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New Mutations, Prenatal Diagnosis, and Founder Effect

Claudia Di Blasi, PhD; Daniela Piga, PhD; Paolo Brioschi, PhD; Isabella Moroni, MD; Antonella Pini, MD; Alessandra Ruggieri, PhD; Simona Zanotti, PhD; Graziella Uziel, MD; Laura Jarre, MD; Elvio Della Giustina, MD; Carmela Scuderi, MD; Christoffer Jonsrud, MD; Renato Mantegazza, MD; Lucia Morandi, MD; Marina Mora, PhD

Arch Neurol. 2005;62:1582-1586.

Objective  To determine if laminin-2 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 conformation polymorphism and sequencing, in 15 patients with undetectable or greatly reduced laminin-2 expression. We also performed 4 prenatal diagnoses and investigated 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-2 absence or, in 1 case, a homozygous missense mutation producing partial protein expression and milder phenotype. LAMA2 mutations were undetected 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 pregnancy continued; in 1 case, the fetus was affected and aborted. In 2 patients, the Cys967Stop mutation and identical haplotypes flanking the LAMA2 gene indicated a founder effect.

Conclusions  The clinical phenotype was severe in most patients with LAMA2 mutations and associated with undetectable protein expression. One case with no protein and another with partial expression had milder phenotypes. Typical white matter alterations on magnetic resonance imaging were found in all patients with LAMA2 mutations, supporting the utility of magnetic resonance imaging in differential diagnosis. The founder mutation (Cys967Stop) probably originated in Albania. Genetic characterization of affected families is mainly of use for prenatal diagnosis.

Author Affiliations: Divisions of Neuromuscular Diseases (Drs Di Blasi, Piga, Brioschi, Ruggieri, Zanotti, Mantegazza, Morandi, and Mora) and Child Neurology (Drs Moroni and Uziel), Istituto Nazionale Neurologico "C. Besta," Milano, Italy; Division of Child Neurology, Ospedale Maggiore, Bologna, Italy (Dr Pini); Division of Child Neurology, Ospedale Martini, Torino, Italy (Dr Jarre); Division of Child Neurology, Arcispedale S. Maria Nuova, Reggio Emilia, Italy (Drs Della Giustina and Jonsrud); Istituto "Oasi Maria SS," Troina, Enna, Italy (Dr Scuderi); Department of Medical Genetics, University Hospital of North Norway, Tromsø (Drs Giustina and Jonsrud).

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