RESUMO
The pathogenesis of hypothalamic hamartoma (HH) associated with epilepsy is unknown. We have identified an individual with HH and refractory epilepsy exhibiting subtle dysmorphic features. High-resolution karyotype identified a duplication of the terminal end of 6p (6p25.1-25.3), confirmed by fluorescent in situ-hybridization (FISH). Copy number analysis with high-density (250K) single nucleotide polymorphism (SNP) genotyping microarrays characterized the abnormality as a series of amplified regions between 1.4 Mb and 10.2 Mb, with a small tandem deletion from 8.8 Mb to 9.7 Mb. There are 38 RefSeq genes within the duplicated regions, and no known coding sequences within the deletion. This unique patient helps identify 6p25.1-25.3 as a possible susceptibility locus for sporadic HH.
Assuntos
Aberrações Cromossômicas , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 6 , Suscetibilidade a Doenças , Epilepsia/genética , Hamartoma/genética , Hamartoma/patologia , Doenças Hipotalâmicas/genética , Criança , Transtornos Cromossômicos/complicações , Transtornos Cromossômicos/patologia , Epilepsia/complicações , Epilepsia/patologia , Feminino , Fatores de Transcrição Forkhead/genética , Hamartoma/complicações , Humanos , Doenças Hipotalâmicas/complicações , Doenças Hipotalâmicas/patologia , Hibridização in Situ Fluorescente/métodos , Imageamento por Ressonância Magnética , Análise em Microsséries , Polimorfismo de Nucleotídeo ÚnicoRESUMO
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.
