LAMA2 variants associated with muscular dystrophy, brain structural abnormalities, and epilepsy: a genotype-phenotype study

Background: LAMA2-related congenital muscular dystrophy (LAMA2-MD) is a genetically heterogeneous disorder defined by progressive muscle weakness, brain structural abnormalities, epilepsy, and multisystem involvement. The primary goal of this study was to characterize the clinical features, temporal progression, and genotype-phenotype correlations of LAMA2-MD.

Methods: Medical records of patients with genetically confirmed LAMA2-MD were extracted from a clinical data repository and analyzed retrospectively. Clinical manifestations, laboratory findings, and neuroimaging features were systematically reviewed and compared across different age groups. Variant data were retrieved from public databases to perform comprehensive genetic analyses.

Results: A total of five patients (two males and three females) were enrolled, delayed motor milestones and varying degrees of ankle contractures and persistent motor impairment in all patients were the initial presenting symptom at diagnosis in all cases, and two patients also exhibited cognitive delays. Laboratory analysis of muscle enzymes showed varying degrees of abnormalities, with creatine kinase (CK) levels displaying the most significant elevation. Cranial magnetic resonance imaging (MRI) revealed symmetrical white matter abnormalities in four patients. Seizures were documented in three school-aged patients. All patients carried compound heterozygous variants in the LAMA2 gene. A literature review indicated that the most common variant types were stop-gain and missense variants: stop-gain variants were predominantly associated with complete merosin deficiency (MDC1A), whereas missense variants typically correlated with late-onset limb-girdle muscular dystrophy.

Conclusion: LAMA2-MD exhibits a broad phenotypic spectrum and a progressive disease course. Early manifestations include muscle weakness, delayed achievement of developmental milestones, joint contractures, seizures and characteristic intracranial abnormalities.

1 Introduction

Congenital muscular dystrophy type 1A (MDC1A) is an autosomal recessive disorder caused by variants in the laminin alpha 2 chain gene (LAMA2). As the most common subtype of congenital muscular dystrophy (CMD), it accounts for 30% to 50% of all CMD cases (1–3). A study conducted in China further reported that approximately 36.4% of CMD patients are diagnosed with MDC1A (4). The core clinical manifestations of MDC1A include muscle weakness, elevated serum creatine phosphokinase (CPK) levels, inability to ambulate independently, and cerebral white matter abnormalities. These symptoms can progress to respiratory insufficiency which was a major contributor to early mortality in affected patients.

MDC1A exhibits high clinical heterogeneity in severity which presents as neonatal-onset merosin-deficient muscular dystrophy (the classic MDC1A phenotype) or a milder form, such as childhood- or adult-onset autosomal recessive limb-girdle muscular dystrophy 23 (LGMDR23) (5). To encompass this phenotypic spectrum, some researchers have proposed the umbrella term “LAMA2-related muscular dystrophy (LAMA2-MD)” (6). Seizures have been documented in 8% to 20% of LAMA2-MD patients, and cerebral white matter abnormalities typically involve periventricular and subcortical regions.

Epidemiologically, the prevalence of the LGMDR23 phenotype is estimated to range from 1 in 16,000 to 1 in 21,500 individuals, while the incidence of CMD caused by complete or partial merosin deficiency is approximately 0.7 to 2.5 per 100,000 people. However, the exact incidence of LAMA2-MD as a whole remains unestablished, and its clinical phenotypic variability and temporal progression continue to be active areas of clinical investigation.

In this study, we retrospective analyzed the clinical data, diagnostic and therapeutic processes of LAMA2-MD patients in order to characterize the disease’s clinical heterogeneity and temporal evolution.

2 Methods

2.1 Study population

This retrospective study included patients with genetically confirmed LAMA2-related congenital muscular dystrophy (LAMA2-MD) who were evaluated at Jiangxi Provincial Children’s Hospital (Nanchang, Jiangxi, China) between January 2010 and June 2024. Clinical data were collected from both outpatient and inpatient medical records.

2.2 Clinical data collection

Detailed clinical data were extracted from medical records including: presenting symptoms and medical history; findings from physical examinations and laboratory tests for muscle enzymology [alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK), and CK-MB]; cranial magnetic resonance imaging (MRI) results; and cardiac ultrasound findings.

2.3 Literature and database review

A systematic literature search was conducted to compare our findings with previously reported cases. Relevant studies published between January 2010 and June 2024 were retrieved from both domestic (Chinese) and international databases.

For Chinese-language literature, searches were performed in the China National Knowledge Infrastructure (CNKI), Wanfang Data, and VIP Chinese Journal Database using the keywords: “congenital muscular dystrophy type 1A” “LAMA2 gene” and “laminin-α2.” For international literature, PubMed was searched with the keywords: “congenital muscular dystrophy type 1A (CMD1A),” “LAMA2 gene,” and “merosin.”

To systematically summarize genetic variants of LAMA2, the ClinVar, DECIPHER, and Ensembl databases were queried using the search term “LAMA2.” Reported pathogenic and likely pathogenic variants, along with their associated phenotypic characteristics, were extracted and analyzed.

2.4 Ethics statement

This study was approved by the Medical Ethics Committee of Jiangxi Children’s Hospital (Approval number: JXSETYY-YXKY-20240189). Written informed consent was obtained from the parents or legal guardians of all pediatric patients.

2.5 Statistical analysis

Data analysis was performed using SPSS version 26.0 software. Descriptive analysis was conducted for each observed variable. Numerical variables were expressed as mean ± standard deviation (SD), along with minimum and maximum values.

3 Results

3.1 Patient characteristics

Five patients (two males and three females) were genetically diagnosed with LAMA2-MD, the age at first diagnosis ranged from 3 months to 78 months (Median = 37.47, IQR = 4.29–58.32, Range = 3.10–76.63). Four of them were first evaluated in neurology department, and one in rehabilitation department. Patient 1 was first diagnosed in the rehabilitation department due to motor development delay. Three years later, she was hospitalized in the department of neurology. Patient 2 was admitted to the hospital for treatment at 3 years and 4 months due to recurrent seizures for 5 months. Over the next 9 years, the patient was hospitalized more than 20 times due to recurrent epileptic symptoms. The other three patients did not have long-term and detailed records due to cooperation of their families.

3.2 Clinical phenotypes

All five patients exhibited motor developmental delay, with motor milestones of different degrees were delayed. Three patients experienced more than two seizures before this study. Their seizures were characterized by sudden loss of consciousness, followed by bilateral tonic–clonic activity lasting 1–3 min. All patients did not capture the ictal EEG, interictal EEG with a slow background, but there was no typical epileptic discharge. In addition, neurological physical examination revealed varying degrees of ankle contractures and persistent motor impairment in all patients.

3.3 Muscle enzyme analysis

All five patients demonstrated elevated muscle enzyme (Table 1). Among them, CK exhibited most significant affected with levels ranged from 332u/L to 4631u/L (Median = 719.00, IQR = 403.00–3691.16, Range = 332.00–4631.00) (Figure 1).

Table 1

Table 1. Clinical data of all the enrolled cases.

Figure 1

Figure 1. Muscle enzymatic test results in all cases (sorted by test time). CK and LDH correspond to the primary ordinate, CK-MB, AST, and ALT correspond to the secondary ordinate.

3.4 Neuroimaging findings

All enrolled patients underwent cranial MRI, including T1W, T2W, T2-Flair, DWI, and ADC sequences, with crown, transverse, sagittal views. Four patients exhibited bilateral symmetrical white matter signal abnormalities, most pronounced on T2W, and T2-Flair sequences, while DWI showed no obvious diffusion limited performance (Figure 2). Due to the inconsistent time of MRI in five patients, the age of the child with no white matter lesions was detected in the one patient (1 year and 1 month) (Table 1).

Figure 2

Figure 2. Cranial MRI of all the enrolled patients. Roman numerals indicate the case number, Ⓐ T1W sequence, Ⓑ T2W sequence, Ⓒ T2Flair sequence and Ⓓ DWI sequence.

3.5 Variants evaluation

The variants for Case 1 were a splicing variant [c.1027+3 A>G, which predicted to influence acceptor loss (SpliceAI score:0.6) and donor loss (SpliceAI score:0.71)] and a frameshift deletion variant (c.1147delC, p.Glu383Lysfs*6, which predicted to a substitute from Glu to Lys at 383th and generate an early stop codon six amino acids later of LAMA2). The variants for Case 2 were two nonsense variants at 1,319 and 1,826, respectively, (c.3955C>T, p.Arg1319*, c.5476C>T, p.Arg1826*). Variants for case 3 were a splicing variant [c.7899-1 G>A, which predicted to influence acceptor loss (SpliceAI score:0.99) and acceptor gain (SpliceAI score:0.89)] and a nonsense variant at 2604 (c.7810C>T, p.Arg2604*). The variants for Case 4 were also two nonsense variants which located at 1,699 and 2,383, respectively, (c.5095del, p.Leu1699*, c.7147C>T, p.Arg2383*). Variants for case 5 were a nonsense variant at 758th (c.2272C>T, p.Glu758*) and a missense variant (c.6624G>C, p.Trp2208Cys) which was collected in ClinVar database as Uncertain significance (VUS). Further analysis revealed the tryptophan to cysteine substitution at position 2,208 led to an increase in the hydrogen bond between residue 2,208 and 2,215 from 3.0Å to 3.1Å, which may affect the stability and function of the protein (Table 1; Figure 3). Among all variants, one variants from patient 1 (c.1147delC, p.Glu383Lysfs*6), one from patient 4 (c.5095del, p.Leu1699*) and one variant from patient 5 (c.2272C>T p.Glu758*) were not collected in ClinVar database or reported in published paper. No other CNVs were observed based on the whole exon sequencing data, analysis method was described as previous study (7). The detailed information such as variant type, genome location, ACMG classification were also listed in Tables 1, 2.

Figure 3

Figure 3. LAMA2 protein 3D structure of wild-type and mutation in p.Trp2208Cys. The residue 2,208 was labeled in yellow in wildtype (left) and purple in mutation (right). The hydrogen bond was labeled with yellow dotted box.

Table 2

Table 2. Genetic data of all the enrolled cases.

3.6 Literature review and genotype–phenotype correlation

All enrolled patients harbored compound heterozygous variants in LAMA2, the variant sites and affected domains were visualized (Table 1; Figure 4). Up to May 27, 2024, the ClinVar database collected 5,149 variants including 425 deletion, 167 duplication, 28 InDel, 214 insertion and 4,315 single nucleotide variants (Figure 5). Among them, only 542 (10.5%) and 465 were classified as pathogenic (P) or likely pathogenic (LP) variants (9.0%) respectively (Figure 6, data from statistic of ClinVar database). There were 28 reports in the Decipher database, including 20 copy number variants, five SNVs variants, one triploids case, and two single diploids cases. Expression data from the Human Protein Atlas (HPA) showed that LAMA2 was widely expressed in tissues and organs. The GTEx database showed the highest expression time in the fetal stage, followed by adulthood, and in the blastocyst stage.

Figure 4

Figure 4. Schematic representation of the gene variants in the enrolled patients. The variants in our patients were highlighted through red arrows.

Figure 5

Figure 5. The LAMA2 variant types are reported in the ClinVar database.

Figure 6

Figure 6. Interpretation of LAMA2 molecular variation results in the ClinVar database.

In our patients, all of them carried the variants that affect protein structure (stop-gain, frame-shift, or splicing variant) and exhibited early-onset muscular dystrophy and core motor disorders, accompanied by white matter abnormalities (4/5 patients). After review related literatures, we found that the most common variant types were stop-gain and missense variants: stop-gain variants were predominantly associated with complete merosin deficiency (MDC1A), whereas missense variants typically correlated with late-onset limb-girdle muscular dystrophy. This was basically consistent with the results of our patients. This result highlighted the potential differences in clinical presentation between stop gain, frame shift, or splicing variants and missense variants.

4 Discussion

Laminin is an extracellular matrix protein and a major component of the basement membrane (8). During embryonic development, it is believed to mediate cell attachment, migration, and tissue organization by interacting with other extracellular matrix components. Structurally, laminin consists of three subunits (α, β, and γ) linked to one another via disulfide bonds. The LAMA2 gene (OMIM: 156225) encodes the laminin α2 chain, a subunit of both laminin-2 (merosin) and laminin-4 (s-merosin). As a tissue-specific component of the extracellular matrix, the laminin α2 chain plays a critical role in myotube stability and the regulation of apoptosis (9). The LAMA2 gene is located on chromosome 6q22.33 and contains 65 exons, which collectively encode a protein of 3,122 amino acids (10). According to data from the GTEx (Genotype-Tissue Expression) and HPA (Human Protein Atlas) databases, LAMA2 is widely expressed across tissues (including skeletal muscle) during both embryonic development and adulthood. Variants in LAMA2 lead to LAMA2-related disorders (LAMA2-RDs), which exhibit a broad clinical phenotypic spectrum, ranging from early-onset severe forms to late-onset mild progressive disease. These disorders include congenital muscular dystrophy with complete merosin deficiency (MDC1A), congenital muscular dystrophy with partial merosin deficiency, and autosomal recessive limb-girdle muscular dystrophy 23 (LGMDR23) (5). Its core clinical manifestations include early infantile motor developmental delay, marked elevation of serum creatine kinase (CK) levels, joint contractures, and progressive respiratory involvement. Consistent with these typical features, all patients in our study presented with motor developmental delay, elevated muscle enzyme levels, and ankle contractures (Table 1). According to the HPA and GTEx database, LAMA2 also expressed in brain and cortex. The variants of loss of function (Lof) resulted the dysfunction of LAMA2 protein and contributed to the white matter abnormalities which was also observed in our patients. This further highlighted the stop gain, frameshift, or splicing variants’ contribution to brain development.

In addition to the aforementioned clinical phenotypes, characteristic cranial imaging findings serve as an effective clinical screening tool for the LAMA2-related disease spectrum. Previous studies indicated that most patients present with periventricular white matter abnormalities, a finding potentially linked to the role of G proteins in peripheral nerve development and glial cell adhesion (11). Salvati et al. (12) reported that 93.6% of patients exhibited diffuse subcortical or periventricular white matter signal abnormalities, while approximately 36.2% had cortical developmental malformations.

Consistent with these prior observations, 80% of patients (4 out of 5) in our cohort displayed periventricular white matter abnormalities. Notably, one patient showed no such imaging changes. However, genetic testing for this patient identified compound heterozygous LAMA2 variants: a maternal variant (c.5095del, p.Leu1699*) and a paternal variant (c.7147C>T, p.Arg2383*). Clinically, this patient presented with motor developmental delay, ankle contractures, and abnormal muscle enzyme levels. The absence of cerebral white matter abnormalities in this case may be attributed to the patient’s young age at the time of imaging; this hypothesis requires confirmation through long-term follow-up. Three patients experienced two or more seizures which characterized as motor seizures with loss of consciousness. Interictal electroencephalography demonstrated a slow background rhythm, with absence of epileptiform discharges. However, the prevalence of seizures in LAMA2-related disorders remains controversial in the literature: previous studies have suggested that intellectual disability and/or seizures are rare (13), while Camelo, Salvati, and colleagues have reported marked clinical phenotypic heterogeneity, with seizure rates ranging from 19.2% to 74%—and even proposed that seizures may represent a core symptom of LAMA2-related diseases (9, 11). The reasons for the differences in epilepsy incidence between our study and other studies may duo to multiple reasons including the differences in patient age distribution, follow-up duration, or epilepsy diagnostic criteria, etc.

Seizure types in these disorders are diverse, with generalized tonic-clonic seizures being the most common (12). A small number of cases present with focal motor seizures (with or without impaired consciousness), while typical or atypical absence seizures are rare, and myoclonic seizures are extremely uncommon. Notably, Guo et al. (14) did not document a history of epilepsy in 43 patients (from both domestic and international cohorts) they reviewed, this discrepancy may stem from incomplete case data or insufficient long-term follow-up. At our center, the three patients with seizures developed symptoms 3–8 years after their initial presentation. The ages at seizure onset were 91 months, 117 months, and 151 months (mean: 119.37 ± 36.43 months). Whereas, the mean onset age was 8.13 ± 5.36 years reported by Salvati et al. (12). These results support the temporal evolution of LAMA2-related disorders, emphasizing the need for dynamic clinical monitoring, as well as dietary and lifestyle guidance, throughout the disease course.

The specific mechanism of seizures in LAMA2-related disorders remains unclear. Camelo et al. (15) hypothesized that LAMA2-RD patients with cortical malformations, epilepsy, and intellectual disability harbor genetic variants affecting the laminin G (LG) domain of the laminin-α2 protein. In contrast, Salvati et al. (12) found no significant correlation between cortical developmental malformations and the age of seizure onset. Geranmayeh et al. (16) reported that complete or partial loss of laminin-α2 (merosin) correlates with clinical phenotype severity, age of disease onset, and rate of progression. Oliveira et al. (6) further noted that late-onset LAMA2-MD, most commonly associated with missense variants or in-frame deletions, often presents with brain imaging abnormalities, cognitive impairment, and refractory seizures. However, other studies have failed to identify a clear association between cognitive impairment, seizures, and brain structural abnormalities.

In recent years, research investigating genotype-phenotype correlations in LAMA2-related disorders has expanded. As of May 27, 2024, analysis of LAMA2 genetic variants (summarized in Figure 5) revealed that single nucleotide variants (SNVs) accounted for approximately 83.8% of all variants, while deletions constituted 8.25%. Oliveira et al. (6) reported that stop-gain variants (premature termination codons, PTCs) are the most prevalent genotype in these disorders. Such variants are associated with the complete absence of laminin-α2 protein in muscle biopsies and correlate with the congenital muscular dystrophy type 1A (MDC1A) phenotype—the severe, early-onset form of LAMA2-related disease. In contrast, missense variants are less frequent; they typically result in partial laminin-α2 defects and are linked to milder phenotypic presentations. A single-center study conducted by the Department of Pediatrics at Peking University First Hospital analyzed 134 children with hereditary myopathies, among whom 22 were diagnosed with MDC1A. Genetic testing of these 22 MDC1A patients identified 8 cases with compound heterozygous variants [combining LAMA2 SNVs and copy number variations (CNVs)] and 14 cases with compound heterozygous SNVs alone. Consistent with these findings, all patients in our cohort harbored compound heterozygous LAMA2 variants (detailed in Table 1). Detailed variant site information was available for only two patients, one of whom carried a nonsense point mutation. As illustrated in Figure 3, the variants were localized to the laminin G-like domain, helix domain I, and laminin EGF-like domain regions of the laminin-α2 protein, respectively.

Notably, Oliveira et al.’s (6) work further corroborates genotype–phenotype associations in LAMA2-related disorders: stop-gain (PTC) variants are strongly associated with the MDC1A phenotype and complete merosin deficiency, whereas missense variants typically lead to partial merosin defects and milder disease manifestations. The truncating variants typically caused severe damaging effects of gene function, while missense potentially associated with mild damaging effects. The difference of functional effects among genotype may explain the phenotypic variation.

Similar genotype–phenotype associations were also observed in other genes, such as APC2 (17), CCDC22 (18), DLG3 (19), TANC2 (20), SRCAP (21), SZT2 (22).

To date, clinical studies on LAMA2-related disorders have primarily documented neuromuscular manifestations, which are limited to four well-characterized phenotypes (6, 23): (1) congenital muscular dystrophy type 1A (MDC1A) with complete merosin deficiency; (2) congenital muscular dystrophy with partial merosin deficiency; (3) late-onset autosomal recessive limb-girdle muscular dystrophy type 23 (LGMDR23); and (4) peripheral neuropathy. Notably, no clinical manifestations involving the ear, pituitary gland, adrenal gland, or uterus have been reported in the literature. These observations suggest that the clinical phenotypes associated with LAMA2 variants may be broader than previously recognized. The spatiotemporal (tissue- and developmental stage-specific) expression patterns of LAMA2 could help retroactively supplement our understanding of unrecognized LAMA2-related phenotypes. More importantly, these expression patterns may serve as a theoretical and prospective basis for expanding the clinical phenotype spectrum of LAMA2-related disorders, highlighting the need for further research into non-neuromuscular manifestations.

4.1 Limitation of this study

Firstly, this study only included 5 patients, which may lead to insufficient statistical power and limited representativeness, influencing to support the clinical heterogeneity of LAMA2-MD (LAMA2-related muscular dystrophy) and the rules of genotype–phenotype correlation. Secondly, since it was a retrospective study, muscle tissue samples from patients were not obtained to verify at the protein level which may affect the support of genotype–phenotype correlation analysis. Thirdly, the age range of the patients was relatively wide (age at first diagnosis: 3 months to 78 months), and there may be significant differences in the follow-up duration among different patients. Such imbalances in age and follow-up duration may interfere with the analysis results of “disease progression over time.” Finally, one patient carried a missense variant of VUS (c.6624G>C, p.Trp2208Cys). The speculation that this variant may affect protein function was only based on structural simulation and lacks experimental verification.

5 Conclusion

LAMA2-related disorders exhibit marked clinical heterogeneity and a progressive disease course over time. The temporal evolution of LAMA2-related disorders and the heterogeneous involvement of tissues/organs can be characterized by reviewing real-world clinical data records (CDRs) from modern hospital information systems. Additionally, the clinical phenotypic spectrum of these disorders can be retroactively refined using the spatiotemporal expression patterns of the LAMA2 gene.

Data availability statement

The datasets presented in this article are not readily available due to ethical restrictions and privacy concerns related to human genetic/clinical data. Requests to access the datasets (raw clinical and processed data) should be directed to the corresponding author Xiongying Yu (eXV4eWp4ZXRoQDE2My5jb20=).

Ethics statement

The studies involving humans were approved by the Medical Ethics Committee of Jiangxi Children’s Hospital (Approval number: JXSETYY-YXKY-20240189). The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin.

Author contributions

JZha: Writing – original draft. YY: Writing – original draft. FC: Writing – original draft. ZY: Writing – original draft. HW: Writing – original draft. YC: Writing – original draft. JZho: Writing – review & editing. XY: Writing – review & editing.

Funding

The author(s) declared that financial support was not received for this work and/or its publication.

Acknowledgments

Although this study did not require follow-up from patients and their families, we still appreciate the understanding and trust of all patients and their families.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that Generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Abbreviations

ACMG, American College of Medical Genetics; CDR, Clinical data repository; LAMA2, laminin α2 gene; MDC1A, Congenital muscular dystrophy type 1A; CMD, congenital muscular dystrophy; EEG, Electroencephalograph; MRI, Magnetic resonance imaging; EMR, Electronic medical record.

References

1. Tome, FM, Evangelista, T, Leclerc, A, Sunada, Y, Manole, E, Estournet, B, et al. Congenital muscular dystrophy with merosin deficiency. C R Acad Sci III. (1994) 317:351–7.

Google Scholar

2. Mostacciuolo, ML, Miorin, M, Martinello, F, Angelini, C, Perini, P, and Trevisan, CP. Genetic epidemiology of congenital muscular dystrophy in a sample from North-East Italy. Hum Genet. (1996) 97:277–9. doi: 10.1007/BF02185752,

PubMed Abstract | Crossref Full Text | Google Scholar

3. Miyagoe-Suzuki, Y, Nakagawa, M, and Takeda, S. Merosin and congenital muscular dystrophy. Microsc Res Tech. (2000) 48:181–91. doi: 10.1002/(SICI)1097-0029(20000201/15)48:3/4<>3.0.CO;2-Q,

PubMed Abstract | Crossref Full Text | Google Scholar

4. Ge, L, Zhang, C, Wang, Z, Chan, SHS, Zhu, W, Han, C, et al. Congenital muscular dystrophies in China. Clin Genet. (2019) 96:207–15. doi: 10.1111/cge.13560,

PubMed Abstract | Crossref Full Text | Google Scholar

5. Gavassini, BF, Carboni, N, Nielsen, JE, Danielsen, ER, Thomsen, C, Svenstrup, K, et al. Clinical and molecular characterization of limb-girdle muscular dystrophy due to LAMA2 mutations. Muscle Nerve. (2011) 44:703–9. doi: 10.1002/mus.22132

Crossref Full Text | Google Scholar

6. Oliveira, J, Gruber, A, Cardoso, M, Taipa, R, Fineza, I, Goncalves, A, et al. LAMA2 gene mutation update: toward a more comprehensive picture of the laminin-alpha2 variome and its related phenotypes. Hum Mutat. (2018) 39:1314–37. doi: 10.1002/humu.23599,

PubMed Abstract | Crossref Full Text | Google Scholar

7. Talevich, E, Shain, AH, Botton, T, and Bastian, BC. CNVkit: genome-wide copy number detection and visualization from targeted DNA sequencing. PLoS Comput Biol. (2016) 12:e1004873. doi: 10.1371/journal.pcbi.1004873,

PubMed Abstract | Crossref Full Text | Google Scholar

8. Luo, S, Liu, ZG, Wang, J, Luo, JX, Ye, XG, Li, X, et al. Recessive LAMA5 variants associated with partial epilepsy and spasms in infancy. Front Mol Neurosci. (2022) 15:825390. doi: 10.3389/fnmol.2022.825390,

PubMed Abstract | Crossref Full Text | Google Scholar

9. Allamand, V, and Guicheney, P. Merosin-deficient congenital muscular dystrophy, autosomal recessive (MDC1A, MIM#156225, LAMA2 gene coding for alpha2 chain of laminin). Eur J Hum Genet. (2002) 10:91–4. doi: 10.1038/sj.ejhg.5200743,

PubMed Abstract | Crossref Full Text | Google Scholar

10. Vuolteenaho, R, Nissinen, M, Sainio, K, Byers, M, Eddy, R, Hirvonen, H, et al. Human laminin M chain (merosin): complete primary structure, chromosomal assignment, and expression of the M and a chain in human fetal tissues. J Cell Biol. (1994) 124:381–94. doi: 10.1083/jcb.124.3.381,

PubMed Abstract | Crossref Full Text | Google Scholar

11. Mehta, P, and Piao, X. Adhesion G-protein coupled receptors and extracellular matrix proteins: roles in myelination and glial cell development. Dev Dyn. (2017) 246:275–84. doi: 10.1002/dvdy.24473,

PubMed Abstract | Crossref Full Text | Google Scholar

12. Salvati, A, Bonaventura, E, Sesso, G, Pasquariello, R, and Sicca, F. Epilepsy in LAMA2-related muscular dystrophy: a systematic review of the literature. Seizure. (2021) 91:425–36. doi: 10.1016/j.seizure.2021.07.020,

PubMed Abstract | Crossref Full Text | Google Scholar

13. Xiong, H, Tan, D, Wang, S, Song, S, Yang, H, Gao, K, et al. Genotype/phenotype analysis in Chinese laminin-alpha2 deficient congenital muscular dystrophy patients. Clin Genet. (2015) 87:233–43. doi: 10.1111/cge.12366

Crossref Full Text | Google Scholar

14. Guo, L, Tang, WM, and Song, YZ. Clinical features and LAMA2 mutations of patients with congenital muscular dystrophy type 1A: a case report and literature review. Zhongguo Dang Dai Er Ke Za Zhi. (2020) 22:608–13. doi: 10.7499/j.issn.1008-8830.2001102

Crossref Full Text | Google Scholar

15. Camelo, CG, Artilheiro, MC, Martins Moreno, CA, Ferraciolli, SF, Serafim Silva, AM, Fernandes, TR, et al. Brain MRI abnormalities, epilepsy and intellectual disability in LAMA2 related dystrophy - a genotype/phenotype correlation. J Neuromuscul Dis. (2023) 10:483–92. doi: 10.3233/JND-221638,

PubMed Abstract | Crossref Full Text | Google Scholar

16. Geranmayeh, F, Clement, E, Feng, LH, Sewry, C, Pagan, J, Mein, R, et al. Genotype-phenotype correlation in a large population of muscular dystrophy patients with LAMA2 mutations. Neuromuscul Disord. (2010) 20:241–50. doi: 10.1016/j.nmd.2010.02.001,

PubMed Abstract | Crossref Full Text | Google Scholar

17. Jin, L, Li, Y, Luo, S, Peng, Q, Zhai, QX, Zhai, JX, et al. Recessive APC2 missense variants associated with epilepsies without neurodevelopmental disorders. Seizure. (2023) 111:172–7. doi: 10.1016/j.seizure.2023.08.008,

PubMed Abstract | Crossref Full Text | Google Scholar

18. He, YL, Ye, YC, Wang, PY, Liang, XY, Gu, YJ, Zhang, SQ, et al. CCDC22 variants caused X-linked focal epilepsy and focal cortical dysplasia. Seizure. (2024) 123:1–8. doi: 10.1016/j.seizure.2024.10.007,

PubMed Abstract | Crossref Full Text | Google Scholar

19. He, YY, Luo, S, Jin, L, Wang, PY, Xu, J, Jiao, HL, et al. DLG3 variants caused X-linked epilepsy with/without neurodevelopmental disorders and the genotype-phenotype correlation. Front Mol Neurosci. (2023) 16:1290919. doi: 10.3389/fnmol.2023.1290919

Crossref Full Text | Google Scholar

20. Luo, S, Zhang, WJ, Jiang, M, Ren, RN, Liu, L, Li, YL, et al. De novo TANC2 variants caused developmental and epileptic encephalopathy and epilepsy. Epilepsia. (2025) 66:2365–78. doi: 10.1111/epi.18358,

PubMed Abstract | Crossref Full Text | Google Scholar

21. Liang, XY, Meng, XH, Wu, WC, Guo, J, Luo, S, Wang, PY, et al. De novo SRCAP variants cause developmental and epileptic encephalopathy and the phenotypic spectrum. Epilepsia. (2025). doi: 10.1111/epi.18695

Crossref Full Text | Google Scholar

22. Trivisano, M, Rivera, M, Terracciano, A, Ciolfi, A, Napolitano, A, Pepi, C, et al. Developmental and epileptic encephalopathy due to SZT2 genomic variants: emerging features of a syndromic condition. Epilepsy Behav. (2020) 108:107097. doi: 10.1016/j.yebeh.2020.107097,

PubMed Abstract | Crossref Full Text | Google Scholar

23. Liang, XP, Wang, S, Zhang, W, Yuan, Y, Ding, J, Chang, XZ, et al. Peripheral nerve injury in LAMA2-related congenital muscular dystrophy patients. Zhonghua Er Ke Za Zhi. (2017) 55:95–9. doi: 10.3760/cma.j.issn.0578-1310.2017.02.008,

PubMed Abstract | Crossref Full Text | Google Scholar