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. 2024 Apr 12;19(1):160.
doi: 10.1186/s13023-024-03170-5.

Genetic analysis of 37 cases with primary periodic paralysis in Chinese patients

Xuechao Zhao #  1 , Haofeng Ning #  2 , Lina Liu  1 , Chaofeng Zhu  1 , Yinghui Zhang  3 , Guifang Sun  4 , Huanan Ren  1 , Xiangdong Kong  5
Affiliations

Genetic analysis of 37 cases with primary periodic paralysis in Chinese patients

Xuechao Zhao et al. Orphanet J Rare Dis. .

Abstract

Background: Primary periodic paralysis (PPP) is an inherited disorders of ion channel dysfunction characterized by recurrent episodes of flaccid muscle weakness, which can classified as hypokalemic (HypoPP), normokalemic (NormoPP), or hyperkalemic (HyperPP) according to the potassium level during the paralytic attacks. However, PPP is charactered by remarkable clinical and genetic heterogeneity, and the diagnosis of suspected patients is based on the characteristic clinical presentation then confirmed by genetic testing. At present, there are only limited cohort studies on PPP in the Chinese population.

Results: We included 37 patients with a clinical diagnosis of PPP. Eleven (29.7%) patients were tested using a specific gene panel and 26 (70.3%) by the whole-exome sequencing (WES). Twenty-two cases had a genetic variant identified, representing a diagnostic rate of 59.5% (22/37). All the identified mutations were either in the SCN4A or the CACNA1S gene. The overall detection rate was comparable between the panel (54.5%: 6/11) and WES (61.5%: 16/26). The remaining patients unresolved through panel sequencing were further analyzed by WES, without the detection of any mutation. The novel atypical splicing variant c.2020-5G > A affects the normal splicing of the SCN4A mRNA, which was confirmed by minigene splicing assay. Among 21 patients with HypoPP, 15 patients were classified as HypoPP-2 with SCN4A variants, and 6 HypoPP-1 patients had CACNA1S variants.

Conclusions: Our results suggest that SCN4A alleles are the main cause in our cohort, with the remainder caused by CACNA1S alleles, which are the predominant cause in Europe and the United States. Additionally, this study identified 3 novel SCN4A and 2 novel CACNA1S variants, broadening the mutation spectrum of genes associated with PPP.

Keywords: CACNA1S and SCN4A genes; Hypokalemic periodic paralysis; Minigene; Panel and WES; Primary periodic paralysis.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Flowchart showing the methods and results of 37 cases enrolled in our study. Panel: specific gene panel analysis; WES: whole-exome sequencing
Fig. 2
Fig. 2
Pedigree and genetic analysis of five patients with primary periodic paralysis. (A) Patient 17, CACNA1S c.3716G > A mutation. (B) Patient 5, SCN4A c.2111 C > T (p.T704M) mutation. (C) Patient 8, SCN4A c.2015G > A (p.R675Q) mutation. (D) Patient 2, SCN4A c.2024G > A mutation (E) Patient 7, SCN4A c.4774 A > G mutation
Fig. 3
Fig. 3
The effect of variant c.2020-5G > A of SCN4A on mRNA splicing. (A) A Schematic diagram of the vector constructs; (B) Sequencing results of minigene constructs, UP: wildtype, down: mutation; (C) agarose gel electropherograms after RT-PCR; The bands in 293T and HeLa cells are labeled as a, b; Band a represents the Wild-type fragment with 746bps (normal splicing), band b represents the abnormal splicing fragment with 749bps. Band b was 3 bp larger than band a, indistinguishable after electrophoresis on 1% agarose gel; (D) the sequencing results of the bands after TA cloning correspond to the minigenes; (E) Schematic representation of minigene splicing. Band b is an abnormal band with 3 bp retention to the right of Intron12 and Exon A -▽Intron12 (3 bp) -Exon13-Exon B (749 bps)
Fig. 4
Fig. 4
CACNA1S and SCN4A mutations included in our study are pictured in the same structural model channel. Both Cav1.1 and Nav1.4 channels are composed of four homologous transmembrane domains (DI–DIV); each containing six transmembrane domains (S1-S6). Plus (+) symbolizes the positive charges in segment 4 of the calcium/sodium channels. Black square: mutations in the Nav1.4 channel; Blue hexagon: mutations in the Cav1.1 channel. The figure is adapted from Brugnoni et al. (2022)
Fig. 5
Fig. 5
The 3D molecular structure of SCN4A. (A) Homology model of SCN4A mutant protein generated using the SwissModel online server. Magnified views of the wild-type (B) and mutant Leu673_Leu674insGln (C) are shown respectively. The H-bonds are shown as yellow dashed lines, and Gln is indicated by a red arrow
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