LAMA2 Triple Variant in a Mexican Child with Congenital Muscular Dystrophy

Dear Editor,

Merosin-deficient congenital muscular dystrophy type 1 (MDC1A) (OMIM #607855; ORPHA 258)[1] is a rare autosomal recessive disorder characterized by broad phenotypic and genetic heterogeneity. It results from homozygous or compound heterozygous mutations in the LAMA2 gene, located at 6q22.33. MDC1A presents between birth and early infancy, with variable expressivity, including early-onset hypotonia, weak or reduced crying and spontaneous movement, respiratory problems, feeding difficulties, and mild distal contractures. Muscle weakness affects the axial muscles, especially those of the neck and spine, and the proximal muscles of the upper extremities. Most patients exhibit delayed motor skill development, characterized by the inability to ambulate independently and elevated creatine kinase (CPK) levels. Other findings include various nervous system conditions, such as brain atrophy and seizures.[2,3] It is one of the most frequent congenital muscular dystrophies (CMD), accounting for 30%–40% of cases, with current estimates suggesting a global birth prevalence of approximately 8.3 per million individuals.[4]

We describe a 9-month-old male patient born to young, nonconsanguineous parents from a small Mayan community (<2500 inhabitants). Delivery occurred via cesarean section at week 38 due to intrauterine growth restriction and oligohydramnios. Upon birth, the patient exhibited adequate tone and strength, as evidenced by an Apgar of 9–10. However, he experienced neurodevelopmental delay at 4 weeks of age, indicated by inadequate head support, which made rolling and sitting difficult. Magnetic resonance imaging of the brain revealed cerebral cortical atrophy [Figure 1]. Elevated CPK analysis (3897 mg/mL, normal reference range 55–170) supported the suspicion of CMD. The patient is receiving physical therapy. He is currently 3 years old, has improved postural, cervical, and facial muscle control, has not been able to walk, and has difficulty swallowing solid food. There is no evidence of joint contractures, intellectual impairment, or seizures.

Figure 1.

Magnetic resonance imaging of the patient at 3 months of age, showing cortical atrophy. (a) Sagittal view. (b) Transverse view

In 2022, the patient underwent analysis using a panel of 53 genes, the Invitae Comprehensive Muscular Dystrophy Panel, via next-generation sequencing. Three mutations in the LAMA2 gene were identified in the index case: a pathogenic variant, c.8244+1G>A (splice donor); a likely pathogenic variant, c.112+2_112+12del (splice site); and a variant of uncertain significance, c.2945G>A (p.Ser982Asn). Parental analysis revealed that the c.112+2_112+12del and c.2945G>A variants co-segregate on the paternal chromosome, whereas the c.8244+1G>A variant is on the maternal chromosome. This observation elucidates that the affected individual is compound heterozygous. Further analysis showed that the maternal grandmother lacked the c.8244+1G>A variant, the aunt carried it, and the grandfather was an obligate carrier. Paternal relatives were unaffected and untested [Figure 2].

Figure 2.

Molecular analysis results presented within a three-generation pedigree of the family

The c.8244+1G>A variant (Clin Var ID: 550992 [IVS58+1G>A]) affects a canonical splice site in intron 58 and is classified as pathogenic. It is predicted to result in a premature termination codon, leading to an absent or disrupted protein product, and is present at low frequencies in population databases (rs749522728, gnomAD 0.0009%).

The c.112+2_112+12del variant is considered likely pathogenic and is rare in population databases such as gnomAD (0.0002%). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function, which is known to be pathogenic.[5]

The c.2945G>A (ClinVar ID: 1355346 [p.Ser982Asn]) is a rare variant (rs755096239, gnomAD 0.009%) of uncertain significance. Advanced modeling of protein sequence and biophysical properties performed at Invitae indicates that this missense variant is not expected to disrupt LAMA2 protein function.

The child’s presentation—early hypotonia, axial greater than limb weakness, markedly elevated CK, and cortical atrophy without early seizures—is compatible with MDC1A.[6] While cortical atrophy is frequent in MDC1A, cognitive impairment is variable, and seizures may appear later, warranting surveillance. Published Mexican reports of LAMA2 disease are limited, including a classic MDC1A case with a homozygous nonsense mutation (R2578X)[7] and a small adult cohort with a likely limb-girdle muscular dystrophy R23 phenotype.[8] It is possible that patients with this gene are underdiagnosed in the Mexican population, given the limited access to molecular studies.

Based on the present findings, reclassification of the c.112+2_112+12del variant as pathogenic should be considered. According to the Sherloc framework, which refines American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG-AMP) guidelines, this variant meets several criteria: Pathogenic Very Strong 1 (PVS1): the deletion affects the canonical GT dinucleotide at +2, disrupting a highly conserved splice site; Pathogenic Supporting 3 (PP3): gene-specific splicing prediction algorithms (e.g., SpliceAI and MaxEntScan) indicate a high probability of splice site loss; Pathogenic Moderate 2 (PM2): the variant is absent or rare in population databases (e.g., gnomAD); Benign Supporting 2 (BP2): The variant is observed in trans with a known pathogenic splice-site variant (c.8244+1G>A).

Segregation analysis is limited, as the patient is an only child and the parents opted not to have additional children following the diagnosis. Therefore, PP1 is not applicable. Although functional studies are not available (PS3), a substitution at the same donor site position (c.112+2T>C) has been reported in a patient with LAMA2-related congenital muscular dystrophy, further supporting the functional importance of this region.[9]

Based on the cumulative Sherloc score (PVS1+PP3+BP2 = 9.0)[10] and considering the clinical context of compound heterozygosity and predicted splicing disruption, the c.112+2_112+12del variant should be reclassified as pathogenic.

In conclusion, this case of LAMA2-related CMD in a Mexican child illustrates the interpretive value of allelic phasing and provides evidence to reclassify c.112+2_112+12del as pathogenic, further correlating this finding with the clinical manifestations. This case contributes to the growing understanding of LAMA2-related disorders and highlights the importance of molecular diagnostics in underrepresented populations.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient’s parents have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and that due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.