scholarly journals Genotype–phenotype correlations and nephroprotective effects of RAAS inhibition in patients with autosomal recessive Alport syndrome

2021 ◽  
Author(s):  
Yanqin Zhang ◽  
Jan Böckhaus ◽  
Fang Wang ◽  
Suxia Wang ◽  
Diana Rubel ◽  
...  
Keyword(s):  
Alport Syndrome ◽  
Autosomal Recessive ◽  
Kidney Diseases ◽  
Response To Therapy ◽  
Response To Treatment ◽  
Rapid Decline ◽  
Onset Age ◽  
Missense Variants ◽  
Pathogenic Variants ◽  
Small Patient

Abstract Background Autosomal recessive Alport syndrome (ARAS) is caused by pathogenic variants in both alleles of either COL4A3 or COL4A4 genes. Reports on ARAS are rare due to small patient numbers and there are no reports on renin-angiotensin-aldosterone system (RAAS) inhibition therapy in ARAS. Methods Retrospective study in 101 patients with ARAS from Chinese Registry Database of Hereditary Kidney Diseases and European Alport Registry. Genotype–phenotype correlations and nephroprotective effects of RAAS inhibition in ARAS were evaluated. Results Median age was 15 years (range 1.5–46 years). Twelve patients progressed to stage 5 chronic kidney disease (CKD5) at median age 20.5 years. Patients without missense variants had both higher prevalence and earlier onset age of hearing loss, nephrotic-range proteinuria, more rapid decline of eGFR, and earlier onset age of CKD5 compared to patients with 1 or 2 missense variants. Most patients (79/101, 78%) currently are treated with RAAS inhibitors; median age at therapy initiation was 10 years and mean duration 6.5 ± 6.0 years. Median age at CKD5 for untreated patients was 24 years. RAAS inhibition therapy delayed CKD5 onset in those with impaired kidney function (T-III) to median age 35 years, but is undefined in treated patients with proteinuria (T-II) due to low number of events. No treated patients with microalbuminuria (T-I) progressed to CKD5. ARAS patients with 1 or 2 missense variants showed better response to treatment than patients with non-missense-variants. Conclusions Our study provides the first evidence for early use of RAAS inhibition therapy in patients with ARAS. Furthermore, genotype in ARAS correlates with response to therapy in favor of missense variants.

scholarly journals Cell-based analysis of CAD variants identifies individuals likely to benefit from uridine therapy

2020 ◽  
Vol 22 (10) ◽  
pp. 1598-1605 ◽  
Author(s):  
Francisco del Caño-Ochoa ◽  
Bobby G. Ng ◽  
Malak Abedalthagafi ◽  
Mohammed Almannai ◽  
Ronald D. Cohn ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Clinical Presentation ◽  
De Novo ◽  
Clinical Phenotype ◽  
Transient Transfection ◽  
Missense Variants ◽  
De Novo Biosynthesis ◽  
Pathogenic Variants ◽  
Large Size ◽  
A Cell

Abstract Purpose Pathogenic autosomal recessive variants in CAD, encoding the multienzymatic protein initiating pyrimidine de novo biosynthesis, cause a severe inborn metabolic disorder treatable with a dietary supplement of uridine. This condition is difficult to diagnose given the large size of CAD with over 1000 missense variants and the nonspecific clinical presentation. We aimed to develop a reliable and discerning assay to assess the pathogenicity of CAD variants and to select affected individuals that might benefit from uridine therapy. Methods Using CRISPR/Cas9, we generated a human CAD-knockout cell line that requires uridine supplements for survival. Transient transfection of the knockout cells with recombinant CAD restores growth in absence of uridine. This system determines missense variants that inactivate CAD and do not rescue the growth phenotype. Results We identified 25 individuals with biallelic variants in CAD and a phenotype consistent with a CAD deficit. We used the CAD-knockout complementation assay to test a total of 34 variants, identifying 16 as deleterious for CAD activity. Combination of these pathogenic variants confirmed 11 subjects with a CAD deficit, for whom we describe the clinical phenotype. Conclusions We designed a cell-based assay to test the pathogenicity of CAD variants, identifying 11 CAD-deficient individuals who could benefit from uridine therapy.

scholarly journals Cell-based analysis of CAD variants identifies individuals likely to benefit from uridine therapy

2020 ◽  
Author(s):  
Francisco del Caño-Ochoa ◽  
Bobby G. Ng ◽  
Malak Abedalthagafi ◽  
Mohammed Almannai ◽  
Ronald D. Cohn ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Clinical Presentation ◽  
De Novo ◽  
Clinical Phenotype ◽  
Transient Transfection ◽  
Missense Variants ◽  
Pathogenic Variants ◽  
Large Size ◽  
A Cell ◽  
Growth Phenotype

ABSTRACTPurposePathogenic autosomal recessive variants in CAD, encoding the multienzymatic protein initiating pyrimidine de novo biosynthesis, cause a severe inborn metabolic disorder treatable with a dietary supplement of uridine. This condition is difficult to diagnose given the large size of CAD with over 1000 missense variants and the non-specific clinical presentation. We aimed to develop a reliable and discerning assay to assess the pathogenicity of CAD variants and to select affected individuals that might benefit from uridine therapy.MethodsUsing CRISPR/Cas9, we generated a human CAD-knockout cell line that requires uridine supplements for survival. Transient transfection of the knockout cells with recombinant CAD restores growth in absence of uridine. This system determines missense variants that inactivate CAD and do not rescue the growth phenotype.ResultsWe identified 25 individuals with biallelic variants in CAD and a phenotype consistent with a CAD deficit. We used the CAD-knockout complementation assay to test a total of 34 variants, identifying 16 as deleterious for CAD activity. Combination of these pathogenic variants confirmed 11 subjects with a CAD deficit, for whom we describe the clinical phenotype.ConclusionsWe designed a cell-based assay to test the pathogenicity of CAD variants, identifying 11 CAD deficient individuals, who could benefit from uridine therapy.

scholarly journals Identification of C3GN Presenting in a Proband with Family History of Alport Syndrome

2020 ◽  
Author(s):  
yin ding ◽  
xuanli tang ◽  
yuanyuan du ◽  
hongyu chen ◽  
dongrong yu ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Alport Syndrome ◽  
Kidney Diseases ◽  
Binding Capacity ◽  
Rapid Development ◽  
Molecular Genetic ◽  
In Silico Analysis ◽  
Molecular Genetic Testing ◽  
Gene Encoding ◽  
Pathogenic Variants

Abstract BackgroundAlport syndrome and C3GN are all rare kidney diseases and frequently responsible for familial hematuria, proteinuria and/or coexistent renal impairment. With the rapid development of molecular genetic testing, Alport syndrome have been restricted mostly to causal variants in the COL4A5 or COL4A3/COL4A4 genes. And a broad range of genetic contributors in the complement and complement-regulating proteins definitely implicate in the pathogenesis of C3GN.MethodsWe sought a family with persistent microscopic hematuria associated with renal failure. Clinicopathologic and follow-up data were obtained, and molecular genetic testing was used to screen pathogenic variants. ResultsWe describe a three-generation family with Alport syndrome showing a dominant maternally transmitted inheritance. Notably, renal biopsy showed the concurrent histological evidence of C3GN in the proband and further classified as CFHR5-related nephropathy due to a rare heterozygous variation in gene-encoding CFHR5, c.508G>A. The alteration leads to replacement of a highly conserved residue at position 170 of the β-strand subunit of CFHR5 (p.Val170Met). In silico analysis, the variation was predicted to deregulate complement activation by altering the structural property and enhancing C3b binding capacity to compete with CFH, which was in a good agreement with experimental data previously published.ConclusionsThe comorbidity findings between Alport Syndrome and C3GN indicate an underlying overlap, and await further study.

MO1010CLINICAL VARIABILITY OF ALPORT SYNDROME IN CHILDREN WITH MISSENSE COL4A5  VARIANTS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Marina Aksenova ◽  
Tatjana Lepaeva ◽  
Tatjana Nikishina ◽  
Oxana Piruzeeva ◽  
Varvara Obuhova ◽  
...  
Keyword(s):  
Alport Syndrome ◽  
Clinical Symptoms ◽  
Age At Onset ◽  
Sensorineural Deafness ◽  
Missense Mutations ◽  
Mild Phenotype ◽  
Missense Variants ◽  
Pathogenic Variants ◽  
Significant Difference ◽  
The Mean

Abstract Background and Aims The phenotype-genotype relation is well established in patients (especially male) with X-linked Alport syndrome (XLAS). The aim of study was to define the spectrum of COL4A5 pathogenic variants and impact of missense mutation on disease progression. Method The NGS-based genetic testing of COL4A3, COL4A4, COL4A5 was performed in 186 children with suspected Alport syndrome. The comparison of clinical symptoms (frequency, age of presentation of macrohematuria, proteinuria, eGFR decrease, sensorineural deafness (SND), level of proteinuria (mg/m2/day) and eGFR (ml/min/1.73m2) at the last presentation) was carried out in male with XLAS due to different COL4A5 variants. Results The XLAS was diagnosed in 93 children (Ме 7,5[4;11], 51М) from 79 families. The following COL4A5 variants were revealed: missense (n=70, q=0.75), splice site (n=10 from 9 families, q=0.11), frame shift (n=6, q=0.06), nonsense (n=7, q=0.08). Missense variants were presented by COL4A5 c.1871G>A, p.(Gly624Asp) in 26% of cases (n=18). The mean age of ESRD was lower in male family member (35[24;35] years vs 48[40;55], p=0.023) with non COL4A5 p.(Gly624Asp). There was no difference in age on last presentation (13[9;14] vs 12[8;15], p=0.091) between pts with COL4A5 p.(Gly624Asp) and other missense variants. There was significant difference between the male with p.Gly624Asp and other missense variants in frequency of proteinuria (0.61 vs 0.25, p=0.043), SND (0.5 vs 0.08, p=0.03), age at onset (5[3;7] vs 14[8;16], p=0.02) and degree of proteinuria (441[78;1158] vs 66[22;160], p=0.023) and eGFR level (83[66;109] vs 96[91;104], p=0.048) at the last examination. Conclusion The XLAS is caused by missense variants in ¾ of cases in our cohort. We confirmed the other European studies results: the COL4A5 p.(Gly624Asp) is the most common variant of missense mutations characterized by mild phenotype of XLAS.

Melanoma: Prognostic Factors and Factors Predictive of Response to Therapy

2020 ◽  
Vol 27 (17) ◽  
pp. 2792-2813
Author(s):  
Martina Strudel ◽  
Lucia Festino ◽  
Vito Vanella ◽  
Massimiliano Beretta ◽  
Francesco M. Marincola ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Lactate Dehydrogenase ◽  
Checkpoint Inhibitors ◽  
Survival Rates ◽  
Elevated Serum ◽  
Predictive Biomarkers ◽  
Response To Therapy ◽  
Response To Treatment ◽  
Prognostic Features ◽  
Programmed Death

Background: A better understanding of prognostic factors and biomarkers that predict response to treatment is required in order to further improve survival rates in patients with melanoma. Predictive Biomarkers: The most important histopathological factors prognostic of worse outcomes in melanoma are sentinel lymph node involvement, increased tumor thickness, ulceration and higher mitotic rate. Poorer survival may also be related to several clinical factors, including male gender, older age, axial location of the melanoma, elevated serum levels of lactate dehydrogenase and S100B. Predictive Biomarkers: Several biomarkers have been investigated as being predictive of response to melanoma therapies. For anti-Programmed Death-1(PD-1)/Programmed Death-Ligand 1 (PD-L1) checkpoint inhibitors, PD-L1 tumor expression was initially proposed to have a predictive role in response to anti-PD-1/PD-L1 treatment. However, patients without PD-L1 expression also have a survival benefit with anti-PD-1/PD-L1 therapy, meaning it cannot be used alone to select patients for treatment, in order to affirm that it could be considered a correlative, but not a predictive marker. A range of other factors have shown an association with treatment outcomes and offer potential as predictive biomarkers for immunotherapy, including immune infiltration, chemokine signatures, and tumor mutational load. However, none of these have been clinically validated as a factor for patient selection. For combined targeted therapy (BRAF and MEK inhibition), lactate dehydrogenase level and tumor burden seem to have a role in patient outcomes. Conclusions: With increasing knowledge, the understanding of melanoma stage-specific prognostic features should further improve. Moreover, ongoing trials should provide increasing evidence on the best use of biomarkers to help select the most appropriate patients for tailored treatment with immunotherapies and targeted therapies.

scholarly journals Classical Xanthinuria in Nine Israeli Families and Two Isolated Cases from Germany: Molecular, Biochemical and Population Genetics Aspects

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 788
Author(s):  
Hava Peretz ◽  
Ayala Lagziel ◽  
Florian Bittner ◽  
Mustafa Kabha ◽  
Meirav Shtauber-Naamati ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Heterologous Protein ◽  
Heterologous Protein Expression ◽  
Type I ◽  
Type Ii ◽  
Amino Acid Residues ◽  
Cysteine Desulfurase ◽  
Cofactor Binding ◽  
Pathogenic Variants ◽  
Expression Studies

Classical xanthinuria is a rare autosomal recessive metabolic disorder caused by variants in the XDH (type I) or MOCOS (type II) genes. Thirteen Israeli kindred (five Jewish and eight Arab) and two isolated cases from Germany were studied between the years 1997 and 2013. Four and a branch of a fifth of these families were previously described. Here, we reported the demographic, clinical, molecular and biochemical characterizations of the remaining cases. Seven out of 20 affected individuals (35%) presented with xanthinuria-related symptoms of varied severity. Among the 10 distinct variants identified, six were novel: c.449G>T (p.(Cys150Phe)), c.1434G>A (p.(Trp478*)), c.1871C>G (p.(Ser624*)) and c.913del (p.(Leu305fs*1)) in the XDH gene and c.1046C>T (p.(Thr349Ileu)) and c.1771C>T (p.(Pro591Ser)) in the MOCOS gene. Heterologous protein expression studies revealed that the p.Cys150Phe variant within the Fe/S-I cluster-binding site impairs XDH biogenesis, the p.Thr349Ileu variant in the NifS-like domain of MOCOS affects protein stability and cysteine desulfurase activity, while the p.Pro591Ser and a previously described p.Arg776Cys variant in the C-terminal domain affect Molybdenum cofactor binding. Based on the results of haplotype analyses and historical genealogy findings, the potential dispersion of the identified variants is discussed. As far as we are aware, this is the largest cohort of xanthinuria cases described so far, substantially expanding the repertoire of pathogenic variants, characterizing structurally and functionally essential amino acid residues in the XDH and MOCOS proteins and addressing the population genetic aspects of classical xanthinuria.

scholarly journals Diagnostic exome-based preconception carrier testing in consanguineous couples: results from the first 100 couples in clinical practice

2021 ◽  
Author(s):  
Suzanne C. E. H. Sallevelt ◽  
Alexander P. A. Stegmann ◽  
Bart de Koning ◽  
Crool Velter ◽  
Anja Steyls ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Rare Variants ◽  
Clinical Care ◽  
Carrier Testing ◽  
Carrier Status ◽  
Routine Diagnostics ◽  
Affected Offspring ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Genetics And Genomics

Abstract Purpose Consanguineous couples are at increased risk of being heterozygous for the same autosomal recessive (AR) disorder(s), with a 25% risk of affected offspring as a consequence. Until recently, comprehensive preconception carrier testing (PCT) for AR disorders was unavailable in routine diagnostics. Here we developed and implemented such a test in routine clinical care. Methods We performed exome sequencing (ES) for 100 consanguineous couples. For each couple, rare variants that could give rise to biallelic variants in offspring were selected. These variants were subsequently filtered against a gene panel consisting of ~2,000 genes associated with known AR disorders (OMIM-based). Remaining variants were classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, after which only likely pathogenic and pathogenic (class IV/V) variants, present in both partners, were reported. Results In 28 of 100 tested consanguineous couples (28%), likely pathogenic and pathogenic variants not previously known in the couple or their family were reported conferring 25% risk of affected offspring. Conclusion ES-based PCT provides a powerful diagnostic tool to identify AR disease carrier status in consanguineous couples. Outcomes provided significant reproductive choices for a higher proportion of these couples than previous tests.

scholarly journals Implementing Personalized Medicine in COVID-19 in Andalusia: An Opportunity to Transform the Healthcare System

2021 ◽  
Vol 11 (6) ◽  
pp. 475
Author(s):  
Joaquín Dopazo ◽  
Douglas Maya-Miles ◽  
Federico García ◽  
Nicola Lorusso ◽  
Miguel Ángel Calleja ◽  
...  
Keyword(s):  
Public Health ◽  
Health Care ◽  
Clinical Practice ◽  
Personalized Medicine ◽  
Local Level ◽  
Individual Variability ◽  
Response To Therapy ◽  
Control Measures ◽  
Response To Treatment ◽  
Specific Patient

The COVID-19 pandemic represents an unprecedented opportunity to exploit the advantages of personalized medicine for the prevention, diagnosis, treatment, surveillance and management of a new challenge in public health. COVID-19 infection is highly variable, ranging from asymptomatic infections to severe, life-threatening manifestations. Personalized medicine can play a key role in elucidating individual susceptibility to the infection as well as inter-individual variability in clinical course, prognosis and response to treatment. Integrating personalized medicine into clinical practice can also transform health care by enabling the design of preventive and therapeutic strategies tailored to individual profiles, improving the detection of outbreaks or defining transmission patterns at an increasingly local level. SARS-CoV2 genome sequencing, together with the assessment of specific patient genetic variants, will support clinical decision-makers and ultimately better ways to fight this disease. Additionally, it would facilitate a better stratification and selection of patients for clinical trials, thus increasing the likelihood of obtaining positive results. Lastly, defining a national strategy to implement in clinical practice all available tools of personalized medicine in COVID-19 could be challenging but linked to a positive transformation of the health care system. In this review, we provide an update of the achievements, promises, and challenges of personalized medicine in the fight against COVID-19 from susceptibility to natural history and response to therapy, as well as from surveillance to control measures and vaccination. We also discuss strategies to facilitate the adoption of this new paradigm for medical and public health measures during and after the pandemic in health care systems.

scholarly journals Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype

2021 ◽  
Author(s):  
Paolo Zanoni ◽  
Katharina Steindl ◽  
Deepanwita Sengupta ◽  
Pascal Joset ◽  
Angela Bahr ◽  
...  
Keyword(s):  
Loss Of Function ◽  
Mild Phenotype ◽  
Psychological Issues ◽  
Missense Variants ◽  
Mild Developmental Delay ◽  
Pathogenic Variants ◽  
In Silico Modeling ◽  
And Function ◽  
Methylation Activity

Abstract Purpose Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf–Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood. Methods We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro. Results The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS. Patients carrying missense variants were significantly taller and had more frequent behavioral/psychological issues compared with those harboring truncating variants. Structural in silico modeling suggested interference with NSD2’s folding and function for all missense variants in known structures. In vitro testing showed reduced methylation activity and failure to reconstitute H3K36me2 in NSD2 knockout cells for most missense variants. Conclusion NSD2 loss-of-function variants lead to a distinct, rather mild phenotype partially overlapping with WHS. To avoid confusion for patients, NSD2 deficiency may be named Rauch–Steindl syndrome after the delineators of this phenotype.

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