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

Abstract

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.

Keywords: Exome sequencing; Galactosialidosis; Protective protein cathepsin A.

Figure 1

Facial characteristics include hypertelorism with a depressed nasal bridge, malar hypoplasia and a prominent pre-maxilla.

Figure 2

Panels a shows CT scan evidencing tracheal stenosis and tracheomalacia. Panels b and c display X-rays images showing effacement of vertebral pedicles, platyspondyly and irregularity of the endplates of the spine. Panel d shows undertubulation of the femur. Panel e shows narrowing of the inferior ilia and flared iliac wings giving the “ping pong paddle” configuration seen in dysostosis multiplex.

Figure 3

Pedigree of the family sequenced in this study. Upper panel shows Sanger sequencing confirmation and segregation of identified mutations in CTSA in affected proband and both unaffected parents. Mutation p.Y267N is inherited from the father; while novel 2-bp deletion causes a frameshift mutation. Lower panel shows WES reads [Robinson et al 2011].