Clinical features, mutation spectrum and factors related to reaching molecular diagnosis in a cohort of patients with distal myopathies.

Background: Distal myopathies (MPDs) are heterogeneous diseases of complex diagnosis whose prevalence and distribution in specific populations are unknown.

Methods: Demographic, clinical, genetic, neurophysiological, histopathological and muscle imaging characteristics of a MPDs cohort from a neuromuscular reference center were analyzed to study their epidemiology, features, genetic distribution and factors related to diagnosis.

Results: The series included 219 patients (61% were men, 94% Spanish and 41% sporadic cases).

Exploring non-coding variants and evaluation of antisense oligonucleotides for splicing redirection in Usher syndrome.

Exploring non-coding regions is increasingly gaining importance in the diagnosis of inherited retinal dystrophies. Deep-intronic variants causing aberrant splicing have been identified, prompting the development of antisense oligonucleotides (ASOs) to modulate splicing. We performed a screening of five previously described deep-intronic variants among monoallelic patients with Usher syndrome (USH) or isolated retinitis pigmentosa.

STUB1 Mutations as Possible Genetic Modifiers in Spinocerebellar Ataxia Type 8.

Background: Spinocerebellar ataxia type 8 (SCA8) is a dominantly inherited expansion disorder with highly variable penetrance. ATXN8OS/ATXN8 expanded alleles have been identified in association with other types of hereditary ataxias, pointing to a possible genetic synergism.

Objectives: We aimed to further investigate the molecular background of patients with SCA8 diagnosis.

Intermediate Repeat Expansion in the Gene as a Risk Factor in the ALS and FTD Spanish Population.

Intermediate CAG expansions in the gene ataxin-2 () are a known risk factor for ALS, but little is known about their role in FTD risk. Moreover, their contribution to the risk and phenotype of patients might vary in populations with different genetic backgrounds. The aim of this study was to assess the relationship of intermediate CAG expansions in with the risk and phenotype of ALS and FTD in the Spanish population.

The LIFR Inhibitor EC359 Effectively Targets Type II Endometrial Cancer by Blocking LIF/LIFR Oncogenic Signaling.

Endometrial cancer (ECa) is the most common female gynecologic cancer. When comparing the two histological subtypes of endometrial cancer, Type II tumors are biologically more aggressive and have a worse prognosis than Type I tumors. Current treatments for Type II tumors are ineffective, and new targeted therapies are urgently needed.

Spinocerebellar Ataxia 36 is a Frequent Cause of Hereditary Ataxia in Eastern Spain.

Background: Autosomal dominant spinocerebellar ataxia 36 (SCA36) is caused by hexanucleotide repeat expansion in the gene.

Objectives: To assess frequency, clinical and genetic features of SCA36 in Eastern Spain.

Methods: expansion was tested in a cohort of undiagnosed cerebellar ataxia families (n = 84).

Diagnostic Efficacy of Genetic Studies in a Series of Hereditary Cerebellar Ataxias in Eastern Spain.

Background And Objectives: To determine the diagnostic efficacy of clinical exome-targeted sequencing (CES) and spinocerebellar ataxia 36 (SCA36) screening in a real-life cohort of patients with cerebellar ataxia (CA) from Eastern Spain.

Methods: A total of 130 unrelated patients with CA, negative for common trinucleotide repeat expansions (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, dentatorubral pallidoluysian atrophy [DRPLA], and Friedreich ataxia), were studied with CES. Bioinformatic and genotype-phenotype analyses were performed to assess the pathogenicity of the variants encountered.

Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G>C Variant in SMN2.

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by biallelic loss or pathogenic variants in the SMN1 gene. Copy number and modifier intragenic variants in SMN2, an almost identical paralog gene of SMN1, are known to influence the amount of complete SMN proteins. Therefore, SMN2 is considered the main phenotypic modifier of SMA, although genotype−phenotype correlation is not absolute.

Dystrophinopathy Phenotypes and Modifying Factors in DMD Exon 45-55 Deletion.

Objective: Duchenne muscular dystrophy (DMD) exon 45-55 deletion (del45-55) has been postulated as a model that could treat up to 60% of DMD patients, but the associated clinical variability and complications require clarification. We aimed to understand the phenotypes and potential modifying factors of this dystrophinopathy subset.

Methods: This cross-sectional, multicenter cohort study applied clinical and functional evaluation.

Functional assays of non-canonical splice-site variants in inherited retinal dystrophies genes.

Inherited retinal dystrophies are a group of disorders characterized by the progressive degeneration of photoreceptors leading to loss of the visual function and eventually to legal blindness. Although next generation sequencing (NGS) has revolutionized the molecular diagnosis of these diseases, the pathogenicity of some mutations casts doubts. After the screening of 208 patients with a panel of 117 genes, we obtained 383 variants that were analysed in silico with bioinformatic prediction programs.

Clinical and genetic characteristics of 21 Spanish patients with biallelic pathogenic SPG7 mutations.

Spastic paraplegia type 7 (SPG7) is one of the most common hereditary spastic paraplegias. SPG7 mutations most often lead to spastic paraparesis (HSP) and/or hereditary cerebellar ataxia (HCA), frequently with mixed phenotypes. We sought to clinically and genetically characterize a Spanish cohort of SPG7 patients.

Updating the Genetic Landscape of Inherited Retinal Dystrophies.

Inherited retinal dystrophies (IRD) are a group of diseases characterized by the loss or dysfunction of photoreceptors and a high genetic and clinical heterogeneity. Currently, over 270 genes have been associated with IRD which makes genetic diagnosis very difficult. The recent advent of next generation sequencing has greatly facilitated the diagnostic process, enabling to provide the patients with accurate genetic counseling in some cases.

Usher Syndrome: Genetics of a Human Ciliopathy.

Usher syndrome (USH) is an autosomal recessive syndromic ciliopathy characterized by sensorineural hearing loss, retinitis pigmentosa and, sometimes, vestibular dysfunction. There are three clinical types depending on the severity and age of onset of the symptoms; in addition, ten genes are reported to be causative of USH, and six more related to the disease. These genes encode proteins of a diverse nature, which interact and form a dynamic protein network called the "Usher interactome".

CONCOMITANT MUTATIONS IN INHERITED RETINAL DYSTROPHIES: Why the Reproductive and Therapeutic Counseling Should Be Addressed Cautiously.

Purpose: To highlight the challenge of correct reproductive and therapeutic counseling in complex pedigrees with different inherited retinal dystrophies (IRD).

Methods: Two hundred eight patients diagnosed with nonsyndromic IRD underwent full ophthalmologic examination and molecular analysis using targeted next-generation sequencing.

Results: Five families (4%) carried mutations in more than one gene that contribute to different IRD.

Improving the Management of Patients with Hearing Loss by the Implementation of an NGS Panel in Clinical Practice.

A cohort of 128 patients from 118 families diagnosed with non-syndromic or syndromic hearing loss (HL) underwent an exhaustive clinical evaluation. Molecular analysis was performed using targeted next-generation sequencing (NGS) with a custom panel that included 59 genes associated with non-syndromic HL or syndromic HL. Variants were prioritized according to the minimum allele frequency and classified according to the American College of Medical Genetics and Genomics guidelines.

Expanding the Clinical and Molecular Heterogeneity of Nonsyndromic Inherited Retinal Dystrophies.

A cohort of 172 patients diagnosed clinically with nonsyndromic retinal dystrophies, from 110 families underwent full ophthalmologic examination, including retinal imaging, electrophysiology, and optical coherence tomography, when feasible. Molecular analysis was performed using targeted next-generation sequencing (NGS). Variants were filtered and prioritized according to the minimum allele frequency, and finally classified according to the American College of Medical Genetics and Genomics guidelines.

Expanding the Genetic Landscape of Usher-Like Phenotypes.

Purpose: Usher syndrome (USH) is a rare disorder characterized by retinitis pigmentosa (RP) and sensorineural hearing loss. Several genes are responsible for the disease, but not all cases are explained by mutations in any of these, supporting the fact that there remain other unknown genes that have a role in the syndrome. We aimed to find the genetic cause of presumed USH patients lacking pathogenic mutations in the known USH genes.

Heterozygous pathogenic variants in GLI1 are a common finding in isolated postaxial polydactyly A/B.

Postaxial polydactyly (PAP) is a frequent limb malformation consisting in the duplication of the fifth digit of the hand or foot. Morphologically, this condition is divided into type A and B, with PAP-B corresponding to a more rudimentary extra-digit. Recently, biallelic truncating variants in the transcription factor GLI1 were reported to be associated with a recessive disorder, which in addition to PAP-A, may include syndromic features.

Genetic Screening of the Usher Syndrome in Cuba.

Background: Usher syndrome (USH) is a recessive inherited disease characterized by sensorineural hearing loss, retinitis pigmentosa, and sometimes, vestibular dysfunction. Although the molecular epidemiology of Usher syndrome has been well studied in Europe and United States, there is a lack of studies in other regions like Africa or Central and South America.

Methods: We designed a NGS panel that included the 10 USH causative genes (, , , , , , , , , and ), four USH associated genes (, , , and ), and the region comprising the deep-intronic c.

New mutations found by Next-Generation Sequencing screening of Spanish patients with Nemaline Myopathy.

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).

High-throughput sequencing for the molecular diagnosis of Usher syndrome reveals 42 novel mutations and consolidates CEP250 as Usher-like disease causative.

Usher syndrome is a rare disorder causing retinitis pigmentosa, together with sensorineural hearing loss. Due to the phenotypic and genetic heterogeneity of this disease, the best method to screen the causative mutations is by high-throughput sequencing. In this study, we tested a semiconductor chip based sequencing approach with 77 unrelated patients, as a molecular diagnosis routine.

Unravelling the pathogenic role and genotype-phenotype correlation of the USH2A p.(Cys759Phe) variant among Spanish families.

Introduction: Mutations in USH2A cause both isolated Retinitis Pigmentosa (RP) and Usher syndrome (that implies RP and hearing impairment). One of the most frequent variants identified in this gene and among these patients is the p.(Cys759Phe) change.

Comparison of the Relative Potential for Epigenetic and Genetic Variation To Contribute to Trait Stability.

The theoretical ability of epigenetic variation to influence the heritable variation of complex traits is gaining traction in the study of adaptation. This theory posits that epigenetic marks can control adaptive phenotypes but the relative potential of epigenetic variation in comparison to genetic variation in these traits is not presently understood. To compare the potential of epigenetic and genetic variation in adaptive traits, we analyzed the influence of DNA methylation variation on the accumulation of chemical defense compounds glucosinolates from the order Brassicales.

Correlation between SMA type and SMN2 copy number revisited: An analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases.

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss or mutations in SMN1. According to age of onset, achieved motor abilities, and life span, SMA patients are classified into type I (never sit), II (never walk unaided) or III (achieve independent walking abilities). SMN2, the highly homologous copy of SMN1, is considered the most important phenotypic modifier of the disease.