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Novel congenital myopathy locus identified in Native American Indians at 12q13.13-14.1

From the Center for Human Genetics (D.S.S., J.M.S., B.C., K.L.D.), Duke University Medical Center, Durham, NC; Departments of Pediatrics and Genetics (D.S.S., C.M.P., A.S.A.), University of North Carolina at Chapel Hill; University of Arkansas for Medical Sciences (S.G.K.), Little Rock; Neurogenomics Division (V.L.Z., D.A.S.), Translational Genomics Research Institute, Phoenix, AZ; and The Institute for Human Genomics (J.R.G.), University of Miami, FL.

Address correspondence and reprint requests to Dr. Demetra Stamm, Center for Human Genetics, Duke University Medical Center, Box 3445, 595 LaSalle Street, Durham, NC 27710 demetra.stamm{at}ucdmc.ucdavis.edu

Background: Native American myopathy (NAM) is an autosomal recessive congenital myopathy first reported in the Lumbee Indian people. Features of NAM include congenital weakness, cleft palate, ptosis, short stature, and susceptibility to malignant hyperthermia provoked by anesthesia.

Method: We identified five individuals with NAM from the Lumbee population, and hypothesized that these affected individuals have disease alleles shared identical-by-descent inherited from common ancestry. To identify a NAM disease locus, homozygosity mapping methods were employed on a genomewide 10K single-nucleotide polymorphism (SNP) screen. To confirm regions of homozygosity identified in the SNP screen, microsatellite repeat markers were genotyped within those homozygous segments.

Results: The SNP data demonstrated five regions of shared homozygosity in individuals with NAM. The additional genotyping data narrowed the region to one common segment of homozygosity spanning D12S398 to rs3842936 mapping to 12q13.13-14.1. Notably, loss of heterozygosity estimates from the SNP data also detected this same 12q region in the affected individuals.

Conclusion: This study reports the first gene mapping of Native American myopathy (NAM) using single-nucleotide polymorphism–based homozygosity mapping in only a few affected individuals from simplex families and identified a novel NAM locus. Identifying the genetic basis of NAM may suggest new genetic etiologies for other more common conditions such as congenital myopathy and malignant hyperthermia.

GLOSSARY: CNV = copy number variants; LD = linkage disequilibrium; LOH = loss of heterozygosity; MH = malignant hyperthermia; NAM = Native American myopathy; SNP = single-nucleotide polymorphism.

Supplemental data at www.neurology.org

e-Pub ahead of print on October 8, 2008, at www.neurology.org.

Dr. Marcy Speer died on August 4, 2007, after a 2-year battle with breast cancer.

Supported by the Muscular Dystrophy Association.

Disclosure: The authors report no disclosures.

Received December 9, 2007. Accepted in final form June 4, 2008.