Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophy (LGMD2C, LGMD2D, LGMD2E, and LGMD2F) that are caused, respectively, by mutations in the SGCG, SGCA, SGCB, and SGCD genes. Knowledge about the clinical and genetic features of sarcoglycanopathies in Chinese patients is limited. The aims of this study were to investigate in detail the clinical manifestations, sarcoglycan expression, and gene mutations in Chinese patients with sarcoglycanopathies and to identify possible correlations between them. Of 3638 patients for suspected neuromuscular diseases (1733 with inherited myopathies, 1557 with acquired myopathies, and 348 unknown), 756 patients had next-generation sequencing (NGS) diagnostic panel. Twenty-five patients with sarcoglycanopathies (11.5%) were identified from 218 confirmed LGMDs, comprising 18 with LGMD2D, 6 with LGMD2E, and one with LGMD2C. One patient with LGMD2D also had Charcot-Marie-Tooth 1A. The clinical phenotypes of the patients with LGMD2D or LGMD2E were markedly heterogeneous. Muscle biopsy showed a dystrophic pattern in 19 patients and mild myopathic changes in 6. The percentage of correct prediction of genotype based on expression of sarcoglycan was 36.0% (4 LGMD2D, 4 LGMD2E, and one LGMD2C). There was a statistically significant positive correlation between reduction of α-sarcoglycan level and disease severity in LGMD2D. Thirty-five mutations were identified in SGCA, SGCB, SGCG, and PMP22, 16 of which were novel. Exon 3 of SGCA was a hotspot region for mutations in LGMD2D. The missense mutation c.662G > A (p.R221H) was the most common mutation in SGCA. Missense mutations in both alleles of SGCA were associated with a relative benign disease course. No obvious clinical, sarcoglycan expression, and genetic correlation was found in LGMD2E. This study expands the clinical and genetic spectrum of sarcoglycanopathies in Chinese patients and provides evidence that disease severity of LGMD2D may be predicted by α-sarcoglycan expression and SGCA mutation.

The precise genetic diagnosis of dystrophinopathies can be challenging, largely due to rare deep intronic variants and more complex structural variants (SVs). We report on the genetic characterization of a dystrophinopathy patient. He remained without a genetic diagnosis after routine genetic testing, dystrophin protein and mRNA analysis, and short‐ and long‐read whole DMD gene sequencing. We finally identified a novel complex SV in DMD via long‐read whole‐genome sequencing. The variant consists of a large‐scale (~1Mb) inversion/deletion‐insertion rearrangement mediated by LINE‐1s. Our study shows that long‐read whole‐genome sequencing can serve as a clinical diagnostic tool for genetically unsolved dystrophinopathies.

Background and Purpose—: Distribution patterns of iron deposition in deep gray matter and their association with clinical characteristics in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) remain unclear. We aimed to evaluate iron deposition in deep gray matter in patients with CADASIL using 7.0-T susceptibility-weighted imaging and mapping and to explore its correlations with clinical characteristics. Methods—: Thirty-nine patients with CADASIL, confirmed via genetic analysis or skin biopsy, were enrolled. We examined patients using the Mini-Mental State Examination, modified Rankin Scale, and brain 7.0-T magnetic resonance imaging and obtained magnetic resonance imaging lesion loads, small vessel disease scores, and susceptibility mapping. The following regions of interest were selected: caudate nucleus, putamen, globus pallidus, thalamus, substantia nigra, and red nucleus. The quantitative differences in the susceptibility of deep gray matter between the CADASIL and control groups and the correlations between deep gray matter susceptibility and clinical characteristics were identified. Results—: Compared with the control group, the CADASIL group showed significantly increased susceptibility of caudate nucleus, putamen, thalamus, substantia nigra, and red nucleus. The susceptibility of deep gray matter in basal ganglia region, including caudate nucleus, putamen, and thalamus, significantly increased with age or disease duration and positively correlated with small vessel disease scores in patients with CADASIL. Moreover, the susceptibility of thalamus positively correlated with modified Rankin Scale scores after adjusting for age and disease duration and that of putamen negatively correlated with Mini-Mental State Examination scores in patients with CADASIL after adjusting for age. Conclusions—: Our findings indicate an association between abnormal iron deposition in deep gray matter of patients with CADASIL and their clinical characteristics. Therefore, excess iron deposition in deep gray matter, as indicated by 7.0-T susceptibility-weighted imaging and mapping, might not only be a novel magnetic resonance imaging feature but also a potential biomarker for CADASIL severity.