First Observation of Compound Heterozygosity for Hb S/Hb Lepore-Hollandia in India.
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ABSTRACT:
SUBMITTER: Mun A
PROVIDER: S-EPMC8315253 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Haemoglobin (Hb) Adana (HBA2:c.179>A) interacts with deletional and nondeletional ?-thalassaemia mutations to produce HbH disorders with varying clinical manifestations from asymptomatic to severe anaemia with significant hepatosplenomegaly. Hb Adana carriers are generally asymptomatic and haemoglobin subtyping is unable to detect this highly unstable ?-haemoglobin variant. This study identified 13 patients with compound heterozygosity for Hb Adana with either the 3.7?kb gene deletion (-?(3.7)), Hb Constant Spring (HbCS) (HBA2:c.427T>C) or Hb Paksé (HBA2:429A>T). Multiplex Amplification Refractory Mutation System was used for the detection of five deletional and six nondeletional ?-thalassaemia mutations. Duplex-PCR was used to confirm Hb Paksé and HbCS. Results showed 84.6% of the Hb Adana patients were Malays. Using DNA studies, compound heterozygosity for Hb Adana and HbCS (?(codon 59)?/?(CS)?) was confirmed in 11 patients. A novel point in this investigation was that DNA studies confirmed Hb Paksé for the first time in a Malaysian patient (?(codon 59)?/?(Paksé)?) after nine years of being misdiagnosis with Hb Adana and HbCS (?(codon 59)?/?(CS)?). Thus, the reliance on haematology studies and Hb subtyping to detect Hb variants is inadequate in countries where thalassaemia is prevalent and caused by a wide spectrum of mutations.
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Project description:We report two unrelated cases of compound heterozygosity for hemoglobin (Hb) variant Broomhill and the Southeast Asian (- - SEA/) ?-thalassemia deletion, whose clinical features and laboratory findings have never been reported. Hematological analyses revealed abnormal values for both cases as ?-thalassemia traits, and capillary electrophoresis suggested an abnormal peak that was incompletely separated from the Hb A peak. A suspension array system and Sanger sequencing were used to characterize the genotypes. Sanger sequencing confirmed the presence of Hb Broomhill [?114(GH2)Pro?Ala; HBA1: c.343C>G]. Eventually, both cases were accurately diagnosed as compound heterozygotes for Hb Broomhill and the (- - SEA/) ?-thalassemia deletion, which is the first known report of these variants. This information will be useful when providing appropriate genetic counselling and prenatal diagnosis.
| S-EPMC7683915 | biostudies-literature
Project description:The aim of this study was to define the genetic basis of arrhythmogenic right ventricular cardiomyopathy (ARVC).Arrhythmogenic right ventricular cardiomyopathy, characterized by right ventricular fibrofatty replacement and arrhythmias, causes sudden death. Autosomal dominant inheritance, reduced penetrance, and 7 desmosome-encoding causative genes are known. The basis of low penetrance is poorly understood.Arrhythmogenic right ventricular cardiomyopathy probands and family members were enrolled, blood was obtained, lymphoblastoid cell lines were immortalized, deoxyribonucleic acid was extracted, polymerase chain reaction (PCR) amplification of desmosome-encoding genes was performed, PCR products were sequenced, and diseased tissue samples were studied for intercellular junction protein distribution with confocal immunofluorescence microscopy and antibodies against key proteins.We identified 21 variants in plakophilin-2 (PKP2) in 38 of 198 probands (19%), including missense, nonsense, splice site, and deletion/insertion mutations. Pedigrees showed wide intra-familial variability (severe early-onset disease to asymptomatic individuals). In 9 of 38 probands, PKP2 variants were identified that were encoded in trans (compound heterozygosity). The 38 probands hosting PKP2 variants were screened for other desmosomal genes mutations; second variants (digenic heterozygosity) were identified in 16 of 38 subjects with PKP2 variants (42%), including desmoplakin (DSP) (n = 6), desmoglein-2 (DSG2) (n = 5), plakophilin-4 (PKP4) (n = 1), and desmocollin-2 (DSC2) (n = 1). Heterozygous mutations in non-PKP 2 desmosomal genes occurred in 14 of 198 subjects (7%), including DSP (n = 4), DSG2 (n = 5), DSC2 (n = 3), and junctional plakoglobin (JUP) (n = 2). All variants occurred in conserved regions; none was identified in 700 ethnic-matched control subjects. Immunohistochemical analysis demonstrated abnormalities of protein architecture.These data suggest that the genetic basis of ARVC includes reduced penetrance with compound and digenic heterozygosity. Disturbed junctional cytoarchitecture in subjects with desmosomal mutations confirms that ARVC is a disease of the desmosome and cell junction.
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Project description:Spondylocarpotarsal synostosis syndrome (SCTS) is characterized by intervertebral fusions and fusion of the carpal and tarsal bones. Biallelic mutations in FLNB cause this condition in some families, whereas monoallelic variants in MYH3, encoding embryonic heavy chain myosin 3, have been implicated in dominantly inherited forms of the disorder. Here, five individuals without FLNB mutations from three families were hypothesized to be affected by recessive SCTS on account of sibling recurrence of the phenotype. Initial whole-exome sequencing (WES) showed that all five were heterozygous for one of two independent splice-site variants in MYH3. Despite evidence indicating that three of the five individuals shared two allelic haplotypes encompassing MYH3, no second variant could be located in the WES datasets. Subsequent genome sequencing of these three individuals demonstrated a variant altering a 5' UTR splice donor site (rs557849165 in MYH3) not represented by exome-capture platforms. When the cohort was expanded to 16 SCTS-affected individuals without FLNB mutations, nine had truncating mutations transmitted by unaffected parents, and six inherited the rs557849165 variant in trans, an observation at odds with the population allele frequency for this variant. The rs557849165 variant disrupts splicing in the 5' UTR but is still permissive of MYH3 translational initiation, albeit with reduced efficiency. Although some MYH3 variants cause dominant SCTS, these data indicate that others (notably truncating variants) do not, except in the context of compound heterozygosity for a second hypomorphic allele. These observations make genetic diagnosis challenging in the context of simplex presentations of the disorder.
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Project description:PURPOSE: To describe the first instance of genotyping in a Latin American family with Wolfram syndrome (WS). METHODS: Four affected siblings and their healthy parents were studied. Ophthalmologic examination included best corrected visual acuity determination, funduscopy, fluorescein retinal angiography, and Goldmann kinetic perimetry. Molecular methods included linkage analysis using microsatellites markers located on the markers located on the Wofram syndrome 1 (WFS1) region at 4p16.1, PCR amplification and direct nucleotide sequencing analysis of the complete coding region and exon/intron junctions of WFS1. In addition, allele-specific cloning and sequencing techniques were used to characterize a heterozygous frameshift mutation. RESULTS: The four affected siblings presented with a homogeneous clinical picture characterized by early onset diabetes mellitus, severe optic atrophy, and progressive hearing loss. Linkage analysis indicated that all four sibs were heterozygous for markers linked to the WFS1 region and that each inherited the same allele from the mother and the same from the father, suggesting compound heterozygosity. Direct WFS1 analysis disclosed a paternally inherited novel missense R177P mutation whereas allele-specific cloning and sequencing revealed a novel WFS1 16 bp deletion that was inherited from the mother. CONCLUSIONS: Our report of two novel WFS1 mutations expands the molecular spectrum of Wolfram syndrome. This is the first documented case of the molecular basis of the disease in a Latin American family. Analysis of more patients from this population will establish if compound heterozygosity is commonly found in affected individuals from this ethnic group.
| S-EPMC2483297 | biostudies-literature
Project description:BACKGROUND- Homozygous or compound heterozygous mutations in KCNQ1 cause Jervell and Lange-Nielsen syndrome, a rare, autosomal-recessive form of long-QT syndrome characterized by deafness, marked QT prolongation, and a high risk of sudden death. However, it is not understood why some individuals with mutations on both KCNQ1 alleles present without deafness. In this study, we sought to determine the prevalence and genetic determinants of this phenomenon in a large referral population of patients with long-QT syndrome. METHODS AND RESULTS- A retrospective analysis of all patients with long-QT syndrome evaluated from July 1998 to April 2012 was used to identify those with ?1 KCNQ1 mutation. Of the 249 KCNQ1-positive patients identified, 15 (6.0%) harbored a rare putative pathogenic mutation on both KCNQ1 alleles. Surprisingly, 11 of these patients (73%) presented without the sensorineural deafness associated with Jervell and Lange-Nielsen syndrome. The degree of QT-interval prolongation and the number of breakthrough cardiac events were similar between patients with and without deafness. Interestingly, truncating mutations were more prevalent in patients with Jervell and Lange-Nielsen syndrome (79%) than in nondeaf patients (36%; P<0.001) derived from this study and those in the literature. CONCLUSIONS- In this study, we provide evidence that the recessive inheritance of a severe long-QT syndrome type 1 phenotype in the absence of an auditory phenotype may represent a more common pattern of long-QT syndrome inheritance than previously anticipated and that these cases should be treated as a higher-risk long-QT syndrome subset similar to their Jervell and Lange-Nielsen syndrome counterparts. Furthermore, mutation type may serve as a genetic determinant of deafness, but not cardiac expressivity, in individuals harboring ?1 KCNQ1 mutation on each allele.
| S-EPMC3683572 | biostudies-literature
Project description:The Y-box proteins YBX2 and YBX3 bind RNA and DNA and are required for metazoan development and fertility. However, possible functional redundancy between YBX2 and YBX3 has prevented elucidation of their molecular function as RNA masking proteins and identification of their target RNAs. To investigate possible functional redundancy between YBX2 and YBX3, we attempted to construct Ybx2-/-;Ybx3-/- double mutants using a previously reported Ybx2-/- model and a newly generated global Ybx3-/- model. Loss of YBX3 resulted in reduced male fertility and defects in spermatid differentiation. However, homozygous double mutants could not be generated as haploinsufficiency of both Ybx2 and Ybx3 caused sterility characterized by extensive defects in spermatid differentiation. RNA sequence analysis of mRNP and polysome occupancy in single and compound Ybx2/3 heterozygotes revealed loss of translational repression almost exclusively in the compound Ybx2/3 heterozygotes. RNAseq analysis also demonstrated that Y-box protein dose-dependent loss of translational regulation was inversely correlated with the presence of a Y box recognition target sequence, suggesting that Y box proteins bind RNA hierarchically to modulate translation in a range of targets.
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Project description:HbE Beta thalassemia is phenotypically very diverse disease. We aim to study role of various genetic factors in determining severity of this disease. 243 diagnosed cases of HbE Beta thalassemia were included in this study. Patients were divided in two arms-transfusion dependent and non-transfusion dependent arms. Various factors (percentage of haemoglobin F, hemoglobin E, type of Beta mutation, Xmn1 polymorphism, alpha deletion, HPFH mutation) were evaluated in these patients. Xmn1 polymorphism (homozygous and heterozygous), presence of HPFH mutation and alpha deletion were more prevalent in NTDT arm versus TDT arm (p value < 0.001). Higher prevelance of severe beta mutation IVS 1-5 (G → C) mutation {64(61.54%) vs 38(27.34); p value < 0.001} was found in TDT arm when above factors were excluded from analysis. Higher mean haemoglobin F and mean Hemoglobin E percentage was associated with NTDT arm (p value < 0.001). Various factors (hemoglobin F and E percentage, Xmn1 polymorphism, HPFH mutation, alpha deletion and IVS 1-5 Beta mutation) were identified to affect severity of this cohort.
| S-EPMC7042442 | biostudies-literature
Project description:OBJECTIVES:The aim of this study was to detect the genetic cause of deafness in a large Iranian family. Due to the importance of SLC26A4 in causing hearing loss, information about the gene mutations can be beneficial in molecular detection and management of deaf patients. METHODS:We investigated the genetic etiology in a large consanguineous family with 9 deaf patients from Fars province of Iran with no GJB2 mutations. Initially, linkage analysis was performed by four DFNB4 short tandem repeat markers. The result showed linkage to DFNB4 locus. Following that, DNA sequencing of all 21 exons, their adjacent intronic sequences and the promoter of SLC26A4 was carried out for mutation detection. RESULTS:Two novel mutations (c.863-864insT and c.881-882delAC) were identified in exon 7 of the gene, in both homozygous and compound heterozygous state in patients. CONCLUSION:Our results supported the importance of the SLC26A4 mutations in the etiology of hearing loss among the Iranian patients and therefore its mutation screening should be considered after GJB2 in the molecular diagnostics of hearing loss, especially when enlarged vestibular aqueduct or goiter is detected.
| S-EPMC3863667 | biostudies-literature
Project description:Krüppel-like factor 1 (KLF1) regulates erythroid lineage commitment, globin switching, and the terminal maturation of red blood cells. Variants in human KLF1 have been identified as an important causative factor in a wide spectrum of phenotypes. This study investigated two unrelated male children in China who had refractory anemia associated with poikilocythemia. These were accompanied by an upregulation of biochemical markers of hemolysis, along with abnormal hemoglobin (Hb) level and elevated reticulocyte counts. Next-generation sequencing revealed that the patients were compound heterozygotes for a KLF1 frameshift mutation c.525_526insCGGCGCC (p.(Gly176ArgfsTer179)) and one of two missense variants, c.892?G>C (p.(Ala298Pro)) and c.1012C>T (p.(Pro338Ser)). The subjects had microcytic hypochromic anemia, and their healthy parents had single mutation. The two missense mutations affected a highly conserved codon in the zinc finger DNA-binding domain of KLF1, but the protein stability was unaffected in K-562 cells. A KLF1-targeted promoter-reporter assay showed that the two mutations reduce the expression of the HBB, BCL11A, and CD44 genes involved in erythropoiesis, with consequent dyserythropoiesis and an ?/non-? chain imbalance. A systematic analysis was performed of the phenotypes associated with the KLF1 mutations in the two families, and the clinical characteristics and differential diagnoses of the disease are presented. This is the first report of an autosomal recessive anemia presenting with microcytic hypochromia, abnormal Hb profile, and other distinctive erythrocyte phenotypes, and provides insight into the multiple roles of KLF1 during erythropoiesis.
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