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Objective: To determine if laminin-α2 deficiency is due to mutations in the LAMA2 gene or secondary to mutations in other congenital muscular dystrophy genes. Methods: We performed molecular analysis of LAMA2, by single-strand conforma tion polymorphism and sequencing, in 15 patients with undetectable or greatly re duced laminin-α2 expression. We also performed 4 prenatal diagnoses and invest igated a founder effect. Results: We found 1 known and 9 previously undescribed LAMA2 mutations spanning all protein domains. These were nonsense or frameshifts causing laminin-α2 absence or, in 1 case, a homozygous missense mutation prod ucing partial protein expression and milder phenotype. LAMA2 mutations were unde tected in 5 patients, in 2 of whom FKRP mutations explained the phenotype. In 3 prenatal cases, the fetus was heterozygous for the mutation of interest and preg nancy continued; in 1 case, the fetus was affected and aborted. In 2 patients, t he Cys967Stop mutation and identical haplotypes flanking the LAMA2 gene indicate d a founder effect. Conclusions: The clinical phenotype was severe in most patie nts with LAMA2 mutations and associated with undetectable protein expression. On e case with no protein and another with partial expression had milder phenotypes . Typical white matter alterations on magnetic resonance imaging were found in a ll patients with LAMA2 mutations, supporting the utility of magnetic resonance i maging in differential diagnosis. The founder mutation (Cys967Stop) probably ori ginated in Albania. Genetic characterization of affected families is mainly of u se for prenatal diagnosis.
Methods: We performed molecular analysis of LAMA2, by single-strand conformation polymorphism and sequencing, in 15 patients We also performed 4 prenatal diagnoses and invest igated a founder effect. Results: We found 1 known and 9 previously undescribed LAMA2 mutations spanning all protein domains. These were nonsense or frameshifts causing laminin-α2 absence or, in 1 case, a homozygous missense mutation prod ucing partial protein expression and milder phenotype. LAMA2 mutations were undected in 5 patients, in 2 of whom FKRP mutations explained the phenotype. In 3 prenatal cases, the fetus was heterozygous for the mutation of interest and preg nancy continued; in 1 case, the fetus was affected and aborted. In 2 patients, t he Cys967Stop mutation and identical ha plotypes flanking the LAMA2 gene indicate da founder effect. Conclusions: The clinical phenotype was severe in most patients with LAMA2 mutations and associated with undetectable protein expression. On e case with no protein and another with partial expression had milder phenotypes. Typical white matter alterations on magnetic resonance imaging were found in a ll patients with LAMA2 mutations, supporting the utility of magnetic resonance imaging in differential diagnosis. The founder mutation (Cys967Stop) probably ori ginated in Albania. Genetic characterization of affected families is mainly of u se for prenatal diagnosis.