A founder variant in the RYR1 gene is associated with hyperCKemia, myalgia and muscle cramps.

Background And Purpose: Pathogenic variants in the RYR1 gene have been associated with a variety of conditions, ranging from congenital myopathy to adult manifestations. Our aim was to characterize the p.Leu2286Val variant in 17 Basque patients, to accurately determine its correlation with clinical features and to explore the possible founder effect of the variant.

Desmoid tumour: a rare cause of congenital unilateral calf enlargement mimicking calf hypertrophy.

Desmoid tumours, also known as aggressive fibromatosis, are rare tumours derived from mesenchymal stem cells, accounting for only 0.03 % of all tumours. While 85-90 % of cases are sporadic, desmoid tumours can occasionally be associated with Gardner syndrome (or Familial Adenomatous Polyposis), which is linked to variants in the tumour suppressor gene, APC (adenomatous polyposis coli) gene on chromosome 5.

Diagnosing missed cases of spinal muscular atrophy in genome, exome, and panel sequencing datasets.

Purpose: We set out to develop a publicly available tool that could accurately diagnose spinal muscular atrophy (SMA) in exome, genome or panel sequencing datasets aligned to a GRCh37, GRCh38, or T2T reference genome.

Methods: The SMA Finder algorithm detects the most common genetic causes of SMA by evaluating reads that overlap the c.840 position of the SMN1 and SMN2 paralogs.

Evidentiary basis of the first regulatory qualification of a digital primary efficacy endpoint.

Stride velocity 95th centile (SV95C) is a wearable-derived endpoint representing the 5% fastest strides taken during everyday living. In July 2023, SV95C received European Medicines Agency (EMA) qualification for use as a primary endpoint in trials of patients with Duchenne muscular dystrophy (DMD) aged ≥ 4 years-becoming the first digital endpoint to receive such qualification. We present the data supporting this qualification, providing insights into the evidentiary basis of qualification as a digital clinical outcome assessment.

A Titin Truncating Variant Causing a Dominant Myopathy With Cardiac Involvement in a Large Family: The Exception That Proves the Rule.

Background: Titin truncating variants (TTNtvs) have been repeatedly reported as causative of recessive but not dominant skeletal muscle disorders.

Objective: To determine whether a single heterozygous nonsense variant in can be responsible for the observed dominant myopathy in a large family.

Methods: In this case series, all available family members (8 affected and 6 healthy) belonging to a single family showing autosomal dominant inheritance were thoroughly examined clinically and genetically.

Expert panel curation of 31 genes in relation to limb girdle muscular dystrophy.

Objective: Limb girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous autosomal conditions with some degree of phenotypic homogeneity. LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy. Advances in massively parallel sequencing have led to a surge in genes linked to LGMD.

Performance of upper limb entry item to predict forced vital capacity in dysferlin-deficient limb girdle muscular dystrophy.

Dysferlin-deficient limb girdle muscular dystrophy (LGMD R2), also referred to as dysferlinopathy, can be associated with respiratory muscle weakness as the disease progresses. Clinical practice guidelines recommend biennial lung function assessments in patients with dysferlinopathy to screen for respiratory impairment. However, lack of universal access to spirometry equipment and trained specialists makes regular monitoring challenging.

Dominant stop-loss HNRNPA1 variants in juvenile-onset myopathy.

Introduction/aims: Heterogeneous nuclear ribonucleoprotein A1 is involved in nucleic acid homeostatic functions. The encoding gene HNRNPA1 has been associated with several neuromuscular disorders including an amyotrophic lateral sclerosis-like phenotype, distal hereditary motor neuropathy, multisystem proteinopathy, and various myopathies. We report two unrelated individuals with monoallelic stop loss variants affecting the same codon of HNRNPA1.

An Integrated Transcriptomics and Genomics Approach Detects an X/Autosome Translocation in a Female with Duchenne Muscular Dystrophy.

Duchenne and Becker muscular dystrophies, caused by pathogenic variants in , are the most common inherited neuromuscular conditions in childhood. These diseases follow an X-linked recessive inheritance pattern, and mainly males are affected. The most prevalent pathogenic variants in the gene are copy number variants (CNVs), and most patients achieve their genetic diagnosis through Multiplex Ligation-dependent Probe Amplification (MLPA) or exome sequencing.

Efficacy of avalglucosidase alfa on forced vital capacity percent predicted in treatment-naïve patients with late-onset Pompe disease: A pooled analysis of clinical trials.

Background: The efficacy of avalglucosidase alfa (AVA) versus alglucosidase alfa (ALG) on forced vital capacity percent predicted (FVCpp) in patients with late-onset Pompe disease (LOPD) has been assessed in the Phase 3 COMET trial (NCT02782741). Due to the rarity of LOPD and thus small sample size in COMET, additional data were analyzed to gain further insights into the efficacy of AVA versus ALG.

Methods: Data from treatment-naive patients with LOPD were pooled from COMET and Phase 1/2 NEO1/NEO-EXT (NCT01898364/NCT02032524) trials for patients treated with AVA, and Phase 3 LOTS trial (NCT00158600) for patients treated with ALG.

Probing diffusion of water and metabolites to assess white matter microstructure in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a progressive X-linked neuromuscular disorder caused by the absence of functional dystrophin protein. In addition to muscle, dystrophin is expressed in the brain in both neurons and glial cells. Previous studies have shown altered white matter microstructure in patients with DMD using diffusion tensor imaging (DTI).

Meaningful changes in motor function in Duchenne muscular dystrophy (DMD): A multi-center study.

Evaluations of treatment efficacy in Duchenne muscular dystrophy (DMD), a rare genetic disease that results in progressive muscle wasting, require an understanding of the 'meaningfulness' of changes in functional measures. We estimated the minimal detectable change (MDC) for selected motor function measures in ambulatory DMD, i.e.

Development of the CDISC Pediatrics User Guide: a CDISC and conect4children collaboration.

Introduction: The conect4children (c4c) project aims to facilitate efficient planning and delivery of paediatric clinical trials. One objective of c4c is data standardization and reuse. Interoperability and reusability of paediatric clinical trial data is challenging due to a lack of standardization.

CIAO1 loss of function causes a neuromuscular disorder with compromise of nucleocytoplasmic Fe-S enzymes.

Cytoplasmic and nuclear iron-sulfur (Fe-S) enzymes that are essential for genome maintenance and replication depend on the cytoplasmic Fe-S assembly (CIA) machinery for cluster acquisition. The core of the CIA machinery consists of a complex of CIAO1, MMS19 and FAM96B. The physiological consequences of loss of function in the components of the CIA pathway have thus far remained uncharacterized.

Disease-associated comorbidities, medication records and anthropometric measures in adults with Duchenne muscular dystrophy.

We investigated the comorbidities, associated factors, and the relationship between anthropometric measures and respiratory function and functional abilities in adults with Duchenne muscular dystrophy (DMD). This was a single-centre cross-sectional study in genetically diagnosed adults with DMD (>16 years old). Univariate and multivariate analyses identified factors associated with dysphagia, constipation, Body Mass Index (BMI), and weight.

Expert Panel Curation of 31 Genes in Relation to Limb Girdle Muscular Dystrophy.

Introduction: Limb girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous autosomal conditions with some degree of phenotypic homogeneity. LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy. Advances in massively parallel sequencing have led to a surge in genes linked to LGMD.

Unravelling undiagnosed rare disease cases by HiFi long-read genome sequencing.

Solve-RD is a pan-European rare disease (RD) research program that aims to identify disease-causing genetic variants in previously undiagnosed RD families. We utilised 10-fold coverage HiFi long-read sequencing (LRS) for detecting causative structural variants (SVs), single nucleotide variants (SNVs), insertion-deletions (InDels), and short tandem repeat (STR) expansions in extensively studied RD families without clear molecular diagnoses. Our cohort includes 293 individuals from 114 genetically undiagnosed RD families selected by European Rare Disease Network (ERN) experts.

Exome copy number variant detection, analysis, and classification in a large cohort of families with undiagnosed rare genetic disease.

Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and, with new innovative methods, can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the Genomics Research to Elucidate the Genetics of Rare Diseases consortium and analyzed using the seqr platform.

Functional abilities, respiratory and cardiac function in a large cohort of adults with Duchenne muscular dystrophy treated with glucocorticoids.

Background And Purpose: The transition to adult services, and subsequent glucocorticoid management, is critical in adults with Duchenne muscular dystrophy. This study aims (1) to describe treatment, functional abilities, respiratory and cardiac status during transition to adulthood and adult stages; and (2) to explore the association between glucocorticoid treatment after loss of ambulation (LOA) and late-stage clinical outcomes.

Methods: This was a retrospective single-centre study on individuals with Duchenne muscular dystrophy (≥16 years old) between 1986 and 2022.

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.

In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene.