Genetic profile of Brazilian patients with LAMA2‐related dystrophies

Author:

Camelo Clara Gontijo1,Moreno Cristiane de Araujo Martins1,Artilheiro Mariana da Cunha1,Fonseca Alulin Tácio Quadros Monteiro1,Gurgel Gianetti Juliana2,Barbosa André Vinícius3,Donis Karina Carvalho4,Saute Jonas Alex Morales4ORCID,Pessoa André5,Van der Linden Hélio67,Gonçalves Ana Rita Alcântara8910,Kulikowski Leslie Domenici1ORCID,Kok Fernando1,Zanoteli Edmar1

Affiliation:

1. Department of Neurology Faculdade de Medicina da Universidade de São Paulo (FMUSP) São Paulo SP Brazil

2. Department of Pediatrics, Faculty of Medicine Universidade Federal de Minas Gerais Belo Horizonte Brazil

3. Department of Pediatric Neurology Fundação Hospitalar do Estado de Minas Gerais Belo Horizonte Brazil

4. Medical Genetics Division and Neurology Division Hospital de Clínicas de Porto Alegre Porto Alegre Brazil

5. Children's Hospital Albert Sabin Fortaleza Brazil

6. Rehabilitation Center Dr. Henrique Santillo Goiânia Brazil

7. Neurology Institute of Goiânia Goiânia Brazil

8. Centro de Genética Médica Jacinto Magalhães Centro Hospitalar Universitário de Santo António (CHUdSA) Porto Portugal

9. UMIB–Unit for Multidisciplinary Research in Biomedicine, ICBAS–School of Medicine and Biomedical Sciences University of Porto Porto Portugal

10. ITR–Laboratory for Integrative and Translational Research in Population Health Porto Portugal

Abstract

AbstractLAMA2‐related dystrophies (LAMA2‐RD) constitute a rare neuromuscular disorder with a broad spectrum of phenotypic severity. Our understanding of the genotype–phenotype correlations in this condition remains incomplete, and reliable clinical data for clinical trial readiness is limited. In this retrospective study, we reviewed the genetic data and medical records of 114 LAMA2‐RD patients enrolled at seven research centers in Brazil. We identified 58 different pathogenic variants, including 21 novel ones. Six variants were more prevalent and were present in 81.5% of the patients. Notably, the c.1255del, c.2049_2050del, c.3976 C>T, c.5234+1G>A, and c.4739dup variants were found in patients unable to walk and without cortical malformation. In contrast, the c.2461A>C variant was present in patients who could walk unassisted. Among ambulatory patients, missense variants were more prevalent (p < 0.0001). Although no specific hotspot regions existed in the LAMA2, 51% of point mutations were in the LN domain, and 88% of the missense variants were found within this domain. Functional analysis was performed in one intronic variant (c.4960‐17C>A) and revealed an out‐of‐frame transcript, indicating that the variant creates a cryptic splicing site (AG). Our study has shed light on crucial phenotype–genotype correlations and provided valuable insights, particularly regarding the Latin American population.

Publisher

Wiley

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