|Title||Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness.|
|Publication Type||Journal Article|
|Year of Publication||2017|
|Authors||Johnson, K, Topf, A, Bertoli, M, Phillips, L, Claeys, KG, Stojanovic, VRakocevic, Perić, S, Hahn, A, Maddison, P, Akay, E, Bastian, AE, Łusakowska, A, Kostera-Pruszczyk, A, Lek, M, Xu, L, MacArthur, DG, Straub, V|
|Journal||Orphanet J Rare Dis|
|Date Published||2017 11 17|
|Keywords||Adolescent, Adult, Aged, Aged, 80 and over, alpha-Glucosidases, Child, Child, Preschool, Cohort Studies, Female, Genetic Variation, Glycogen Storage Disease Type II, Humans, Male, Middle Aged, Muscle Weakness, Muscular Dystrophies, Limb-Girdle, Whole Exome Sequencing, Young Adult|
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.
|Alternate Journal||Orphanet J Rare Dis|
|PubMed Central ID||PMC5693551|
|Grant List||UM1 HG008900 / HG / NHGRI NIH HHS / United States |
UM1 HG008900 / EY / NEI NIH HHS / United States
UM1 HG008900 / HL / NHLBI NIH HHS / United States
175083 / / Ministarstvo Prosvete, Nauke i Tehnološkog Razvoja (RS) / International