RESUMO
BACKGROUND: Ellis-van Creveld syndrome (EvC) is a recessive disorder characterised by acromesomelic limb shortening, postaxial polydactyly, nail-teeth dysplasia and congenital cardiac defects, primarily caused by pathogenic variants in EVC or EVC2. Weyers acrofacial dysostosis (WAD) is an ultra-rare dominant condition allelic to EvC. The present work aimed to enhance current knowledge on the clinical manifestations of EvC and WAD and broaden their mutational spectrum. METHODS: We conducted molecular studies in 46 individuals from 43 unrelated families with a preliminary clinical diagnosis of EvC and 3 affected individuals from a family with WAD and retrospectively analysed clinical data. The deleterious effect of selected variants of uncertain significance was evaluated by cellular assays. MAIN RESULTS: We identified pathogenic variants in EVC/EVC2 in affected individuals from 41 of the 43 families with EvC. Patients from each of the two remaining families were found with a homozygous splicing variant in WDR35 and a de novo heterozygous frameshift variant in GLI3, respectively. The phenotype of these patients showed a remarkable overlap with EvC. A novel EVC2 C-terminal truncating variant was identified in the family with WAD. Deep phenotyping of the cohort recapitulated 'classical EvC findings' in the literature and highlighted findings previously undescribed or rarely described as part of EvC. CONCLUSIONS: This study presents the largest cohort of living patients with EvC to date, contributing to better understanding of the full clinical spectrum of EvC. We also provide comprehensive information on the EVC/EVC2 mutational landscape and add GLI3 to the list of genes associated with EvC-like phenotypes.
Assuntos
Síndrome de Ellis-Van Creveld , Linhagem , Fenótipo , Humanos , Síndrome de Ellis-Van Creveld/genética , Síndrome de Ellis-Van Creveld/patologia , Masculino , Feminino , Criança , Proteínas de Membrana/genética , Mutação , Pré-Escolar , Proteína Gli3 com Dedos de Zinco/genética , Adolescente , Adulto , Proteínas do Tecido Nervoso/genética , Estudos de Coortes , Lactente , Proteínas/genética , Estudos Retrospectivos , Peptídeos e Proteínas de Sinalização IntercelularRESUMO
PURPOSE: This study aimed to identify the genetic cause of a new multiple congenital anomalies syndrome observed in three individuals from two unrelated families. METHODS: Clinical assessment was conducted prenatally and at different postnatal stages. Genetic studies included exome sequencing (ES) combined with single-nucleotide polymorphism (SNP) array based homozygosity mapping and trio ES. Dermal fibroblasts were used for functional assays. RESULTS: A clinically recognizable syndrome characterized by severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with an additional hypoplastic digit between the fourth and fifth digits of hands and/or feet was identified. Additional features included eye abnormalities, hearing impairment, and electroencephalogram anomalies. ES detected different homozygous truncating variants in MAPKAPK5 in both families. Patient-derived cells showed no expression of MAPKAPK5 protein isoforms and reduced levels of the MAPKAPK5-interacting protein ERK3. F-actin recovery after latrunculin B treatment was found to be less efficient in patient-derived fibroblasts than in control cells, supporting a role of MAPKAPK5 in F-actin polymerization. CONCLUSION: Our data indicate that loss-of-function variants in MAPKAPK5 result in a severe developmental disorder and reveal a major role of this gene in human brain, heart, and limb development.
Assuntos
Deficiências do Desenvolvimento , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Serina-Treonina Quinases/genética , Sindactilia , Criança , Deficiências do Desenvolvimento/genética , Humanos , Fenótipo , Sindactilia/genéticaRESUMO
Aberrant expression of CD2 and/or CD25 by bone marrow, peripheral blood or other extracutaneous tissue mast cells is currently used as a minor World Health Organization diagnostic criterion for systemic mastocytosis. However, the diagnostic utility of CD2 versus CD25 expression by mast cells has not been prospectively evaluated in a large series of systemic mastocytosis. Here we evaluate the sensitivity and specificity of CD2 versus CD25 expression in the diagnosis of systemic mastocytosis. Mast cells from a total of 886 bone marrow and 153 other non-bone marrow extracutaneous tissue samples were analysed by multiparameter flow cytometry following the guidelines of the Spanish Network on Mastocytosis at two different laboratories. The 'CD25+ and/or CD2+ bone marrow mast cells' World Health Organization criterion showed an overall sensitivity of 100% with 99.0% specificity for the diagnosis of systemic mastocytosis whereas CD25 expression alone presented a similar sensitivity (100%) with a slightly higher specificity (99.2%). Inclusion of CD2 did not improve the sensitivity of the test and it decreased its specificity. In tissues other than bone marrow, the mast cell phenotypic criterion revealed to be less sensitive. In summary, CD2 expression does not contribute to improve the diagnosis of systemic mastocytosis when compared with aberrant CD25 expression alone, which supports the need to update and replace the minor World Health Organization 'CD25+ and/or CD2+' mast cell phenotypic diagnostic criterion by a major criterion based exclusively on CD25 expression.
Assuntos
Antígenos CD2/análise , Imunofenotipagem , Subunidade alfa de Receptor de Interleucina-2/análise , Mastócitos/imunologia , Mastocitose Sistêmica/diagnóstico , Organização Mundial da Saúde , Biomarcadores/análise , Exame de Medula Óssea , Distribuição de Qui-Quadrado , Citometria de Fluxo , Fidelidade a Diretrizes , Humanos , Imunofenotipagem/métodos , Imunofenotipagem/normas , Mastocitose Sistêmica/imunologia , Variações Dependentes do Observador , Fenótipo , Guias de Prática Clínica como Assunto , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , EspanhaRESUMO
FXR1 is an alternatively spliced gene that encodes RNA binding proteins (FXR1P) involved in muscle development. In contrast to other tissues, cardiac and skeletal muscle express two FXR1P isoforms that incorporate an additional exon-15. We report that recessive mutations in this particular exon of FXR1 cause congenital multi-minicore myopathy in humans and mice. Additionally, we show that while Myf5-dependent depletion of all FXR1P isoforms is neonatal lethal, mice carrying mutations in exon-15 display non-lethal myopathies which vary in severity depending on the specific effect of each mutation on the protein.
Assuntos
Genes Recessivos , Predisposição Genética para Doença/genética , Músculo Esquelético/metabolismo , Mutação , Miopatias Congênitas Estruturais/genética , Oftalmoplegia/genética , Proteínas de Ligação a RNA/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/deficiência , Animais , Células Cultivadas , Éxons/genética , Expressão Gênica , Células HEK293 , Células HeLa , Humanos , Camundongos Transgênicos , Miopatias Congênitas Estruturais/congênito , Miopatias Congênitas Estruturais/metabolismo , Oftalmoplegia/congênito , Oftalmoplegia/metabolismo , Proteínas de Ligação a RNA/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismoRESUMO
BACKGROUND: Serum baseline tryptase (sBT) is a minor diagnostic criterion for systemic mastocytosis (SM) of undetermined prognostic impact. We monitored sBT levels in indolent SM (ISM) patients and investigated its utility for predicting disease behaviour and outcome. METHODS: In total 74 adult ISM patients who were followed for ≥48 months and received no cytoreductive therapy were retrospectively studied. Patients were classified according to the pattern of evolution of sBT observed. RESULTS: Overall 16/74 (22%) cases had decreasing sBT levels, 48 (65%) patients showed increasing sBT levels and 10 (13%) patients showed a fluctuating pattern. Patients with significantly increasing sBT (sBT slope ≥0.15) after 48 months of follow-up showed a slightly greater rate of development of diffuse bone sclerosis (13% vs. 2%) and hepatomegaly plus splenomegaly (16% vs. 5%), as well as a significantly greater frequency of multilineage vs. mast cells (MC)-restricted KIT mutation (pâ=â0.01) together with a greater frequency of cases with progression of ISM to smouldering and aggressive SM (pâ=â0.03), and a shorter progression-free survival (pâ=â0.03). CONCLUSIONS: Monitoring of sBT in ISM patients is closely associated with poor prognosis disease features as well as with disease progression, pointing out the need for a closer follow-up in ISM patients with progressively increasing sBT values.