Dados do Trabalho

Título

GENETIC PROFILE OF LAMA2-RELATED MUSCULAR DYSTROPHY PATIENTS IN A LARGE BRAZILIAN COHORT

Introdução

LAMA2-related muscular dystrophy (LAMA2-RD) is an autosomal recessive disease caused by mutations in the LAMA2 gene. It varies in severity, from a severe form of congenital muscular dystrophies (CMD-LAMA2) - in which most patients never achieve walking capacity - to a more rare and less severe form of limb-girdle muscular dystrophy (LGMD-23).

Objetivo

We aimed to describe and establish genotype–phenotype correlations in a large Brazilian cohort.

Método

Clinical and genetic data of LAMA2-RD patients enrolled from six research centers (FMUSP, Escola Paulista de Medicina, FMUFMG, Hospital de Clínicas de Porto Alegre, FHEMIG, Hospital Infantil Albert Sabin) between March 2018 and April 2023 were collected and analyzed.

Resultados e Conclusões

One hundred and twelve patients were included: 79 (75.2%) patients never achieved walking capacity and 26 (24.8%) patients were able to walk.
84 patients were submitted to brain MRI, and from those 12 patients (14.2%) presented with cortical malformations (polymicrogyria, lissencephaly-pachygyria, and cobblestone),12 patients (14.2%) presented with epilepsy, and 8 (9.5%) had intellectual disability. We found 46 distinct mutations and twenty-two variants were novel (52%). The top three high-frequency disease-causing variants in Brazilian patients were: 1) c.1255del (p.Ile419Leufs*4) in 22 patients; 2) c.2461A>C (Thr821Pro) in 15 patients and 3) c.3976C>T (p.Arg1326*). The frameshift variant c.1255del (p.Ile419Leufs*4) was never published and is probably a founder mutation in Brazil, with all patients unable to walk. All the 15 patients with at least one c.2461A>C (Thr821Pro) mutation were able to walk. Null variants were more frequent in LAMA2-CMD (56.9%) than in LGMDR23 (21.4%), while missense disease-causing variants were more frequent in LGMDR23 than in LAMA2-CMD (P = .0072; OR:6.48). One intronic variant never published (c.4960-17C>A) was found in four patients, one in homozyogous. A functional study was performed using muscle biopsy and revealed the presence of the transcript r.4959_4960ins[4960-15_4960-1], which affects intron 34. This transcript is out-of-frame (p.Arg1653_Ala1654insAsnLeuAspHisTer) and creates a different splicing site.
This study provides better understanding of genotype–phenotype correlations in LAMA2-related muscular dystrophy and supports therapeutic targets for future research.

Palavras Chave

LAMA2, phenotype, genotype

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Nenhum deles tem conflito de interesses com esse trabalho

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Área

Doenças neuromusculares