Abstract
The FKRP-related disorders include the limb-girdle muscular dystrophy type 2I (LGMD2I, MIM#607155)
which has a clinical overlap with dystrophinopathies. Except for Brazil, LGMD2I has
not been described in other Latin-American countries, despite that 1/64 Mexican-ancestry
individuals carry the commonest European p.(Leu276Ile) pathogenic FKRP variant (rs28937900, 1000 Genomes Project Phase 3), suggesting an underdiagnosis.
Sequencing of exon 4 of FKRP in 60 unrelated Mexican patients with presumptive diagnoses of dystrophinopathy without
DMD gene deletions, or with a neuromuscular disorder of unknown etiology, revealed two
patients (2/60, 3.3%): one of them with an unreported pathogenic genotype, p.[Leu276Ile];[Asn463Asp]
and a Duchenne-like phenotype; and the other that stands as the third reported case
bearing the severe genotype, p.[Asn463Asp];[Asn463Asp] leading to a congenital presentation
(MIM#606612). We identified two patients heterozygous for the p.(Arg143Ser) and the
novel p.(Arg48Pro) variants, respectively, which were absent in 200 control alleles.
Protein modeling suggests that p.(Arg143Ser) is a tolerated change, while p.(Arg48Pro)
induces a structural modification, although further molecular confirmation of dystrophinopathy
was obtained in the p.(Arg48Pro) patient. Our results justify the inclusion of FKRP-related disorders in the differential diagnosis of Mexican neuromuscular patients.
The commonly reported heterozygous FKRP genotypes deserve attention to avoid LGMD2I molecular misdiagnosis.
Keywords
α-dystroglycanopathies - Duchenne and Becker muscular dystrophies - fukutin-related
protein - protein modeling - variants of uncertain significance
