Recessive LAMA5 Variants Associated With Partial Epilepsy and Spasms in Infancy

Sheng Luo; Zhi-Gang Liu; Juan Wang; Jun-Xia Luo; Xing-Guang Ye; Xin Li; Qiong-Xiang Zhai; Xiao-Rong Liu; Jie Wang; Liang-Di Gao; Fu-Li Liu; Zi-Long Ye; Huan Li; Zai-Fen Gao; Qing-Hui Guo; Bing-Mei Li; Yong-Hong Yi; Wei-Ping Liao

doi:10.3389/fnmol.2022.825390

Recessive LAMA5 Variants Associated With Partial Epilepsy and Spasms in Infancy

Front Mol Neurosci. 2022 May 19:15:825390. doi: 10.3389/fnmol.2022.825390. eCollection 2022.

Authors

Sheng Luo¹, Zhi-Gang Liu^{2

3}, Juan Wang¹, Jun-Xia Luo⁴, Xing-Guang Ye^{2

3}, Xin Li⁵, Qiong-Xiang Zhai⁶, Xiao-Rong Liu¹, Jie Wang¹, Liang-Di Gao¹, Fu-Li Liu⁷, Zi-Long Ye¹, Huan Li¹, Zai-Fen Gao⁴, Qing-Hui Guo⁵, Bing-Mei Li¹, Yong-Hong Yi¹, Wei-Ping Liao¹

Affiliations

¹ Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Department of Neurology, Institute of Neuroscience, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
² The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.
³ Department of Pediatrics, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University, Foshan, China.
⁴ Epilepsy Center, Qilu Children's Hospital of Shandong University, Jinan, China.
⁵ Department of Pediatrics, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
⁶ Department of Neurology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
⁷ Department of Neurology, The First People's Hospital of Foshan, Foshan, China.

Abstract

Objective: The LAMA5 gene encodes the laminin subunit α5, the most abundant laminin α subunit in the human brain. It forms heterotrimers with the subunit β1/β2 and γ1/γ3 and regulates neurodevelopmental processes. Genes encoding subunits of the laminin heterotrimers containing subunit α5 have been reported to be associated with human diseases. Among LAMAs encoding the laminin α subunit, LAMA1-4 have also been reported to be associated with human disease. In this study, we investigated the association between LAMA5 and epilepsy.

Methods: Trios-based whole-exome sequencing was performed in a cohort of 118 infants suffering from focal seizures with or without spasms. Protein modeling was used to assess the damaging effects of variations. The LAMAs expression was analyzed with data from the GTEX and VarCards databases.

Results: Six pairs of compound heterozygous missense variants in LAMA5 were identified in six unrelated patients. All affected individuals suffered from focal seizures with mild developmental delay, and three patients presented also spasms. These variants had no or low allele frequencies in controls and presented statistically higher frequency in the case cohort than in controls. The recessive burden analysis showed that recessive LAMA5 variants identified in this cohort were significantly more than the expected number in the East Asian population. Protein modeling showed that at least one variant in each pair of biallelic variants affected hydrogen bonds with surrounding amino acids. Among the biallelic variants in cases with only focal seizures, two variants of each pair were located in different structural domains or domains/links, whereas in the cases with spasms, the biallelic variants were constituted by two variants in the identical functional domains or both with hydrogen bond changes.

Conclusion: Recessive LAMA5 variants were potentially associated with infant epilepsy. The establishment of the association between LAMA5 and epilepsy will facilitate the genetic diagnosis and management in patients with infant epilepsy.

Keywords: LAMA5 gene; infant-onset epilepsy; laminins; spasms; trios-based WES.