Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Nov 17;12(1):173.
doi: 10.1186/s13023-017-0722-1.

Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness

Katherine Johnson  1 , Ana Töpf  1 , Marta Bertoli  1 , Lauren Phillips  1 , Kristl G Claeys  2   3   4 , Vidosava Rakocevic Stojanovic  5 , Stojan Perić  5 , Andreas Hahn  6 , Paul Maddison  7 , Ela Akay  7 , Alexandra E Bastian  8 , Anna Łusakowska  9 , Anna Kostera-Pruszczyk  9 , Monkol Lek  10   11 , Liwen Xu  10   11 , Daniel G MacArthur  10   11 , Volker Straub  12
Affiliations

Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness

Katherine Johnson et al. Orphanet J Rare Dis. .

Abstract

Background: Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by a primary deficiency of α-glucosidase and the associated accumulation of glycogen in lysosomal vacuoles. The deficiency of α-glucosidase can often be detected using an inexpensive and readily accessible dried blood spot test when Pompe disease is suspected. Like several neuromuscular disorders, Pompe disease typically presents with progressive weakness of limb-girdle muscles and respiratory insufficiency. Due to the phenotypic heterogeneity of these disorders, however, it is often difficult for clinicians to reach a diagnosis for patients with Pompe disease. Six hundred and six patients from a European population were recruited onto our study. Inclusion criteria stipulated that index cases must present with limb-girdle weakness or elevated serum creatine kinase activity. Whole exome sequencing with at least 250 ng DNA was completed using an Illumina exome capture and a 38 Mb baited target. A panel of 169 candidate genes for limb-girdle weakness was analysed for disease-causing variants.

Results: A total of 35 variants within GAA were detected. Ten distinct variants in eight unrelated index cases (and four siblings not sequenced in our study) were considered disease-causing, with the patients presenting with heterogeneous phenotypes. The eight unrelated individuals were compound heterozygotes for two variants. Six patients carried the intronic splice site c.-13 T > G transversion and two of the six patients also carried the exonic p.Glu176ArgfsTer45 frameshift. Four of the ten variants were novel in their association with Pompe disease.

Conclusions: Here, we highlight the advantage of using whole exome sequencing as a tool for detecting, diagnosing and treating patients with rare, clinically variable genetic disorders.

Keywords: Pompe disease; Sequence variants; Whole exome sequencing.

PubMed Disclaimer

Conflict of interest statement

Ethics approval and consent to participate

Full ethics approval was granted for the Newcastle MRC Centre Biobank for Rare and Neuromuscular Diseases by the Newcastle and North Tyneside research ethics committee (REC reference number 09/H0906/28). All patients provided informed consent for the storage and use of their biomaterial in the Newcastle MRC Centre Biobank for Rare and Neuromuscular Diseases.

Consent for publication

Not applicable.

Competing interests

VS is or has been a principal investigator for trials sponsored by Sanofi Genzyme, GSK, Prosensa/BioMarin Pharmaceuticals, Ionis Pharmceuticals and Sarepta Therapeutics. VS received speaker honoraria from Sanofi Genzyme. For the last 3 years VS is or has been on advisory boards for Audentes Therapeutics, Biogen, Bristol-Myer Squibb, Italfarmaco S.p.A., Sarepta Therapeutics, Summit Therapeutics, Tivorsan Pharmaceuticals, TrophyNOD, and Wave Therapeutics. KGC is principal investigator for trials sponsored by Sanofi Genzyme and KGC received speaker honoraria and travel grants from Sanofi Genzyme. The authors’ declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Ten distinct variants within GAA were identified as disease-causing. One variant was intronic and nine were exonic. Six patients were heterozygous for the intronic c.-32-13 T > G variant in addition to an exonic variant and two patients were heterozygous for two exonic variants
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Kishnani PS, Hwu WL, Mandel H, et al. A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. J Pediatr. 2006;148:671–676. doi: 10.1016/j.jpeds.2005.11.033. - DOI - PubMed
    1. Schuller A, Wenninger S, Strigl-Pill N, Schoser B. Toward deconstructing the phenotype of late-onset Pompe disease. Am J Med Genet C Semin Med Genet. 2012;160C:80–88. doi: 10.1002/ajmg.c.31322. - DOI - PubMed
    1. Kishnani PS, Steiner RD, Bali D, et al. Pompe disease diagnosis and management guideline. Genet Med. 2006;8:267–288. doi: 10.1097/01.gim.0000218152.87434.f3. - DOI - PMC - PubMed
    1. Martiniuk F, Chen A, Mack A, et al. Carrier frequency for glycogen storage disease type II in New York and estimates of affected individuals born with the disease. Am J Med Genet. 1998;79:69–72. doi: 10.1002/(SICI)1096-8628(19980827)79:1<69::AID-AJMG16>3.0.CO;2-K. - DOI - PubMed
    1. Ausems MG, Verbiest J, Hermans MP, et al. Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. Eur J Hum Genet. 1999;7:713–716. doi: 10.1038/sj.ejhg.5200367. - DOI - PubMed

MeSH terms

LinkOut - more resources