Challenging Disease Ontology by Instances of Atypical PKHD1 and PKD1 Genetics

BackgroundAutosomal polycystic kidney disease is distinguished into dominant (ADPKD) and recessive (ARPKD) inheritance usually caused by either monoallelic (PKD1/PKD2) or biallelic (PKHD1) germline variation. Clinical presentations are genotype-dependent ranging from fetal demise to mild chronic kidney disease (CKD) in adults. Additionally, exemptions from dominant and recessive inheritance have been reported in both disorders resulting in respective phenocopies. Here, we comparatively report three young adults with microcystic-hyperechogenic kidney morphology based on unexpected genetic alterations beyond typical inheritance.MethodsNext-generation sequencing (NGS)-based gene panel analysis and multiplex ligation-dependent probe amplification (MLPA) of PKD-associated genes, familial segregation analysis, and reverse phenotyping.ResultsThree unrelated individuals presented in late adolescence for differential diagnosis of incidental microcystic-hyperechogenic kidneys with preserved kidney and liver function. Upon genetic analysis, we identified a homozygous hypomorphic PKHD1 missense variant causing pseudodominant inheritance in a family, a large monoallelic PKDH1-deletion with atypical transmission, and biallelic PKD1 missense hypomorphs with recessive inheritance.ConclusionBy this report, we illustrate clinical presentations associated with atypical PKD-gene alterations beyond traditional modes of inheritance. Large monoallelic PKHD1-alterations as well as biallelic hypomorphs of both PKD1 and PKHD1 may lead to mild CKD in the absence of prominent macrocyst formation and functional liver impairment. The long-term renal prognosis throughout life, however, remains undetermined. Increased detection of atypical inheritance challenges our current thinking of disease ontology not only in PKD but also in Mendelian disorders in general.

Download Full-text

Identification of Two Novel Mutations in PKHD1 Gene from Two Families with Polycystic Kidney Disease by Whole Exome Sequencing

Current Genomics ◽

10.2174/1389202922666210219111810 ◽

2021 ◽

Vol 22 ◽

Author(s):

Masoud Heidari ◽

Hamid Gharshasbi ◽

Alireza Isazadeh ◽

Morteza Soleyman-Nejad ◽

Mohammad Hossein Taskhiri ◽

...

Keyword(s):

Kidney Disease ◽

Exome Sequencing ◽

Polycystic Kidney Disease ◽

Whole Exome Sequencing ◽

Novel Mutation ◽

Genetic Diagnosis ◽

Genetic Alterations ◽

Polycystic Kidney ◽

Novel Mutations ◽

Whole Exome

Background:: Polycystic kidney disease (PKD) is an autosomal recessive disorder resulting from mutations in the PKHD1 gene on chromosome 6 (6p12), a large gene spanning 470 kb of genomic DNA. Objective: The aim of the present study was to report newly identified mutations in the PKHD1 gene in two Iranian families with PKD. Materials and Methods: Genetic alterations of a 3-month-old boy and a 27-year-old girl with PKD were evaluated using whole-exome sequencing. The PCR direct sequencing was performed to analyse the co-segregation of the variants with the disease in the family. Finally, the molecular function of the identified novel mutations was evaluated by in silico study. Results: In the 3 month-old boy, a novel homozygous frameshift mutation was detected in the PKHD1 gene, which can cause PKD. Moreover, we identified three novel heterozygous missense mutations in ATIC, VPS13B, and TP53RK genes. In the 27-year-old woman, with two recurrent abortions history and two infant mortalities at early weeks due to metabolic and/or renal disease, we detected a novel missense mutation on PKHD1 gene and a novel mutation in ETFDH gene. Conclusion: In general, we have identified two novel mutations in the PKHD1 gene. These molecular findings can help accurately correlate genotype and phenotype in families with such disease in order to reduce patient births through preoperative genetic diagnosis or better management of disorders.

Download Full-text

A homozygous mutation of GNRHR in a familial case diagnosed with polycystic ovary syndrome

Acta Endocrinologica ◽

10.1530/eje-16-0968 ◽

2017 ◽

Vol 176 (5) ◽

pp. K9-K14 ◽

Cited By ~ 5

Author(s):

Sandrine Caburet ◽

Ronit Beck Fruchter ◽

Bérangère Legois ◽

Marc Fellous ◽

Stavit Shalev ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Sanger Sequencing ◽

Polycystic Ovary ◽

Missense Variant ◽

Genetic Alterations ◽

Homozygous Mutation ◽

Gonadotropin Secretion ◽

Whole Exome ◽

A Genome

Context PCOS is a heterogeneous condition characterized by hyperandrogenism and chronic anovulation and affects about 10% of women. Its etiology is poorly known, but a dysregulation of gonadotropin secretion is one of its hallmarks. Objective As the etiology of PCOS is unclear, we have performed a genome-wide analysis of a consanguineous family with three sisters diagnosed with PCOS. Methods Whole-exome sequencing and Sanger sequencing confirmation. Results Whole-exome sequencing allowed the detection of the missense variant rs104893836 located in the first coding exon of the GNRHR gene and leading to the p.Gln106Arg (p.Q106R) substitution. Sanger sequencing of all available individuals of the family confirmed that the variant was homozygous in the three affected sisters and heterozygous in both parents. Conclusions This is the first description of a GNRHR gene mutation in patients diagnosed with PCOS. Although we do not exclude a possible interaction of the identified variant with the genetic background and/or the environment, our result suggests that genetic alterations in the hypothalamo–pituitary axis may play role in the pathogenesis of PCOS.

Download Full-text

Abstract MP08: Whole Exome Sequencing Study Identified A Novel Variant For Kidney Function And Progression Of Chronic Kidney Disease

Circulation ◽

10.1161/circ.143.suppl_1.mp08 ◽

2021 ◽

Vol 143 (Suppl_1) ◽

Author(s):

Changwei Li ◽

Michael Francis ◽

Adrianna Westbrook ◽

Ruiyuan Zhang ◽

Ye Shen ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Kidney Function ◽

Cystatin C ◽

Smoking Status ◽

Missense Variant ◽

Ckd Progression ◽

Whole Exome

Introduction: Most genetic variants for chronic kidney disease (CKD) have been identified in non-coding regions, with functional roles that are difficult to interpret. Hypothesis: A whole exome sequencing study focusing on coding variants will reveal novel mechanisms of kidney function and CKD. Methods: We performed whole exome sequencing analyses of cystatin C among 29,789 UK Biobank (UKB) participants with further confirmation among 4,297 white and 607 African American participants of the Health and Retirement Study (HRS). Conditional analyses for loci achieving exome-wide significance ( P <3.5х10 -7 ) were conducted in UKB using both the exome (n=29,789) and imputed GWAS data (n=295,122). Genomic findings were tested for relevance to baseline estimated glomerular filtration rate (eGFR) and stringently adjudicated CKD progression events among participants of the Chronic Renal Insufficiency Cohort (CRIC) by race and smoking status, using a base model and a full model ( Table ). Results: We identified a common missense variant, CST9 rs2983640, in a previously reported locus ( CST3 intron rs13038305), of which the minor G allele was associated with lower serum cystatin C level (UKB: beta=-0.03 mg/L, P =7.64х10 -92 ; HRS whites: beta=-0.05 mg/L, P =4.71х10 -6 ; HRS African Americans: beta=-0.03 mg/L, P =0.64; and multi-ethnic meta-analysis beta=-0.03 mg/L, P =2.46х10 -91 ). After controlling for the CST3 variant, the G allele was associated with higher cystatin C level (UKB exome: beta=0.003 mg/L, P =0.04; UKB GWAS: beta=0.003 mg/L, P =1.47х10 -10 ). Similar associations were identified in white CRIC participants (direct effect: beta=-0.05 mg/L, P =0.005; conditional effect: beta=0.004 mg/L, P =0.86). The CST9 rs2983640 G allele was associated with lower baseline eGFR (base model beta=-0.33 ml/min/1.73 m 2 , P =1.98х10 -6 ) and higher hazard of developing CKD progression independent of the reported CST3 variant ( Table ). Conclusions: We identified a novel missense variant influencing cystatin C level and CKD progression.

Download Full-text

Concomitant Burkholderiapseudomallei and Staphylococcus aureus Infection in a chronic kidney disease patient: A Case Report and Literature Review

Bangladesh Journal of Medical Science ◽

10.3329/bjms.v20i2.51565 ◽

2021 ◽

Vol 20 (2) ◽

pp. 456-458

Author(s):

Norjihan Abdul Hamid ◽

Mohd Zulfakar Mazlan ◽

Zeti Norfidiyati Salmuna

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Chronic Kidney Disease Patient ◽

Medical Science ◽

Disease Patient ◽

Asymptomatic Infection ◽

Clinical Presentations ◽

Wide Range ◽

Diagnostic Microbiology ◽

And Staphylococcus Aureus

Melioidosis can happen in humans and animals. It has a wide range of clinical presentations that include asymptomatic infection, ulcers or abscesses of the skin, pneumonia, and multiple internal organ abscesses that may lead to fulminant septic shock. The organism presence in soil and surface of the water. We present a case of a non-diabetic chronic kidney disease patient presented with multiple carbuncles and respiratory melioidosis in which we are able to isolate B. pseudomallei after prolonging the plate incubation for 48-hours. We also suggested available tests in most diagnostic microbiology laboratory for identification of the organism. Bangladesh Journal of Medical Science Vol.20(2) 2021 p.456-458

Download Full-text

Chronic Kidney Disease: The Complex History of the Organization of Long-Term Care and Bioethics. Why Now, More Than Ever, Action is Needed

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph16050785 ◽

2019 ◽

Vol 16 (5) ◽

pp. 785 ◽

Cited By ~ 1

Author(s):

Elisabetta Versino ◽

Giorgina Piccoli

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Cause Of Death ◽

Public Health Problem ◽

Models Of Care ◽

Term Care ◽

Healthcare Budget ◽

Kidney Morphology ◽

Disease Study ◽

Kidney Scarring

Chronic kidney disease (CKD) has been redefined in the new millennium as any alteration of kidney morphology, function, blood, or urine composition lasting for at least 3 months. This broad definition also encompasses diseases or conditions that are associated with normal kidney function, such as a kidney scarring from an acute pyelonephritis episode or a single kidney, as a result of kidney donation. CKD is a relevant public health problem. According to the 2015 Global Burden of Disease Study, it was the 12th leading cause of death, leading to 1.1 million deaths, worldwide, each year. The role of CKD as a cause of death is evident where renal replacement therapy (RRT) is not available, however, its role in increasing death risk is not easily calculated. RRT consumes about 3–5% of the global healthcare budget where dialysis is available without restrictions. While the prevalence of CKD is increasing overall as lifespans extend, being linked to diabetes, hypertension, obesity, and atherosclerosis, CKD is at least partly preventable and its effects may be at least partly counterbalanced by early and appropriate care. We will welcome papers on all aspects of CKD, including organization, cost, and models of care. Papers from developing countries will be particularly welcomed.

Download Full-text

The Application of Next-Generation Sequencing to Define Factors Related to Oral Cancer and Discover Novel Biomarkers

Life ◽

10.3390/life10100228 ◽

2020 ◽

Vol 10 (10) ◽

pp. 228

Author(s):

Soyeon Kim ◽

Joo Won Lee ◽

Young-Seok Park

Keyword(s):

Next Generation Sequencing ◽

Oral Cancer ◽

Genetic Alterations ◽

Eligibility Criterion ◽

Next Generation ◽

Novel Biomarkers ◽

Targeted Gene Therapy ◽

Next Generation Sequencing Ngs ◽

Potential Use ◽

Generation Sequencing

Despite the introduction of next-generation sequencing in the realm of DNA sequencing technology, it is not often used in the investigation of oral squamous cell carcinoma (OSCC). Oral cancer is one of the most frequently occurring malignancies in some parts of the world and has a high mortality rate. Patients with this malignancy are likely to have a poor prognosis and may suffer from severe facial deformity or mastication problems even after successful treatment. Therefore, a thorough understanding of this malignancy is essential to prevent and treat it. This review sought to highlight the contributions of next-generation sequencing (NGS) in unveiling the genetic alterations and differential expressions of miRNAs involved in OSCC progression. By applying an appropriate eligibility criterion, we selected relevant studies for review. Frequently identified mutations in genes such as TP53, NOTCH1, and PIK3CA are discussed. The findings of existing miRNAs (e.g., miR-21) as well as novel discoveries pertaining to OSCC are also covered. Lastly, we briefly mention the latest findings in targeted gene therapy and the potential use of miRNAs as biomarkers. Our goal is to encourage researchers to further adopt NGS in their studies and give an overview of the latest findings of OSCC treatment.

Download Full-text

Heterozygous missense RAD21 variant in a peripheral sclerocornea pedigree

10.1101/547547 ◽

2019 ◽

Cited By ~ 1

Author(s):

Bi Ning Zhang ◽

Tommy Chung Yan Chan ◽

Pancy Oi Sin Tam ◽

Yu Liu ◽

Chi Pui Pang ◽

...

Keyword(s):

Cell Lines ◽

Genetic Variant ◽

Mrna Level ◽

Missense Variant ◽

Genetic Alterations ◽

Chinese Family ◽

Wild Type ◽

Whole Exome ◽

Rare Congenital Disorder ◽

Corneal Diameter

AbstractBackgroundSclerocomea is a rare congenital disorder characterized with cornea opacification. We identified a heterozygous missense RAD21 variant in a non-cons anguineous Chinese family with multiple peripheral sclerocomea patients spanning across three generations inherited in an autosomal dominant manner.MethodsComprehensive ophthalmic examinations were conducted on all 14 members. Whole exome sequencing was used to identify the genetic alterations in the affected pedigree members. Lymphoblastoid cell lines (LCLs) were established using blood samples from all members. Cleavage of RAD21 protein was quantified in these cell lines.ResultsAll affected individuals showed features of scleralization over the peripheral cornea of both eyes. Mean horizontal and vertical corneal diameter were significantly decreased in the affected members. Significant differences were also observed on mean apex pachymetry between affected and unaffected subjects. A RAD21C1348T variant was co-segregated with affected members. Both the wild-type allele and the missense variant were expressed at the mRNA level. This variant caused RAD21 R450C substitution at the separase cleavage site, which led to reduced RAD21 cleavage.ConclusionWe believe this is the first report of genetic variant in sclerocornea without other syndromes. Further work is needed to confirm the RAD21R450C variant with sclerocomea.

Download Full-text

Molecular Basis, Diagnostic Challenges and Therapeutic Approaches of Alport Syndrome: A Primer for Clinicians

International Journal of Molecular Sciences ◽

10.3390/ijms222011063 ◽

2021 ◽

Vol 22 (20) ◽

pp. 11063

Author(s):

Raquel Martínez-Pulleiro ◽

María García-Murias ◽

Manuel Fidalgo-Díaz ◽

Miguel Ángel García-González

Keyword(s):

Kidney Disease ◽

Alport Syndrome ◽

Renal Involvement ◽

Specific Treatment ◽

Hereditary Disease ◽

Pathophysiological Mechanism ◽

Sequencing Technologies ◽

Type Iv ◽

Collagen Genes ◽

Next Generation Sequencing Ngs

Alport syndrome is a genetic and hereditary disease, caused by mutations in the type IV collagen genes COL4A3, COL4A4 and COL4A5, that affects the glomerular basement membrane of the kidney. It is a rare disease with an underestimated prevalence. Genetic analysis of population cohorts has revealed that it is the second most common inherited kidney disease after polycystic kidney disease. Renal involvement is the main manifestation, although it may have associated extrarenal manifestations such as hearing loss or ocular problems. The degree of expression of the disease changes according to the gene affected and other factors, known or yet to be known. The pathophysiology is not yet fully understood, although some receptors, pathways or molecules are known to be linked to the disease. There is also no specific treatment for Alport syndrome; the most commonly used are renin–angiotensin–aldosterone system inhibitors. In recent years, diagnosis has come a long way, thanks to advances in DNA sequencing technologies such as next-generation sequencing (NGS). Further research at the genetic and molecular levels in the future will complete the partial vision of the pathophysiological mechanism that we have, and will allow us to better understand what is happening and how to solve it.

Download Full-text

Comparative assessment of genes driving cancer and somatic evolution

10.1101/2021.08.31.458177 ◽

2021 ◽

Author(s):

Lisa Dressler ◽

Michele Bortolomeazzi ◽

Mohamed Reda Keddar ◽

Hrvoje Misetic ◽

Giulia Sartini ◽

...

Keyword(s):

Genetic Alterations ◽

Comprehensive Overview ◽

Somatic Evolution ◽

Large Size ◽

Somatic Alteration ◽

Evolutionarily Conserved ◽

Cancer Initiation ◽

Germline Variation ◽

Cancer Types ◽

Genetic Events

ABSTRACTGenetic alterations of somatic cells can drive non-malignant clone formation and promote cancer initiation. However, the link between these processes remains unclear hampering our understanding of tissue homeostasis and cancer development. Here we collect a literature-based repertoire of 3355 well-known or predicted drivers of cancer and noncancer somatic evolution in 122 cancer types and 12 noncancer tissues. Mapping the alterations of these genes in 7953 pancancer samples reveals that, despite the large size, the known compendium of drivers is still incomplete and biased towards frequently occurring coding mutations. High overlap exists between drivers of cancer and noncancer somatic evolution, although significant differences emerge in their recurrence. We confirm and expand the unique properties of drivers and identify a core of evolutionarily conserved and essential genes whose germline variation is strongly counter-selected. Somatic alteration in even one of these genes is sufficient to drive clonal expansion but not malignant transformation. Our study offers a comprehensive overview of our current understanding of the genetic events initiating clone expansion and cancer revealing significant gaps and biases that still need to be addressed. The compendium of cancer and noncancer somatic drivers, their literature support and properties are accessible at http://www.network-cancer-genes.org/.

Download Full-text