Diagnosis of late-onset Pompe disease and other muscle disorders by next-generation sequencing | Orphanet Journal of Rare Diseases | Full Text

Diagnosis of late-onset Pompe disease and other muscle disorders by next-generation sequencing | Orphanet Journal of Rare Diseases | Full Text



Research  

Diagnosis of late-onset Pompe disease and other muscle disorders by next-generation sequencing

Lévesque S, Auray-Blais C, Gravel E, Boutin M, Dempsey-Nunez L, Jacques P, Chenier S, Larue S, Rioux M, Al-Hertani W, Nadeau A, Mathieu J, Maranda B, Désilets V, Waters P, Keutzer J, Austin S, Kishnani P

Orphanet Journal of Rare Diseases 2016, 11 :8 (25 January 2016)

Abstract | Full Text | PDF

Diagnosis of late-onset Pompe disease and other muscle disorders by next-generation sequencing

• Sébastien LévesqueEmail author, 
• Christiane Auray-Blais, 
• Elaine Gravel, 
• Michel Boutin, 
• Laura Dempsey-Nunez, 
• Pierre-Etienne Jacques,
• Sébastien Chenier, 
• Sandrine Larue, 
• Marie-France Rioux, 
• Walla Al-Hertani, 
• Amelie Nadeau, 
• Jean Mathieu, 
• Bruno Maranda, 
• Valérie Désilets,
• Paula J. Waters, 
• Joan Keutzer, 
• Stephanie Austin and 
• Priya Kishnani

Orphanet Journal of Rare Diseases201611:8

DOI: 10.1186/s13023-016-0390-6

©  Lévesque et al. 2016

Received: 18 October 2015

Accepted: 17 January 2016

Published: 25 January 2016

Abstract

Background

Late-onset Pompe disease (LOPD) is a rare treatable lysosomal storage disorder characterized by progressive lysosomal glycogen accumulation and muscle weakness, with often a limb-girdle pattern. Despite published guidelines, testing for LOPD is often overlooked or delayed in adults, owing to its low frequency compared to other muscle disorders with similar muscle patterns. Next-generation sequencing has the capability to test concurrently for several muscle disorders. This could potentially lead to increased diagnosis of LOPD, disorders with non-specific muscle weakness or atypical patients.

Methods

We developed a gene panel to further study its clinical utility in a cohort of patients with suspected muscle disorders. We designed a gene panel to analyze the coding sequences and splice site junctions of GAA causing LOPD, along with 77 other genes causing muscle disorders with overlapping phenotypes.

Results

At a median coverage of ~200X (sequences per base), all GAA exons were successfully covered with >20X and only 0.3 % of exons across all genes were <20X. The panel showed an excellent sensitivity (100 %) and specificity (98 %) across all selected genes, using known variations in Pompe patients and controls. We determined its clinical utility by analyzing 34 patients with suspected muscle disorders of undetermined etiology and various muscle patterns, who were referred or followed in neuromuscular and genetics clinics. A putative diagnosis was found in up to 32 % of patients. The gene panel was instrumental in reaching a diagnosis in atypical patients, including one LOPD case. Acid alpha-glucosidase activity was used to confirm the molecular results in all patients.

Conclusion

This work highlights the high clinical utility of gene panels in patients with suspected muscle disorders and its potential to facilitate the diagnosis of patients showing non-specific muscle weakness or atypical phenotypes. We propose that gene panels should be used as a first-tier test in patients with suspected muscle disorders of undetermined etiology, which could further increase overall diagnosis of muscle conditions, and potentially reduce diagnostic delay. Further studies are necessary to determine the impact of first-tier gene panels on diagnostic delay and on treatment outcome for LOPD.

Keywords

Pompe disease Lysosomal disorders Muscle disorders Next-generation sequencing