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Genomic Informatics in the Healthcare System
Published in Salvatore Volpe, Health Informatics, 2022
Another possible explanation for the phenotypic heterogeneity among cases is epigenetic differences. Epigenetic processes such as DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs can alter the activity of a gene without changing the DNA sequence. To further understand and identify the detail of the heterogeneity, a strategy such as the chromatin immunoprecipitation sequencing (ChIP-Seq) or RNA-Seq can be used. Exploring factors that can account for the phenotypic variability may provide insight into the pathways involved in disease. Furthermore, the comprehensive genetic evaluation and investigation of various individuals with these conditions will likely enlighten the fields of genomic locus heterogeneity and allelic heterogeneity of the genes with a broad spectrum of detected variants.
Liver Disease in Cystic Fibrosis
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
Carla Colombo, Pier Maria Battezzati, Clara Fredella, Andrea Crosignani
It is not clear how the basic defect causes the range of disease expression. The CF phenotype is extremely heterogeneous, due to different combination of clinical manifestations with variable severity and time course. However, the clinical variation can be only in part explained on the basis of allelic heterogeneity in CFTR gene.
Molecular Diagnosis of Autosomal Dominant Polycystic Kidney Disease
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Matthew Lanktree, Amirreza Haghighi, Xueweng Song, York Pei
Locus heterogeneity underlies a proportion of variability in disease presentation: patients with PKD1 mutations develop more severe disease with greater cyst burden, larger TKV, and younger age at ESRD than those with PKD2 mutations.4,16,17 Allelic heterogeneity also contributes: patients with protein-truncating mutations have more severe disease than those with nontruncating missense mutations.4 Truncating mutations include nonsense mutations, frameshift insertions or deletions, and canonical splice mutations or large deletions resulting in omission of large portions of the transcript. Nontruncating mutations can include small in-frame insertions or deletions or missense mutations. However, substantial variable expressivity in the ADPKD phenotype is common and family members carrying the same main-effect mutation can have extremely discordant phenotypes.
Next generation sequencing of BRCA genes in glioblastoma multiform Egyptian patients: a pilot study
Published in Archives of Physiology and Biochemistry, 2022
Amira M. Nageeb, Magdy M. Mohamed, Lobna R. Ezz El Arab, Mohamed K. Khalifa, Menha Swellam
Breast cancer type 1 and 2 susceptibility (BRCA1 and BRCA2) genes are essential molecules responsible for homologous recombination – depended double-strand break repairing pathway – as they participate in cellular resistance to alkylating agents (Kondo et al. 2010, Quiros et al. 2011, Short et al. 2011, Zhang et al. 2012). It has been reported that mutations in BRCA1 and/or BRCA2 genes resulted in unfavourable survival (Lee et al. 2014). Thus introducing polymerase inhibitor agents as poly(ADP-ribose) polymerase-1 (PRAPi) targeting mutations may lead to failure of DNA damage repair leading to apoptosis in BRCA1 and BRCA2 defective cells. To accomplish this assignment, identification of all mutations in these genes should be tested. Using conventional genetic testing methods is a Labour intensive and non-specific in some cases, in addition by considering the gene size and the mutation variants of BRCA1 (1706 mutations among 5592 bp gene size) and of BRCA2 (1446 mutations among 10,257 bp gene size). Their high-allelic heterogeneity and the deficiency of mutation hotspots revealed the challenging in genetic testing for the two genes.
Macular Corneal Dystrophy: An Updated Review
Published in Current Eye Research, 2021
Shalini Singh, Sujata Das, Chitra Kannabiran, Saumya Jakati, Sunita Chaurasia
MCD was linked to human chromosome number 16 in families of American and Icelandic origin.32 Akama et al.33,34 identified mutations in the gene for CHST6 among patients with both the types of MCD. MCD type I is the predominant type and involves mutations of the coding regions of CHST6 whereas in MCD type II, deletions and rearrangements have been found in the upstream region of the gene. Various studies show that MCD patients from different regions of the world have mutations in the same gene.22,35–37 There are many mutant alleles identified so far indicating allelic heterogeneity in MCD. Data from about 200 families from across the world analyzed for mutations in CHST6 show that approximately half of all MCD patients reported so far are from India. There is a predominance of missense mutations, detected in about 50% or more of patients with MCD from different populations while nonsense mutations, deletions, insertions or indels are found in about one-third of cases.38 Being an autosomal recessive disorder, MCD is mostly seen in consanguineous and inbred families, in which the majority of patients are homozygous for the mutations, and rest are compound heterozygotes for two different alleles.39 There are no obvious correlations between genotypes and phenotypes of patients with MCD, either the immunophenotypes or clinical features.40,41
Ocular complications and prophylactic strategies in Stickler syndrome: a systematic literature review
Published in Ophthalmic Genetics, 2020
Kirstine B. Boysen, Morten La Cour, Line Kessel
Stickler syndrome is diagnosed clinically, but mutation analysis can be helpful in confirming the diagnosis (31). It has been suggested that mutations in exon 2 in COL2A1 lead to an ocular-only phenotype of STL1 (32). Different sets of diagnostic criteria have been suggested (4,7,24,31,33,34). The criteria proposed by Rose et al. 2005 (35) are widely used, but no consensus for minimal clinical diagnostic criteria exists (35,36). Additionally, it has been suggested that the vitreous phenotype can be used to distinguish between STL1 and STL2 (membranous and ‘beaded’ vitreous, respectively) (31), whereas others have suggested that the different vitreous phenotypes are related to posterior vitreous detachment rather than distinct features of specific genes (37). The diagnosis of SS can be challenging due to considerable phenotypic variations both within and in between families (38–41). While intrafamilial variation indicates the presence of genetic and/or environmental modifiers, allelic heterogeneity could explain why different mutations can result in the same phenotype (42–45).