title: Ancestral founder mutations in calpain-3 in the Indian Agarwal community: historical, clinical, and molecular perspective.
abstract: BACKGROUND
  Clinical heterogeneity of limb-girdle muscular dystrophies (LGMDs, 24 known subtypes), which includes overlapping phenotypes and varying ages of onset and morbidity, adds complexity to clinical and molecular diagnoses.
  
  
  METHODS
  To diagnose LGMD subtype, protein analysis, using immunohistochemistry (IHC) and immunoblotting, was followed by gene sequencing through a panel approach (simultaneous sequencing of known LGMD genes) in 9 patients from unrelated families of the Indian Agarwal community. Haplotype studies were performed by targeted SNP genotyping to establish mutation segregation.
  
  
  RESULTS
  We identified 2 founder mutations in CAPN3, a missense (c.2338G>C; p.D780H) and a splice-site (c.2099-1G>T) mutation, on 2 different haplotype backgrounds. The patients were either heterozygous for both or homozygous for either of these mutations.
  
  
  CONCLUSIONS
  Founder mutations have immediate clinical application, at least in selected population groups. Clinically available gene panels may provide a definitive molecular diagnosis for heterogeneous disorders such as LGMD.
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, Georgia 30322, USA.
authors.forename: Arunkanth
authors.initials: A
authors.lastname: Ankala
authors.forename: Jordan N
authors.initials: JN
authors.lastname: Kohn
authors.forename: Rashna
authors.initials: R
authors.lastname: Dastur
authors.forename: Pradnya
authors.initials: P
authors.lastname: Gaitonde
authors.forename: Satish V
authors.initials: SV
authors.lastname: Khadilkar
authors.forename: Madhuri R
authors.initials: MR
authors.lastname: Hegde
mesh_terms: D000293:Adolescent; D000328:Adult; D002154:Calpain / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D005838:Genotype; D006801:Humans; D007194:India; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D049288:Muscular Dystrophies, Limb-Girdle / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense; D044465:White People / Q000235:genetics*; D055815:Young Adult
chemical_list: D009124:Muscle Proteins; C105884:CAPN3 protein, human; D002154:Calpain