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Long QT syndrome (LQTS) is a lethal cardiac condition. However, the clinical implementation of genetic testing has now made LQTS eminently treatable. Next‐generation sequencing has remarkable potential for both clinical diagnostics and research of LQTS. Here, we investigated the genetic etiology in an LQTS‐suspected Iranian pedigree by whole‐exome sequencing and collected all KCNH2variants with consensus based on publications. WES was performed on the proband of this pedigree to reveal the underlying cause of sudden cardiac death (SCD). The variant found was validated and segregated by polymerase chain reaction and Sanger sequencing. Based on the literature review, KCNH2variants were retrospectively analyzed to identify pathogenic variants, likely pathogenic variants, and variants of uncertain significance by using different prediction tools. WES identified an autosomal dominant nonsense variant, c.1425C>A: p.Tyr475Ter, in the KCNH2gene, which appeared to be the most likely cause of LQTS in this pedigree. Moreover, our comprehensive literature review yielded 511 KCNH2variants in association with the LQTS phenotype, with c.3002G>A (CADD Phred=49) being the most pathogenic variant. Variants in the KCNH2gene are considered a major cause of LQTS worldwide. The detected c.1425C>A is a novel variant to be reported from Iran for the first time. This result indicates the importance of KCNH2screening in a pedigree with SCD cases. KCNH2gene encodes a voltage‐gated potassium ion channel protein, Kv11.1, which leads to cardiomyocyte repolarization. The loss‐of‐function variant of KCNH2makes the Kv11.1 protein dysfunction and Long QT syndrome 2.

Background: Alexander disease (AxD) is a rare leukodystrophy with an autosomal dominant inheritance mode. Variants in GFAPlead to this disorder and it is classified into three distinguishable subgroups: infantile, juvenile, and adult-onset types. Objective: The aim of this study is to report a novel variant causing AxD and collect all the associated variants with juvenile and adult-onset as well. Methods: We report a 2-year-old female with infantile AxD. All relevant clinical and genetic data were evaluated. Search strategy for all AxD types was performed on PubMed. The extracted data include total recruited patients, number of patients carrying a GFAPvariant, nucleotide and protein change, zygosity and all the clinical symptoms. Results: A novel de novo variant c.217A > G: p. Met73Val was found in our case by whole-exome sequencing. In silico analysis categorized this variant as pathogenic. Totally 377 patients clinically diagnosed with juvenile or adult-onset forms were recruited in these articles, among them 212 patients were affected with juvenile or adult-onset form carrier of an alteration in GFAP. A total of 98 variants were collected. Among these variants c.262C > T 11/212 (5.18%), c.1246C > T 9/212 (4.24%), c.827G > T 8/212 (3.77%), c.232G > A 6/212 (2.83%) account for the majority of reported variants. Conclusion: This study highlighted the role of genetic in AxD diagnosing. It also helps to provide more information in order to expand the genetic spectrum of Iranian patients with AxD. Our literature review is beneficial in defining a better genotype–phenotype correlation of AxD disorder.