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Eur J Med Genet. 2014 Jul;57(7):339-344. doi: 10.1016/j.ejmg.2014.04.005. Epub 2014 Apr 24.

Clinical utility of whole-exome sequencing in rare diseases: Galactosialidosis.

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Division of Human Genetics. Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Center for Genomic Medicine and Metabolism. Cardiovascular Foundation of Colombia, Floridablanca, Colombia.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Centers for Mendelian Genomics, Houston, TX, USA.
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Texas Children's Hospital, Houston, TX, USA.
Contributed equally


Rare genetic disorders can go undiagnosed for years as the entire spectrum of phenotypic variation is not well characterized given the reduced number of patients reported in the literature and the low frequency at which these occur. Moreover, the current paradigm for clinical diagnostics defines disease diagnosis by a specified spectrum of phenotypic findings; when such parameters are either missing, or other findings not usually observed are seen, the phenotype driven approach to diagnosis may result in a specific etiological diagnosis not even being considered within the differential diagnosis. The novel implementation of genomic sequencing approaches to investigate rare genetic disorders is allowing not only the discovery of new genes, but also the phenotypic expansion of known Mendelian genetic disorders. Here we report the detailed clinical assessment of a patient with a rare genetic disorder with undefined molecular diagnosis. We applied whole-exome sequencing to this patient and unaffected parents in order to identify the molecular cause of her disorder. We identified compound heterozygous mutations in the CTSA gene, responsible for causing galactosialidosis; the molecular diagnosis was further confirmed by biochemical studies. This report expands on the clinical spectrum of this rare lysosomal disorder and exemplifies how genomic approaches are further elucidating the characterization and understanding of genetic diseases.


Exome sequencing; Galactosialidosis; Protective protein cathepsin A

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