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Citations since 2017
23 Research Items
August 2012 - present
University of Helsinki
- TA/Teacher in biochemistry and genetics. Full list at www.lydiasagath.com/#experience.
June 2015 - March 2016
University of Helsinki
Field of study
- Human genetics
Functional studies of YBX3 variants associated with nemaline myopathy
We report the first mosaic mutation, a deletion of exons 11-107, identified in the nebulin gene in a Finnish patient presenting with a predominantly distal congenital myopathy and asymmetric muscle weakness. The female patient is ambulant and currently 26 years old. Muscle biopsies showed myopathic features with type 1 fibre predominance, strikingl...
The Y-box binding protein 3 (YBX3) has been described as a transcriptional regulator and translational repressor of various proteins in skeletal and heart muscle. Its functions include, among others, the gradual repression of myogenin during myogenesis. By exome sequencing in a Finnish patient with an unusual form of nemaline myopathy, we have foun...
Background: Our previous array, the Comparative Genomic Hybridisation design (CGH-array) for nemaline myopathy (NM), named the NM-CGH array, revealed pathogenic copy number variation (CNV) in the genes for nebulin (NEB) and tropomyosin 3 (TPM3), as well as recurrent CNVs in the segmental duplication (SD), i.e. triplicate, region of NEB (TRI, exons...
The sarcomeric giants nebulin and titin both contain intragenic segmental duplication regions. Segmental duplication regions are prevalent throughout the genome and are known potential hotspots for recurrent copy number variation and may harbour pathogenic aberrations. Using our custom comparative genomic hybridization array, we have shown that gai...
Intragenic segmental duplication regions are potential hotspots for recurrent copy number variation and possible pathogenic aberrations. Two large sarcomeric genes, nebulin and titin, both contain such segmental duplication regions. Using our custom Comparative Genomic Hybridisation array, we have previously shown that a gain or loss of more than o...
The human genome contains repetitive regions, such as segmental duplications, known to be prone to copy number variation. Segmental duplications are highly identical and homologous sequences, posing a specific challenge for most mutation detection methods. The giant nebulin gene is expressed in skeletal muscle. It harbors a large segmental duplicat...
Intragenic segmental duplication regions are potential hotspots for recurrent copy number variation and possible pathogenic aberrations. Two large sarcomeric genes, nebulin and titin, both contain such segmental duplication regions. Using our custom Comparative Genomic Hybridization array, we have previously shown that a gain or loss of more than o...
Segmental duplications (SD) are prone to copy number variations (CNV). SD blocks are typically highly identical sequences, posing a specific challenge for most molecular genetic methods. Nebulin (NEB) is a large structural protein of the thin filament in the sarcomere. In its mid-region, it harbors an SD of eight exons repeated three times – the tr...
Bioinformatics tools for analyzing copy number variants (CNVs) from massively parallel sequencing (MPS) data are less well developed compared to other variant types. We present an efficient bioinformatics pipeline for CNV detection from gene panel MPS data in neuromuscular disorders. CNVs were generated in silico into samples sequenced with a previ...
Nemaline Myopathy (NM) is a rare genetic disorder that encompasses a large spectrum of myopathies characterized by hypotonia and generalized muscle weakness. To date, mutations in thirteen different genes have been associated with NM. The most frequently responsible genes are NEB (50% of cases) and ACTA1 (15–25% of cases). In this report all known...
Primers used to amplify the specific regions. (PDF)
List of selected variants and their bioinformatic annotations relevant for their interpretation. (PDF)
Muscle biopsies analysis from patient 1 by conventional microscopy. A. H&E: There is an increase in fat and connective tissue, internal nuclei and a wide variation in fibre size. B. Shows the presence of abundant rods, as red-staining structures with the Gomori trichrome stain, located mostly in the cytoplasm and often forming clusters. (TIF)
We report the first family with a dominantly inherited mutation of the nebulin gene (NEB). This ∼100 kb in-frame deletion encompasses NEB exons 14-89, causing distal nemaline/cap myopathy in a three-generation family. It is the largest deletion characterized in NEB hitherto. The mutated allele was shown to be expressed at the mRNA level and further...
Introduction Nebulin is a giant actin‐binding protein in the thin filament of the skeletal muscle sarcomere. Studies of nebulin interactions are limited by the size, complexity and poor solubility of the protein. We divided the nebulin super‐repeat region into a super‐repeat panel, and studied nebulin/actin interactions. Methods Actin binding was...
Background: Nemaline myopathy has been associated with mutations in twelve genes to date. However, for some patients diagnosed with nemaline myopathy, definitive mutations are not identified in the known genes, suggesting there are other genes involved. This study describes compound heterozygosity for rare variants in RYR3 in one such patient. Re...
Objective: Copy number variants (CNVs) were analyzed from next-generation sequencing data, with the aim of improving diagnostic yield in skeletal muscle disorder cases. Methods: Four publicly available bioinformatic analytic tools were used to analyze CNVs from sequencing data from patients with muscle diseases. The patients were previously analyz...
Nemaline myopathy (NM) is caused by mutations in at least eleven different genes, but most commonly by recessive mutations in the nebulin gene (NEB), a 183 exon gene essential for correct sarcomere structure and function. NEB harbors a 32kb triplicate region (TRI), in which eight exons are usually repeated three times (ex 82-89, 90-97, 98-105). We...
Variants in the Y-box binding protein 3 (YBX3) gene have been connected to Nemaline myopathy. To better understand the impact of these variants, we are working on localization and interaction studies of the wild-type protein and the variants.
Titin and nebulin, two gigantic sarcomeric proteins, both contain segmental duplication regions in their sequences, and harbor both normal and pathogenic copy number variation. These blocks are challenging to analyze by both Comparative Genomic Hybridization array and Next Generation Sequencing methods - therefore we are developing ddPCR based assays for the analysis of these regions. The method is under validation, and will be subject for a manuscript in the near future.
The extended CGH-array design that we developed covers 178 genes related to neuromuscular disorders, covered at a high tiled coverage. The array constitutes a robust method for copy number variant analysis for diagnostics of neuromuscular disorder patients, and also covers the segmental duplication regions of both nebulin and titin.