Related Disorders: Phenotype and Its Severity Were Associated With the Mode of Inheritance.
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DOI：
10.3389/fped.2021.699568
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发表时间：
2021
影响因子：
2.6
通讯作者：
Jiang Y
中科院分区：
文献类型：
--
作者：
Zhang H;Wu Y;Jiang Y
据报道，cNM2(cystathionine-β-synthase-配对结构域二价金属离子转运介体2)致病变异体可导致低镁血症、癫痫和智力残疾/发育迟缓(ID/DD)。我们发现了两个新的CNNM2新的致病变异体，C.814T>；C和c.976G>；C，他们都表现为婴儿癫痫伴DD和对镁补充剂无效的低镁血症。到目前为止，已报告了21例CNNM2相关疾病。我们结合所有23例病例分析CNNM2相关疾病的特点。表型可分为三种类型：1型，常染色体显性遗传性低镁血症，2型，AD遗传性低镁血症伴癫痫伴ID/DD；3型，常染色体隐性遗传低镁血症伴癫痫伴ID/DD。5例1型患者均无癫痫或ID/DD表现，均有低镁血症，其中3例出现继发性低镁血症。15名2型患者可能有ID/DD和癫痫，这可以通过抗癫痫药物(ASM)控制；它们的变异聚集在CNNM2的DUF21区域。3例3型患儿均于出生后1~6d出现癫痫发作，发作难治，1/3为癫痫持续状态，AR遗传者ID/DD较AD遗传者严重，均有脑部磁共振成像(MRI)异常。除1例血清镁低于正常值下限外，其余患者均有明确的低镁血症。补镁可改善低镁血症，但不能恢复到正常水平。CBS2结构域的变异可能与血清镁含量降低有关。然而，三种不同类型CNNM2相关疾病患者的血清镁水平差异无统计学意义。因此，不同表型的严重程度不能用血清镁降低来解释。我们扩大了CNNM2变异的范围，并将CNNM2相关疾病的表型分为三种类型。我们发现DUF21区变异与CNNM2相关的中枢神经系统表型最相关，而低镁血症在CBS2区变异的患者中更明显，AR遗传性CNNM2相关疾病的表型最严重。这些结果为进一步研究CNNM2的功能提供了重要线索，并为更准确的遗传咨询提供了基础。
CNNM2 (Cystathionine-β-synthase-pair Domain Divalent Metal Cation Transport Mediator 2) pathogenic variants have been reported to cause hypomagnesemia, epilepsy, and intellectual disability/developmental delay (ID/DD). We identified two new cases with CNNM2 novel de novo pathogenic variants, c.814T>C and c.976G>C. They both presented with infantile-onset epilepsy with DD and hypomagnesemia refractory to magnesium supplementation. To date, 21 cases with CNNM2-related disorders have been reported. We combined all 23 cases to analyze the features of CNNM2-related disorders. The phenotypes can be classified into three types: type 1, autosomal dominant (AD) inherited simple hypomagnesemia; type 2, AD inherited hypomagnesemia with epilepsy and ID/DD; and type 3, autosomal recessive (AR) inherited hypomagnesemia with epilepsy and ID/DD. All five type 1 cases had no epilepsy or ID/DD; they all had hypomagnesemia, and three of them presented with symptoms secondary to hypomagnesemia. Fifteen type 2 patients could have ID/DD and seizures, which can be controlled with antiseizure medications (ASMs); their variations clustered in the DUF21 domain of CNNM2. All three type 3 patients had seizures from 1 to 6 days after birth; the seizures were refractory, and 1/3 had status epilepticus; ID/DD in these AR-inherited cases was more severe than that of AD-inherited cases; they all had abnormalities of brain magnetic resonance imaging (MRI). Except for one patient whose serum magnesium was the lower limit of normal, others had definite hypomagnesemia. Hypomagnesemia could be improved after magnesium supplement but could not return to the normal level. Variations in the CBS2 domain may be related to lower serum magnesium. However, there was no significant difference in the level of serum magnesium among the patients with three different types of CNNM2-related disorders. The severity of different phenotypes was therefore not explained by decreased serum magnesium. We expanded the spectrum of CNNM2 variants and classified the phenotypes of CNNM2-related disorders into three types. We found that DUF21 domain variations were most associated with CNNM2-related central nervous system phenotypes, whereas hypomagnesemia was more pronounced in patients with CBS2 domain variations, and AR-inherited CNNM2-related disorders had the most severe phenotype. These results provide important clues for further functional studies of CNNM2 and provide basic foundations for more accurate genetic counseling.
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影响因子：
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通讯作者：
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