TY  - JOUR
A1  - Mair, Dorothea
A1  - Biskup, Saskia
A1  - Kress, Wolfram
A1  - Abicht, Angela
A1  - Brück, Wolfgang
A1  - Zechel, Sabrina
A1  - Knop, Karl Christian
A1  - Koenig, Fatima Barbara
A1  - Tey, Shelisa
A1  - Nikolin, Stefan
A1  - Eggermann, Katja
A1  - Kurth, Ingo
A1  - Ferbert, Andreas
A1  - Weis, Joachim
T1  - Differential diagnosis of vacuolar myopathies in the NGS era
JF  - Brain Pathology
N2  - Altered autophagy accompanied by abnormal autophagic (rimmed) vacuoles detectable by light and electron microscopy is a common denominator of many familial and sporadic non‐inflammatory muscle diseases. Even in the era of next generation sequencing (NGS), late‐onset vacuolar myopathies remain a diagnostic challenge. We identified 32 adult vacuolar myopathy patients from 30 unrelated families, studied their clinical, histopathological and ultrastructural characteristics and performed genetic testing in index patients and relatives using Sanger sequencing and NGS including whole exome sequencing (WES). We established a molecular genetic diagnosis in 17 patients. Pathogenic mutations were found in genes typically linked to vacuolar myopathy (GNE, LDB3/ZASP, MYOT, DES and GAA), but also in genes not regularly associated with severely altered autophagy (FKRP, DYSF, CAV3, COL6A2, GYG1 and TRIM32) and in the digenic facioscapulohumeral muscular dystrophy 2. Characteristic histopathological features including distinct patterns of myofibrillar disarray and evidence of exocytosis proved to be helpful to distinguish causes of vacuolar myopathies. Biopsy validated the pathogenicity of the novel mutations p.(Phe55*) and p.(Arg216*) in GYG1 and of the p.(Leu156Pro) TRIM32 mutation combined with compound heterozygous deletion of exon 2 of TRIM32 and expanded the phenotype of Ala93Thr‐caveolinopathy and of limb‐girdle muscular dystrophy 2i caused by FKRP mutation. In 15 patients no causal variants were detected by Sanger sequencing and NGS panel analysis. In 12 of these cases, WES was performed, but did not yield any definite mutation or likely candidate gene. In one of these patients with a family history of muscle weakness, the vacuolar myopathy was eventually linked to chloroquine therapy. Our study illustrates the wide phenotypic and genotypic heterogeneity of vacuolar myopathies and validates the role of histopathology in assessing the pathogenicity of novel mutations detected by NGS. In a sizable portion of vacuolar myopathy cases, it remains to be shown whether the cause is hereditary or degenerative.
KW  - autophagy
KW  - FSHD
KW  - glycogenin 1
KW  - muscular dystrophy
KW  - myofibrillar myopathy
KW  - next generation sequencing (NGS)
KW  - Pompe disease
KW  - sarcotubular myopathy
KW  - TRIM32
KW  - vacuolar myopathy
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-216048
VL  - 30
IS  - 5
SP  - 877
EP  - 896
ER  - 
TY  - JOUR
A1  - Pluta, Natalie
A1  - Hoffjan, Sabine
A1  - Zimmer, Frederic
A1  - Köhler, Cornelia
A1  - Lücke, Thomas
A1  - Mohr, Jennifer
A1  - Vorgerd, Matthias
A1  - Nguyen, Hoa Huu Phuc
A1  - Atlan, David
A1  - Wolf, Beat
A1  - Zaum, Ann-Kathrin
A1  - Rost, Simone
T1  - Homozygous inversion on chromosome 13 involving SGCG detected by short read whole genome sequencing in a patient suffering from limb-girdle muscular dystrophy
JF  - Genes
N2  - New techniques in molecular genetic diagnostics now allow for accurate diagnosis in a large proportion of patients with muscular diseases. Nevertheless, many patients remain unsolved, although the clinical history and/or the muscle biopsy give a clear indication of the involved genes. In many cases, there is a strong suspicion that the cause must lie in unexplored gene areas, such as deep-intronic or other non-coding regions. In order to find these changes, next-generation sequencing (NGS) methods are constantly evolving, making it possible to sequence entire genomes to reveal these previously uninvestigated regions. Here, we present a young woman who was strongly suspected of having a so far genetically unsolved sarcoglycanopathy based on her clinical history and muscle biopsy. Using short read whole genome sequencing (WGS), a homozygous inversion on chromosome 13 involving SGCG and LINC00621 was detected. The breakpoint in intron 2 of SGCG led to the absence of γ-sarcoglycan, resulting in the manifestation of autosomal recessive limb-girdle muscular dystrophy 5 (LGMDR5) in the young woman.
KW  - inversion
KW  - sarcoglycanopathy
KW  - whole genome sequencing (WGS)
KW  - next generation sequencing (NGS)
KW  - LGMDR5
KW  - muscle disease
KW  - genetic diagnostics
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288122
SN  - 2073-4425
VL  - 13
IS  - 10
ER  -