COVID-19: a challenge and an opportunity

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Host genetic basis of COVID-19: from methodologies to genes

The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is having a massive impact on public health, societies, and economies worldwide. Despite the ongoing vaccination program, treating COVID-19 remains a high priority; thus, a better understanding of the disease is urgently needed. Initially, susceptibility was associated with age, sex, and other prior existing comorbidities. However, as these conditions alone could not explain the highly variable clinical manifestations of SARS-CoV-2 infection, the attention was shifted toward the identification of the genetic basis of COVID-19. Thanks to international collaborations like The COVID-19 Host Genetics Initiative, it became possible the elucidation of numerous genetic markers that are not only likely to help in explaining the varied clinical outcomes of COVID-19 patients but can also guide the development of novel diagnostics and therapeutics. Within this framework, this review delineates GWAS and Burden test as traditional methodologies employed so far for the discovery of the human genetic basis of COVID-19, with particular attention to recently emerged predictive models such as the post-Mendelian model. A summary table with the main genome-wide significant genomic loci is provided. Besides, various common and rare variants identified in genes like TLR7, CFTR, ACE2, TMPRSS2, TLR3, and SELP are further described in detail to illustrate their association with disease severity

Retinoblastoma (hereditary predisposition)

Review on Retinoblastoma, with data on clinics, and the gene involved

Multiple endocrine neoplasia type 2 syndromes may be associated with renal malformations.

Abstract OBJECTIVE: The RET proto-oncogene is known to be the susceptibility gene for various disease phenotypes, including multiple endocrine neoplasia type 2 (MEN 2). Recent studies have also suggested an involvement of RET in the development of the mammalian kidney. Although kidney agenesis or dysgenesis has been observed in mice lacking functional ret, no clinically relevant kidney abnormalities have been reported in individuals with known RET mutations and familial medullary thyroid carcinoma (FMTC). We have studied a family with five members affected with isolated FMTC. DNA analysis was performed and the involved RET mutation was identified. Amongst these patients were a woman and her son. DESIGN: Case report. SETTING: University department. PATIENTS: A 32-year-old woman and her son with FMTC and unilateral renal agenesis. RESULTS: The woman's abdominal ultrasound findings demonstrated unilateral renal absence of the left kidney. Her son, when only a few months old, had undergone surgical treatment for Hirschsprung's disease. Abdominal ultrasonography was performed recently, and left-side renal absence was diagnosed. Intravenous pyelography confirmed the agenesis of his left kidney, whilst the contralateral kidney displayed compensatory hypertrophy. CONCLUSIONS: The involvement of the RET proto-oncogene in the early growth and differentiation of the human kidney is now generally accepted. We believe that at least a proportion of patients with MEN 2 may have undiagnosed renal malformations. We suggest therefore that noninvasive imaging techniques, such as ultrasonography, should be used to explore the presence of renal abnormalities in subjects with demonstrated RET mutations

VEXAS syndrome: a new paradigm for adult-onset monogenic autoinflammatory diseases

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a recently described pathological entity. It is an acquired monogenic autoinflammatory disease caused by somatic mutations of the UBA1 gene in blood cells precursors; the gene encodes one of the two E1 enzyme isoforms that initiates ubiquitylation in cell's cytoplasm. VEXAS syndrome leads to systemic inflammation, with all organs and tissues potentially involved. The clinical picture may be extremely heterogenous, mimicking different other systemic rheumatologic entities coexisting with haematological disorders, especially myelodysplastic syndrome. This new disease represents a very intriguing clinical condition in several respects: it accounts for the paradigm of adult-onset monogenic autoinflammatory diseases determined by a genetic mosaicism resulting in the development of a challenging multiorgan inflammatory condition. Moreover, VEXAS syndrome is perhaps not an exceptionally rare condition and represents an example of a systemic genetic autoinflammatory disease drawing its origin in bone marrow disorders. VEXAS syndrome should be strongly considered in each adult patient with an unexplained systemic inflammatory condition, especially when recurrent fevers, neutrophilic dermatosis, relapsing polychondritis, ocular inflammation and other systemic inflammatory symptoms accompanying myelodysplastic syndrome or other haematological disorders. The syndrome deserves a multidisciplinary approach to reach the diagnosis and ensure the best management of a potentially very challenging condition. To quickly describe the clinical course, long-term outcomes, and the optimal management of this new syndrome it is essential to join forces internationally. To this end, the international AutoInflammatory Disease Alliance (AIDA) registry dedicated to VEXAS syndrome has been developed and is already active. © 2023, The Author(s)

Modelling PCDH19 clustering epilepsy by Neurogenin 2 induction of patient-derived induced pluripotent stem cells

Background: Loss of function mutations in PCDH19 gene causes an X-linked, infant-onset clustering epilepsy, associated with intellectual disability and autistic features. The unique pattern of inheritance includes random X-chromosome inactivation, which leads to pathological tissue mosaicism. Females carrying PCDH19 mutations are affected, while males have a normal phenotype. No cure is presently available for this disease.Methods: Fibroblasts from a female patient carrying frameshift mutation were reprogrammed into human induced pluripotent stem cells (hiPSCs). To create a cell model of PCDH19-clustering epilepsy (PCDH19-CE) where both cell populations co-exist, we created mosaic neurons by mixing wild-type (WT) and mutated (mut) hiPSC clones, and differentiated them into mature neurons with overexpression of the transcriptional factor Neurogenin 2.Results: We generated functional neurons from patient-derived iPSC using a rapid and efficient method of differentiation through overexpression of Neurogenin 2. Was revealed an accelerated maturation and higher arborisation in the mutated neurons, while the mosaic neurons showed the highest frequency of action potential firing and hyperexcitability features, compared to mutated and WT neurons.Conclusions: Our findings provide evidence that PCDH19 c.2133delG mutation affects proper metaphases with increased numbers of centrosomes in stem cells and accelerates neuronal maturation in premature cells. PCDH19 mosaic neurons showed elevated excitability, representing the situation in PCDH19-CE brain. We suggest Ngn2 hiPSC-derived PCDH19 neurons as an informative experimental tool for understanding the pathogenesis of PCDH19-CE and a suitable approach for use in targeted drug screening strategies

Case report: PIK3CA somatic mutation leading to Klippel Trenaunay Syndrome and multiple tumors

We report a case of Klippel Trenaunay Syndrome that was monitored both clinically and molecularly over a period of 9 years. A somatic mosaic mutation of PIK3CA (p(E545G)) was identified using both cfDNA NGS liquid biopsy and tissue biopsy. At the age of 56, due to intervening clonal mutations in PIK3CA background, she developed a squamous cell carcinoma in the right affected leg which was treated surgically. Nine years later, lung bilateral adenocarcinoma arose on PIK3CA mutated tissues supported by different clonal mutations. One year later, the patient died from metastases led by a new FGFR3 clone unresponsive to standard-of-care, immunotherapy-based. Our results highlight the presence of a molecular hallmark underlying neoplastic transformation that occurs upon an angiodysplastic process and support the view that PIK3CA mutated tissues must be treated as precancerous lesions. Importantly, they remark the effectiveness of combining cfDNA NGS liquid and tissue biopsies to monitor disease evolution as well as to identify aggressive clones targetable by tailored therapy, which is more efficient than conventional protocols