Assessment of a targeted resequencing assay as a support tool in the diagnosis of lysosomal storage disorders.
BACKGROUND
With over 50 different disorders and a combined incidence of up to 1/3000 births, lysosomal storage diseases (LSDs) constitute a major public health problem and place an enormous burden on affected individuals and their families. Many factors make LSD diagnosis difficult, including phenotype and penetrance variability, shared signs and symptoms, and problems inherent to biochemical diagnosis. Developing a powerful diagnostic tool could mitigate the protracted diagnostic process for these families, lead to better outcomes for current and proposed therapies, and provide the basis for more appropriate genetic counseling.


METHODS
We have designed a targeted resequencing assay for the simultaneous testing of 57 lysosomal genes, using in-solution capture as the enrichment method and two different sequencing platforms. A total of 84 patients with high to moderate-or low suspicion index for LSD were enrolled in different centers in Spain and Portugal, including 18 positive controls.


RESULTS
We correctly diagnosed 18 positive blinded controls, provided genetic diagnosis to 25 potential LSD patients, and ended with 18 diagnostic odysseys.


CONCLUSIONS
We report the assessment of a next-generation-sequencing-based approach as an accessory tool in the diagnosis of LSDs, a group of disorders which have overlapping clinical profiles and genetic heterogeneity. We have also identified and quantified the strengths and limitations of next generation sequencing (NGS) technology applied to diagnosis.
Unidad Diagnóstico y Tratamiento de Errores Congénitos del Metabolismo (Servicio de Neonatología), Facultad de Medicina y Odontología de la Universidad de Santiago de Compostela, 15706 Santiago de Compostela, La Coruña, Spain. amarmiesse@gmail.com.
Ana
A
Fernández-Marmiesse
Marcos
M
Morey
Merce
M
Pineda
Jesús
J
Eiris
Maria Luz
ML
Couce
Manuel
M
Castro-Gago
Jose Maria
JM
Fraga
Lucia
L
Lacerda
Sofia
S
Gouveia
Maria Socorro
MS
Pérez-Poyato
Judith
J
Armstrong
Daisy
D
Castiñeiras
Jose A
JA
Cocho
D006801:Humans; D016464:Lysosomal Storage Diseases / Q000175:diagnosis* / Q000235:genetics; D017422:Sequence Analysis, DNA