Efficient identification of novel mutations in patients with limb girdle muscular dystrophy

• Published in: Neurogenetics Vol. 11; no. 4; pp. 449 - 455
• Main Authors: Boyden, Steven E., Salih, Mustafa A., Duncan, Anna R., White, Alexander J., Estrella, Elicia A., Burgess, Stephanie L., Seidahmed, Mohammed Z., Al-Jarallah, Abdullah S., Alkhalidi, Hisham M. S., Al-Maneea, Waleed M., Bennett, Richard R., Alshemmari, Salem H., Kunkel, Louis M., Kang, Peter B.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-10-2010; Springer; Springer Nature B.V
• Subjects: Adolescent; Age of Onset; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Child; Child, Preschool; Classical genetics, quantitative genetics, hybrids; Consanguinity; Deoxyribonucleic acid; DNA; Family Health; Female; Fundamental and applied biological sciences. Psychology; Genetic Linkage; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genotype; Homozygote; Human; Human Genetics; Humans; Infant; Lod Score; Male; Molecular and cellular biology; Molecular Medicine; Muscular Dystrophies, Limb-Girdle - genetics; Muscular dystrophy; Mutation; Neurology; Neurosciences; Original; Original Article; Pedigree; Saudi Arabia; Vertebrates: nervous system and sense organs; Saudi Arabia; Asia; Mutations; Limb girdle muscular dystrophy; Saudi Arabian; Homozygosity mapping; Consanguineous; Linkage analysis; Genetic mapping; Human; Nervous system diseases; Pathogenesis; Patient; Identification; Genetic determinism; Neurology; Genetic linkage; Genetics; Mutation
• ISSN: 1364-6745; 1364-6753
• DOI: 10.1007/s10048-010-0250-9

Limb girdle muscular dystrophy type 2 (LGMD2) is a genetically heterogeneous autosomal recessive disorder caused by mutations in 15 known genes. DNA sequencing of all candidate genes can be expensive and laborious, whereas a selective sequencing approach often fails to provide a molecular diagnosis. We aimed to efficiently identify pathogenic mutations via homozygosity mapping in a population in which the genetics of LGMD2 has not been well characterized. Thirteen consanguineous families containing a proband with LGMD2 were recruited from Saudi Arabia, and for 11 of these families, selected individuals were genotyped at 10,204 single nucleotide polymorphisms. Linkage analysis excluded all but one or two known genes in ten of 11 genotyped families, and haplotype comparisons between families allowed further reduction in the number of candidate genes that were screened. Mutations were identified by DNA sequencing in all 13 families, including five novel mutations in four genes, by sequencing at most two genes per family. One family was reclassified as having a different myopathy based on genetic and clinical data after linkage analysis excluded all known LGMD2 genes. LGMD2 subtypes A and B were notably absent from our sample of patients, indicating that the distribution of LGMD2 mutations in Saudi Arabian families may be different than in other populations. Our data demonstrate that homozygosity mapping in consanguineous pedigrees offers a more efficient means of discovering mutations that cause heterogeneous disorders than comprehensive sequencing of known candidate genes.