Unfolding the genetic map of monogenic liver diseases in Egypt

Exome sequencing (ES) has been used in a variety of clinical settings but there are limited data on its utility for diagnosis and/or prediction of monogenic liver diseases. We developed a curated list of 502 genes for monogenic disorders associated with liver phenotypes and analyzed ES data for these genes in 758 patients with chronic liver diseases (CLD). For comparison, we examined ES data in 7856 self-declared healthy controls (HC), and 2187 patients with chronic kidney disease (CKD). Candidate pathogenic (P) or likely pathogenic (LP) variants were initially identified in 19.9% of participants, most of which were attributable to previously reported pathogenic variants with implausibly high allele frequencies. After variant annotation and filtering based on population minor allele frequency (MAF ≤ 10–4 for dominant disorders and MAF ≤ 10–3 for recessive disorders), we detected a significant enrichment of P/LP variants in the CLD cohort compared to the HC cohort (X2 test OR 5.00, 95% CI 3.06–8.18, p value = 4.5e−12). A second-level manual annotation was necessary to capture true pathogenic variants that were removed by stringent allele frequency and quality filters. After these sequential steps, the diagnostic rate of monogenic disorders was 5.7% in the CLD cohort, attributable to P/LP variants in 25 genes. We also identified concordant liver disease phenotypes for 15/22 kidney disease patients with P/LP variants in liver genes, mostly associated with cystic liver disease phenotypes. Sequencing results had many implications for clinical management, including familial testing for early diagnosis and management, preventative screening for associated comorbidities, and in some cases for therapy. Exome sequencing provided a 5.7% diagnostic rate in CLD patients and required multiple rounds of review to reduce both false positive and false negative findings. The identification of concordant phenotypes in many patients with P/LP variants and no known liver disease also indicates a potential for predictive testing for selected monogenic liver disorders.

Clinical and Genetic Spectrum of Monogenic Cholestatic Chronic Liver Diseases in Children – A Single Centre Experience From Kerala

Monogenic liver disease is caused by rare, pathogenic mutations. Exome and genome sequencing frequently identifies variants of unknown significance in these genes. It is not clear whether such non-pathogenic variants...

The population of the province of Newfoundland and Labrador is genetically isolated. This isolation is evidenced by an overabundance of several monogenic disorders. The Newfoundland population, like that of other isolates, is now the focus of interest for identification of genes implicated in common diseases. However, the utility of such populations for this purpose remains unproven. In this paper, we review the current genetic architecture of the province, with respect to geographic isolation, homogeneity, founder effect, genetic drift and extended linkage disequilibrium. Based on these factors, we propose that the population of Newfoundland offers many advantages for genetic mapping of common diseases, compared with admixed populations, and even compared with other isolates.

A Common Connexion Between Gap Junctions, Single Nucleotide Polymorphisms, and Atrial Fibrillation?

Suitability of a specific population for linkage disequilibrium mapping studies of complex traits may be assessed by investigating the background linkage disequilibrium (BLD). We are unaware of studies for quantifying the degree of BLD in the Korean population, although the population may be a good candidate for mapping of complex trait genes through whole-genome association studies. It is useful to investigate the properties of genetic isolates in East Asia and to compare them to genetic isolates in Europe. We analyzed the extent of BLD in the Korean population using 735 microsatellite markers and compared the results with the Icelander population, which is one of the European expanded genetic isolates. The Korean population exhibited a level of BLD comparable with the Icelander population. The inference of population structure using the model with admixture showed that each individual has allele copies originating from K populations in equal proportions. Therefore, we believe that factors other than genetic distance, such as recent admixture, have not contributed to the level of BLD. Our results showed that the Korean population, which is an expanded population with no evidence of admixture, has a BLD level comparable with the Icelander population. Therefore, the Korean population can be used for fine mapping of either complex traits or monogenic diseases.

Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver-directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics.

Searching for the Major Histocompatibility Complex Psoriasis Susceptibility Gene

Liver-Directed Molecular Therapies: Current and Upcoming Strategies.

10 Years ofGenomics,Chromosome 21, and Down Syndrome

Traditional linkage analysis in large families is the most promising approach for mapping disease genes of monogenic heritable disorders when the number of informative meioses is sufficient. With rare diseases, however, the low availability of informative pedigrees poses a significant limitation. As an adjunct to family linkage methods, association studies based on the investigation of individual haplotypes from a number of unrelated patients (i.e. linkage disequilibrium analysis) have recently been employed in mapping hereditary disease loci. However, such haplotype analysis is hampered by a number of effects that influence statistical evaluation, e.g. i) population history and size, ii) allele and haplotype frequencies in the respective population(s), iii) heterogeneous mutation and natural selection processes, and iv) small sample sizes of patient groups. The purpose of the present study was to determine the utility and limitations of haplotype-based genetic mapping in estimating the location of the NYX gene, which has recently been identified as the causative gene for a rare inherited retinal disorder known as the complete type of X-linked congenital stationary night blindness (CSNB1). For this purpose we recapitulated haplotypes and tested for linkage disequilibrium in 20 unrelated male CSNB1 patients from three European populations and 44 healthy individuals. All subjects were genotyped for 17 polymorphic microsatellite loci covering the Xp11.4 region with an average marker density of approximately 0.29 cM. We found that a precise model to describe mutations at loci that erroneously break up linkage is highly required, and that the case population must match the respective disease model.

Gene SNPs and mutations in clinical genetic testing: haplotype-based testing and analysis

Gene mapping of monogenic disorders and complex diseases via genome wide association studies

Background: Children presenting with chronic liver disease have a high likelihood of an underlying genetic disorder. There is a delay in establishing a diagnosis of monogenic liver diseases if relied on typical clinical phenotypes and conventional laboratory investigations or imaging studies alone. Early diagnosis improves patient outcome through timely and adequate therapy.Methods: This study retrospectively analyzed the clinical and genetic spectra of monogenic liver disease in children diagnosed using next-generation sequencing (NGS) in a tertiary care teaching hospital in Kerala. Patients were classified into five groups according to their clinical presentation: neonatal/infantile cholestasis, hepatomegaly/ hepatosplenomegaly, progressive cholestasis (beyond infancy), acute liver failure and decompensated chronic liver disease.Results: There were 31 children enrolled, 14 (45.16%) males and 17 (54.84%) females. The median age at genetic diagnosis was 25.74 months. NGS identified 20 distinct genes related to varying clinical presentation. Six genes were identified in Group A, nine genes were identified in Group B, three genes were identified in Group C and two genes each in Group D and E. JAG1, ABCB4 and PYL1 (13 % each) were the top three genes related to monogenic liver disease in this study.Conclusions: Patients with hepatomegaly or hepatosplenomegaly constituted the major clinical presentation of genetic disorders followed by neonatal/infantile cholestasis in our study. Genetic cholestatic disorders and glycogen storage disorders were the most common monogenic liver diseases. NGS has an important role in the diagnosis of monogenic liver disease in children and can facilitate early medical treatment and predict the prognosis.

Background: Children presenting with chronic liver disease or acute liver failure often have an underlying genetic disorder. The aim of this study was to analyze the clinical and genetic spectra of inherited liver disease in children in a tertiary hospital.Methods: A total of 172 patients were classified into three groups according to their clinical presentation: cholestasis (Group A), liver enzyme elevation (Group B), and hepato/splenomegaly (Group C). Next-generation sequencing (NGS) was performed on all patients recruited in this study. The genotypic and phenotypic spectra of disease in these patients were reviewed.Results: The median age at enrollment of the 172 patients was 12.0 months (IQR: 4.9, 42.5 months), with 52.3% males and 47.7% females. The overall diagnostic rate was 55.8% (96/172) in this group. The diagnostic rates of whole-exome sequencing (WES) and targeted gene panel sequencing (TGPS) were 47.2% and 62.0%, respectively (no significant difference, p = 0.054). We identified 25 genes related to different phenotypes, including 46 novel disease-related pathogenic mutations. The diagnostic rates in the three groups were 46.0% (29/63), 48.6% (34/70), and 84.6% (33/39). ATP7B, SLC25A13, and G6PC were the top three genes related to monogenic liver disease in this study.Conclusion: WES and TGPS show similar diagnostic rates in the diagnosis of monogenic liver disease. NGS has an important role in the diagnosis of monogenetic liver disease and can provide more precise medical treatment and predict the prognosis of these diseases.