title: Genome-wide SNP arrays as a diagnostic tool: clinical description, genetic mapping, and molecular characterization of Salla disease in an Old Order Mennonite population.
abstract: An Old Order Mennonite child was evaluated for gross motor delay, truncal ataxia, and slow linear growth. The diagnostic evaluation, which included sub-specialty consultations, neuroimaging, and metabolic testing, was long, costly, and did not yield a diagnosis. Recognition of a similarly affected second cousin prompted a genome-wide homozygosity mapping study using high-density single nucleotide polymorphism (SNP) arrays. SNP genotypes from two affected individuals and their parents were used to localize the disease locus to a 14.9 Mb region on chromosome 6. This region contained 55 genes, including SLC17A5, the gene encoding the lysosomal N-acetylneuraminic acid transport protein. Direct sequencing of SLC17A5 in the proband revealed homozygosity for the 115C --> T (R39C) sequence variant, the common cause of Salla disease in Finland. Three additional affected Mennonite individuals, ages 8 months to 50 years, were subsequently identified by directed molecular genetic testing. This small-scale mapping study was rapid, inexpensive, and analytically simple. In families with shared genetic heritage, genome-wide SNP arrays with relatively high marker density allow disease gene mapping studies to be incorporated into routine diagnostic evaluations.
authors.affiliation: Clinic for Special Children, Strasburg, PA 17579, USA. kstrauss@clinicforspecialchildren.org
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Strauss
authors.forename: Erik G
authors.initials: EG
authors.lastname: Puffenberger
authors.forename: David W
authors.initials: DW
authors.lastname: Craig
authors.forename: Corrie B
authors.initials: CB
authors.lastname: Panganiban
authors.forename: Anne M
authors.initials: AM
authors.lastname: Lee
authors.forename: Diane
authors.initials: D
authors.lastname: Hu-Lince
authors.forename: Dietrich A
authors.initials: DA
authors.lastname: Stephan
authors.forename: D Holmes
authors.initials: DH
authors.lastname: Morton
mesh_terms: D061085:Agenesis of Corpus Callosum; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D003337:Corpus Callosum / Q000000981:diagnostic imaging; D003431:Cross-Cultural Comparison; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics; D005260:Female; D023281:Genomics; D006801:Humans; D007223:Infant; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D033303:Protestantism; D011859:Radiography; D029461:Sialic Acid Storage Disease / Q000175:diagnosis* / Q000235:genetics*; D027981:Symporters / Q000235:genetics
chemical_list: D027361:Organic Anion Transporters; D027981:Symporters; C421224:sialic acid transport proteins