Browsing by Author "Xu, Liwen (57193611542)"

Variants in the TTN gene have been associated with distal myopathies and other distinctive phenotypes involving skeletal and cardiac muscle. Through whole-exome sequencing we identified a novel stop-gain variant (c.107635C>T, p.(Gln35879Ter)) in the TTN gene, coding a part of the M-line of titin, in 14 patients with autosomal recessive distal myopathy and Serbian ancestry. All patients share a common 1 Mb core haplotype associated with c.107635C>T, suggesting a founder variant. In compound heterozygotes, nine other TTN variants were identified: four stop-gain, three frameshift, one missense and one splice donor variant. Patients homozygous for the common variant did not show significant clinical differences to the compound heterozygous patients. The clinical presentation of all patients was an adult onset distal myopathy with predominant lower limb involvement. In addition, most patients had normal to mildly elevated serum creatine kinase levels, myopathic electromyograms, normal cardiologic and respiratory tests and muscle pathology consistent with a dystrophic process. In this study, we describe a distinct phenotype for patients with distal myopathy associated with novel recessive TTN variants including a Serbian founder variant. Our results expand the phenotypic and genetic spectrum of titinopathies and will facilitate the diagnosis of this condition in patients of Serbian origin.

Variants in the TTN gene have been associated with distal myopathies and other distinctive phenotypes involving skeletal and cardiac muscle. Through whole-exome sequencing we identified a novel stop-gain variant (c.107635C>T, p.(Gln35879Ter)) in the TTN gene, coding a part of the M-line of titin, in 14 patients with autosomal recessive distal myopathy and Serbian ancestry. All patients share a common 1 Mb core haplotype associated with c.107635C>T, suggesting a founder variant. In compound heterozygotes, nine other TTN variants were identified: four stop-gain, three frameshift, one missense and one splice donor variant. Patients homozygous for the common variant did not show significant clinical differences to the compound heterozygous patients. The clinical presentation of all patients was an adult onset distal myopathy with predominant lower limb involvement. In addition, most patients had normal to mildly elevated serum creatine kinase levels, myopathic electromyograms, normal cardiologic and respiratory tests and muscle pathology consistent with a dystrophic process. In this study, we describe a distinct phenotype for patients with distal myopathy associated with novel recessive TTN variants including a Serbian founder variant. Our results expand the phenotypic and genetic spectrum of titinopathies and will facilitate the diagnosis of this condition in patients of Serbian origin.

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. © 2017 The Author(s).

Purpose: Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology. Methods: Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions. Results: We identified suspected pathogenic variants in 52% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2, and SGCA collectively accounted for over half of the solved cases; while variants in newer disease genes, such as BVES and POGLUT1, were also found. The remaining well-characterized unsolved patients (48%) need further investigation. Conclusion: Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes. © 2020, The Author(s).