This study confirms the presence of a genetic component of the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis and genetic distinctions between granulomatosis with ...polyangiitis and microscopic polyangiitis.
Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is a systemic small-vessel vasculitis comprising three clinical syndromes: granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis),
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microscopic polyangiitis, and the Churg–Strauss syndrome.
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ANCA-associated vasculitis commonly causes life-threatening kidney failure or pulmonary hemorrhage, has a fatality rate of 28% at 5 years, and causes substantial long-term morbidity in survivors.
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Granulomatosis with polyangiitis and microscopic polyangiitis are the major clinical syndromes, both often featuring a pauci-immune necrotizing glomerulonephritis. Granulomatosis with polyangiitis is characterized by granulomatous inflammation of the respiratory tract and by autoantibodies against the neutrophil granule serine protease proteinase 3 in 66% of patients (considered . . .
In this work, we present a comprehensive overview of the genetic and non-genetic complexity of eosinophilic granulomatosis with polyangiitis (EGPA). EGPA is a rare complex systemic disease that ...occurs in people presenting with severe asthma and high eosinophilia. After briefly introducing EGPA and its relationship with the anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis (AAVs), we delve into the complexity of this disease. At first, the two main biological actors, ANCA and eosinophils, are presented. Biological and clinical phenotypes related to ANCA positivity or negativity are explained, as well as the role of eosinophils and their pathological subtypes, pointing out their intricate relations with EGPA. Then, the genetics of EGPA are described, providing an overview of the research effort to unravel them. Candidate gene studies have investigated biologically relevant candidate genes; the more recent genome-wide association studies and meta-analyses, able to analyze the whole genome, have confirmed previous associations and discovered novel risk loci; in the end, family-based studies have dissected the contribution of rare variants and the heritability of EGPA. Then, we briefly present the environmental contribution to EGPA, reporting seasonal events and pollutants as triggering factors. In the end, the latest omic research is discussed and the most recent epigenomic, transcriptomic and microbiome studies are presented, highlighting the current challenges, open questions and suggesting approaches to unraveling this complex disease.
Leucine zipper-like transcription regulator 1 (LZTR1) acts as a negative factor that suppresses RAS function and MAPK signaling; mutations in this protein may dysregulate RAS ubiquitination and lead ...to impaired degradation of RAS superfamily proteins. Germline LZTR1 variants are reported in Noonan syndrome, either autosomal dominant or autosomal recessive, and in susceptibility to schwannomatosis. This article explores the genetic and phenotypic diversity of the autosomal dominant LZTR1-related disorders, compiling a cohort of previously published patients (51 with the Noonan phenotype and 123 with schwannomatosis) and presenting two additional adult-onset cases: a male with schwannomatosis and Parkinson’s disease and a female with Noonan syndrome, generalized joint hypermobility, and breast cancer. This review confirms that autosomal dominant LZTR1-related disorders exhibit an extreme phenotypic variability, ranging from relatively mild manifestations to severe and multi-systemic involvement, and offers updated frequences of each clinical feature. The aim is to precisely define the clinical spectrum of LZTR1-related diseases, using also two new emblematic clinical cases. Gaining insight into the mechanisms underneath this variability is crucial to achieve precision diagnostics and the development of therapeutic interventions.
ANCA-associated vasculitis (AAV) is a group of disorders that is caused by inflammation affecting small blood vessels. Both arteries and veins are affected. AAV includes microscopic polyangiitis ...(MPA), granulomatosis with polyangiitis (GPA) renamed from Wegener's granulomatosis, and eosinophilic granulomatosis with polyangiitis (EGPA), renamed from Churg-Strauss syndrome. AAV is primarily due to leukocyte migration and resultant damage. Despite decades of research, the mechanisms behind AAV disease etiology are still not fully understood, although it is clear that genetic and environmental factors are involved. To improve the understanding of the disease, the genetic component has been extensively studied by candidate association studies and two genome-wide association studies. The majority of the identified genetic AAV risk factors are common variants. These have uncovered information that still needs further investigation to clarify its importance. In this review, we summarize and discuss the results of the genetic studies in AAV. We also present the novel approaches to identifying the causal variants in complex susceptibility loci and disease mechanisms. Finally, we discuss the limitations of current methods and the challenges that we still have to face in order to incorporate genomic and epigenomic data into clinical practice.
Novel approaches to uncover the molecular etiology of neurodevelopmental disorders (NDD) are highly needed. Even using a powerful tool such as whole exome sequencing (WES), the diagnostic process may ...still prove long and arduous due to the high clinical and genetic heterogeneity of these conditions. The main strategies to improve the diagnostic rate are based on family segregation, re-evaluation of the clinical features by reverse-phenotyping, re-analysis of unsolved NGS-based cases and epigenetic functional studies. In this article, we described three selected cases from a cohort of patients with NDD in which trio WES was applied, in order to underline the typical challenges encountered during the diagnostic process: (1) an ultra-rare condition caused by a missense variant in
, identified through the updated Solve-RD re-analysis; (2) a patient with Noonan-like features in which the NGS analysis revealed a novel variant in
causing Cornelia de Lange syndrome; and (3) a case with de novo variants in genes involved in the chromatin-remodeling complex, for which the study of the epigenetic signature excluded a pathogenic role. In this perspective, we aimed to (i) provide an example of the relevance of the genetic re-analysis of all unsolved cases through network projects on rare diseases; (ii) point out the role and the uncertainties of the reverse phenotyping in the interpretation of the genetic results; and (iii) describe the use of methylation signatures in neurodevelopmental syndromes for the validation of the variants of uncertain significance.
Germline RET variants are responsible for approximately 25% of medullary thyroid carcinoma (MTC) cases. Identification of RET variant carriers allows for the adoption of preventative measures which ...are dependent on the risk associated with the specific alteration. From 2002 to 2020, at our cancer genetics clinic, RET genetic testing was performed in 163 subjects (102 complete gene analyses and 61 targeted analyses), 72 of whom presented with MTC. A germline RET variant was identified in 31.9% of patients affected by MTC (93.8% of those having positive family history and 14.3% of clinically sporadic cases). Subsequent target testing in relatives allowed us to identify 22 asymptomatic carriers, who could undertake appropriate screening. Overall, patients with germline RET variants differed significantly from those who tested negative by family history (p < 0.001) and mean age at MTC diagnosis (44.45 vs. 56.42 years; p = 0.010), but the difference was not significant when only carriers of moderate risk variants were considered (51.78 vs. 56.42 years; p = 0.281). Out of 12 different variants detected in 49 patients, five (41.7%) were of uncertain significance (VUS). For two of these, p.Ser904Phe and p.Asp631_Leu633delinsGlu, co-segregation and genotype/phenotype analysis, matched with data from the literature, provided evidence supporting their classification in the moderate and the highest/high risk class (with a MEN2B phenotype), respectively.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Germline variants occurring in
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give rise to hereditary breast and ovarian cancer (HBOC) syndrome, predisposing to breast, ovarian, fallopian tube, and peritoneal cancers marked by elevated ...incidences of genomic aberrations that correspond to poor prognoses. These genes are in fact involved in genetic integrity, particularly in the process of homologous recombination (HR) DNA repair, a high-fidelity repair system for mending DNA double-strand breaks. In addition to its implication in HBOC pathogenesis, the impairment of HR has become a prime target for therapeutic intervention utilizing poly (ADP-ribose) polymerase (PARP) inhibitors. In the present review, we introduce the molecular roles of HR orchestrated by BRCA1 and BRCA2 within the framework of sensitivity to PARP inhibitors. We examine the genetic architecture underneath breast and ovarian cancer ranging from high- and mid- to low-penetrant predisposing genes and taking into account both germline and somatic variations. Finally, we consider higher levels of complexity of the genomic landscape such as polygenic risk scores and other approaches aiming to optimize therapeutic and preventive strategies for breast and ovarian cancer.
Neurofibromatosis type I, a genetic disorder due to mutations in the
gene, is characterized by a high mutation rate (about 50% of the cases are de novo) but, with the exception of whole gene ...deletions associated with a more severe phenotype, no specific hotspots and few solid genotype/phenotype correlations. After retrospectively re-evaluating all
gene variants found in the diagnostic activity, we studied 108 patients affected by neurofibromatosis type I who harbored mutations that had not been previously reported in the international databases, with the aim of analyzing their type and distribution along the gene and of correlating them with the phenotypic features of the affected patients. Out of the 108 previously unreported variants, 14 were inherited by one of the affected parents and 94 were de novo. Twenty-nine (26.9%) mutations were of uncertain significance, whereas 79 (73.2%) were predicted as pathogenic or probably pathogenic. No differential distribution in the exons or in the protein domains was observed and no statistically significant genotype/phenotype correlation was found, confirming previous evidences.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The term "arthrogryposis" is used to indicate multiple congenital contractures affecting two or more areas of the body. Arthrogryposis is the consequence of an impairment of embryofetal neuromuscular ...function and development. The causes of arthrogryposis are multiple, and in newborns, it is difficult to predict the molecular defect as well as the clinical evolution just based on clinical findings. We studied a consecutive series of 13 participants who had amyoplasia, distal arthrogryposis (DA), or syndromic forms of arthrogryposis with normal intellectual development and other motor abilities. The underlying pathogenic variants were identified in 11 out of 13 participants. Correlating the genotype with the clinical features indicated that prenatal findings were specific for DA; this was helpful to identify familial cases, but features were non-specific for the involved gene. Perinatal clinical findings were similar among the participants, except for amyoplasia. Dilatation of the aortic root led to the diagnosis of Loeys-Dietz syndrome (LDS) in one case. The phenotype of DA type 5D (DA5D) and Escobar syndrome became more characteristic at later ages due to more pronounced pterygia. Follow-up indicated that DA type 1 (DA1)/DA type 2B (DA2B) spectrum and LDS had a more favorable course than the other forms. Hand clenching and talipes equinovarus/rocker bottom foot showed an improvement in all participants, and adducted thumb resolved in all forms except in amyoplasia. The combination of clinical evaluation with Next Generation Sequencing (NGS) analysis in the newborn may allow for an early diagnosis and, particularly in the DAs, suggests a favorable prognosis.
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