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Background & Aims: Transcription co‐activator factor 20 (TCF20) is a regulator of transcription factors involved in extracellular matrix remodelling. In addition, TCF20 genomic variants in humans have been associated with impaired intellectual disability. Therefore, we hypothesized that TCF20 has several functions beyond those described in neurogenesis, including the regulation of fibrogenesis. Methods: Tcf20 knock‐out (Tcf20−/−) and Tcf20 heterozygous mice were generated by homologous recombination. TCF20 gene genotyping and expression was assessed in patients with pathogenic variants in the TCF20 gene. Neural development was investigated by immufluorescense. Mitochondrial metabolic activity was evaluated with the Seahorse analyser. The proteome analysis was carried out by gas chromatography mass‐spectrometry. Results: Characterization of Tcf20−/− newborn mice showed impaired neural development and death after birth. In contrast, heterozygous mice were viable but showed higher CCl4‐induced liver fibrosis and a differential expression of genes involved in extracellular matrix homeostasis compared to wild‐type mice, along with abnormal behavioural patterns compatible with autism‐like phenotypes. Tcf20−/− embryonic livers and mouse embryonic fibroblast (MEF) cells revealed differential expression of structural proteins involved in the mitochondrial oxidative phosphorylation chain, increased rates of mitochondrial metabolic activity and alterations in metabolites of the citric acid cycle. These results parallel to those found in patients with TCF20 pathogenic variants, including alterations of the fibrosis scores (ELF and APRI) and the elevation of succinate concentration in plasma. Conclusions: We demonstrated a new role of Tcf20 in fibrogenesis and mitochondria metabolism in mice and showed the association of TCF20 deficiency with fibrosis and metabolic biomarkers in humans. [ABSTRACT FROM AUTHOR]

Hereditary palmoplantar keratodermas (PPKs) are a clinically and genetically heterogeneous group of disorders characterized by excessive epidermal thickening of palms and soles. Several genes have been associated with PPK including PERP, a gene encoding a crucial component of desmosomes that has been associated with dominant and recessive keratoderma. We report a patient with recessive erythrokeratoderma (EK) in which whole exome sequencing (WES) prioritized by human phenotype ontology (HPO) terms revealed the presence of the novel variant c.153C > A in the N-terminal region the PERP gene. This variant is predicted to have a nonsense effect, p.(Cys51Ter), resulting in a premature stop codon. We demonstrated a marked reduction in gene expression in cultured skin fibroblasts obtained from the patient. Despite the PERP gene is expressed at low levels in fibroblasts, our finding supports a loss-of-function (LoF) mechanism for the identified variant, as previously suggested in recessive EK. Our study underscores the importance of integrating HPO analysis when using WES for molecular genetic diagnosis in a clinical setting, as it facilitates continuous updates regarding gene–clinical feature associations. [ABSTRACT FROM AUTHOR]

The biallelic pathogenic repeat (AAGGG)400–2000 intronic expansion in the RFC1 gene has been recently described as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and as a major cause of late‐onset ataxia. Since then, many heterozygous carriers have been identified, with an estimated allele frequency of 0.7% to 4% in the healthy population. Here, we describe in two affected CANVAS sisters the presence of the nonsense c.724C > T p.(Arg242*) variant in compound heterozygosity with the pathogenic repeat expansion in the RFC1 gene. Further RNA analysis demonstrated a reduced expression of the p.Arg242* allele in patients confirming an efficient nonsense‐mediated mRNA decay. We also highlight the importance of considering the sequencing of the RFC1 gene for the diagnosis, especially in patients with CANVAS diagnosis carriers of the AAGGG repeat expansion. [ABSTRACT FROM AUTHOR]

Alazami syndrome is a rare disorder with an autosomal recessive inheritance caused by pathogenic biallelic variants in the LARP7 gene. Clinically, it is mainly characterized by short stature, intellectual disability, and dysmorphic facial features. However, the phenotype is not yet well-defined because less than 50 cases have been described to date. Here, we report three new patients from two unrelated Spanish families who, in addition to the defined features of Alazami syndrome, also exhibit unique features that broaden the phenotypic spectrum of the syndrome. Moreover, we describe the novel frameshift variant c.690_699delins27 in the LARP7 gene, in which loss of function is a known mechanism of Alazami syndrome. [ABSTRACT FROM AUTHOR]

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused predominantly by pathogenic variants in NOTCH3 gene. Neither germline nor somatic mosaicism has been previously published in NOTCH3 gene. CADASIL is inherited in an autosomal dominant manner; only rare cases have been associated with de novo pathogenic variants. Mosaicism is more common than previously thought because mosaic variants often stay unrevealed. An apparently de novo variant might actually be a consequence of a parental mosaicism undetectable with Sanger sequencing, especially in the case of low grade mosaicism. Parental testing by sensitive tools like deep targeted next‐generation sequencing (NGS) analysis could detect cases of unrevealed medium or low level mosaicism in patients tested by Sanger sequencing. Here, we report the first patient with mosaic NOTCH3 gene pathogenic variant to our knowledge; the allelic fraction in the leucocyte DNA was low (13%); the pathogenic variant was inhered by his two daughters. The patient was diagnosed by deep targeted NGS analysis after studying his two affected daughters. This report highlights the importance of parental testing by sensitive tools like deep targeted NGS analysis. Detection of mosaicism is of great importance for diagnosis and adequate family genetic counseling. [ABSTRACT FROM AUTHOR]

Introduction: Pompe Disease (PD) is a lysosomal disorder caused by a deficiency of the enzyme acid alpha-glucosidase (GAA), primarily manifesting as a progressive myopathy with early respiratory involvement. Enzyme replacement therapy (ERT) is available since 2006., Materials and Methods: We describe 13 patients with partial GAA deficiency, followed at Hospital 12 de Octubre, 8 of whom were receiving treatment., Results: 8 patients exhibit symptoms, all with late onset. They display axial and proximal weakness predominantly in the lower limbs but maintain autonomous gait. Five patients require non-invasive mechanical ventilation due to respiratory insufficiency. All symptomatic patients receive ERT, and in 7/8 (87.5%), there is a decline in motor and pulmonary function after an average of 8.25 years of treatment (baseline and post-treatment FVC and 6MWT mean 86.6% vs 70.8% and 498 vs 430 meters, respectively)., Conclusion: Not all patients with partial GAA deficiency experience symptoms of PD, and symptomatic patients, despite ERT with recombinant alpha-glucosidase, mostly experience a gradual decline in motor and respiratory function., (Copyright © 2024 Elsevier España, S.L.U. All rights reserved.)