scholarly journals Thalassaemia intermedia caused by coinheritance of a β‐thalassaemia mutation and a de novo duplication of α‐globin genes in the paternal allele

2019 ◽  
Vol 186 (4) ◽  
pp. 620-624 ◽  
Author(s):  
Dejian Pang ◽  
Xuan Shang ◽  
Decheng Cai ◽  
Fei Zhu ◽  
Yi Cheng ◽  
...  
Keyword(s):  
De Novo ◽  
Paternal Allele ◽  
Globin Genes ◽  
Thalassaemia Intermedia

scholarly journals Auxology Is a Valuable Instrument for the Clinical Diagnosis of SHOX Haploinsufficiency in School-Age Children with Unexplained Short Stature

2003 ◽  
Vol 88 (10) ◽  
pp. 4891-4896 ◽  
Author(s):  
Gerhard Binder ◽  
Michael B. Ranke ◽  
David D. Martin
Keyword(s):  
Short Stature ◽  
De Novo ◽  
Fragment Size ◽  
Mutation Screening ◽  
Idiopathic Short Stature ◽  
Paternal Allele ◽  
Leg Length ◽  
Sitting Height ◽  
Arm Span ◽  
Hand Radiography

Abstract SHOX (short stature homeobox-containing gene) mutations causing haploinsufficiency have been reported in some individuals with idiopathic short stature and in many patients with Leri-Weill-dyschondrosteosis. Around 80% of SHOX mutations are complete gene deletions, whereas diverse point mutations account for the rest. The aim of this study was to estimate the prevalence of SHOX mutations in children with idiopathic short stature and to give an unbiased characterization of the haploinsufficiency phenotype of such children. We recruited 140 children (61 girls), in our clinic, with idiopathic short stature, which was defined by the presence of normal IGF-I and free T4; a normal karyotype in females; the absence of endomysium antibodies, of chronic organic, psychological, or syndromatic disease; and by the lack of clear signs of any osteodysplasia. Height, arm span, and sitting height were recorded, and subischial leg length was calculated. Two highly polymorphic microsatellite markers located around the SHOX coding region (CA-SHOX repeat and DXYS233) were PCR-amplified with fluorescent primers and separated in an automatic sequencing machine. Analysis of parental DNA was performed in the probands who had only one fragment size of each of both markers. SHOX haploinsufficiency caused by a SHOX deletion was confirmed in three probands (2%), all females, who carried a de novo deletion through loss of the paternal allele. Their auxological data revealed a significant shortening of arms and legs in the presence of a low-normal sitting height, when compared with the other 137 children tested. Therefore, the extremities-trunk ratio (sum of leg length and arm span, divided by sitting height) for total height was significantly lower in the three SHOX haploinsufficient probands, in comparison with the whole group. This observation was confirmed with the auxological data of five additional patients (four females) previously diagnosed with SHOX haploinsufficiency; all but the youngest girl had height-adjusted extremities-trunk ratios more than 1 sd below the mean. All children with SHOX haploinsufficiency exhibited at least one characteristic radiological sign of Leri-Weill-dyschondrosteosis in their left-hand radiography, namely triangularization of the distal radial epiphysis, pyramidalization of the distal carpal row, or lucency of the distal ulnar border of the radius. Our observations suggest that it is rational to limit SHOX mutation screening to children with an extremities-trunk ratio less than 1.95 + 1/2 height (m) and to add a critical judgment of the hand radiography.

scholarly journals Genotype-phenotype association analysis identifies the role of α globin genes in modulating disease severity of β thalassaemia intermedia in Sri Lanka

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Shiromi Perera ◽  
Angela Allen ◽  
Ishari Silva ◽  
Menaka Hapugoda ◽  
M. Nirmali Wickramarathne ◽  
...  
Keyword(s):  
Sri Lanka ◽  
Disease Severity ◽  
Association Analysis ◽  
Globin Genes ◽  
Thalassaemia Intermedia

scholarly journals Allelic H3K27me3 to allelic DNA methylation switch maintains noncanonical imprinting in extraembryonic cells

2019 ◽  
Vol 5 (12) ◽  
pp. eaay7246 ◽  
Author(s):  
Zhiyuan Chen ◽  
Qiangzong Yin ◽  
Azusa Inoue ◽  
Chunxia Zhang ◽  
Yi Zhang
Keyword(s):  
Dna Methylation ◽  
De Novo ◽  
Genetic Manipulation ◽  
Paternal Allele ◽  
Gene Promoters ◽  
Maternal Allele ◽  
Mammalian Development ◽  
Placental Development ◽  
Early Embryos ◽  
Allele Specific

Faithful maintenance of genomic imprinting is essential for mammalian development. While germline DNA methylation–dependent (canonical) imprinting is relatively stable during development, the recently found oocyte-derived H3K27me3-mediated noncanonical imprinting is mostly transient in early embryos, with some genes important for placental development maintaining imprinted expression in the extraembryonic lineage. How these noncanonical imprinted genes maintain their extraembryonic-specific imprinting is unknown. Here, we report that maintenance of noncanonical imprinting requires maternal allele–specific de novo DNA methylation [i.e., somatic differentially methylated regions (DMRs)] at implantation. The somatic DMRs are located at the gene promoters, with paternal allele–specific H3K4me3 established during preimplantation development. Genetic manipulation revealed that both maternal EED and zygotic DNMT3A/3B are required for establishing somatic DMRs and maintaining noncanonical imprinting. Thus, our study not only reveals the mechanism underlying noncanonical imprinting maintenance but also sheds light on how histone modifications in oocytes may shape somatic DMRs in postimplantation embryos.

De novo IGF2 mutation on the paternal allele in a patient with Silver–Russell syndrome and ectrodactyly

2017 ◽  
Vol 38 (8) ◽  
pp. 953-958 ◽  
Author(s):  
Kaori Yamoto ◽  
Hirotomo Saitsu ◽  
Norio Nakagawa ◽  
Hisakazu Nakajima ◽  
Tatsuji Hasegawa ◽  
...  
Keyword(s):  
De Novo ◽  
Paternal Allele ◽  
Silver Russell Syndrome

scholarly journals Molecular analysis of the erythroid phenotype of a patient with BCL11A haploinsufficiency

2021 ◽  
Vol 5 (9) ◽  
pp. 2339-2349
Author(s):  
Marja W. Wessels ◽  
Marjon H. Cnossen ◽  
Thamar B. van Dijk ◽  
Nynke Gillemans ◽  
K. L. Juliëtte Schmidt ◽  
...  
Keyword(s):  
Gene Expression ◽  
De Novo ◽  
Fetal Hemoglobin ◽  
Chromatin Accessibility ◽  
Neuronal System ◽  
Globin Genes ◽  
Erythroid Progenitors ◽  
Genome Wide ◽  
Localization Signal ◽  
Significant Expression

Abstract The BCL11A gene encodes a transcriptional repressor with essential functions in multiple tissues during human development. Haploinsufficiency for BCL11A causes Dias-Logan syndrome (OMIM 617101), an intellectual developmental disorder with hereditary persistence of fetal hemoglobin (HPFH). Due to the severe phenotype, disease-causing variants in BCL11A occur de novo. We describe a patient with a de novo heterozygous variant, c.1453G>T, in the BCL11A gene, resulting in truncation of the BCL11A-XL protein (p.Glu485X). The truncated protein lacks the 3 C-terminal DNA-binding zinc fingers and the nuclear localization signal, rendering it inactive. The patient displayed high fetal hemoglobin (HbF) levels (12.1-18.7% of total hemoglobin), in contrast to the parents who had HbF levels of 0.3%. We used cultures of patient-derived erythroid progenitors to determine changes in gene expression and chromatin accessibility. In addition, we investigated DNA methylation of the promoters of the γ-globin genes HBG1 and HBG2. HUDEP1 and HUDEP2 cells were used as models for fetal and adult human erythropoiesis, respectively. Similar to HUDEP1 cells, the patient’s cells displayed Assay for Transposase-Accessible Chromatin (ATAC) peaks at the HBG1/2 promoters and significant expression of HBG1/2 genes. In contrast, HBG1/2 promoter methylation and genome-wide gene expression profiling were consistent with normal adult erythropoiesis. We conclude that HPFH is the major erythroid phenotype of constitutive BCL11A haploinsufficiency. Given the essential functions of BCL11A in other hematopoietic lineages and the neuronal system, erythroid-specific targeting of the BCL11A gene has been proposed for reactivation of γ-globin expression in β-hemoglobinopathy patients. Our data strongly support this approach.

scholarly journals A sporadic case of congenital aniridia caused by pericentric inversion inv(11)(p13q14) associated with a 977 kb deletion in the 11p13 region

2020 ◽  
Vol 13 (S8) ◽  
Author(s):  
Tatyana A. Vasilyeva ◽  
Andrey V. Marakhonov ◽  
Marina E. Minzhenkova ◽  
Zhanna G. Markova ◽  
Nika V. Petrova ◽  
...  
Keyword(s):  
General Population ◽  
Pericentric Inversion ◽  
De Novo ◽  
Wilms Tumor ◽  
Normal Karyotype ◽  
Paternal Allele ◽  
De Novo Mutations ◽  
Chromosome 11 ◽  
Dna Diagnosis ◽  
Congenital Aniridia

Abstract Background Because of the significant occurrence of “WAGR-region” deletions among de novo mutations detected in congenital aniridia, DNA diagnosis is critical for all sporadic cases of aniridia due to its help in making an early diagnosis of WAGR syndrome. Standard cytogenetic karyotype study is a necessary step of molecular diagnostics in patients with deletions and in the patients’ parents as it reveals complex chromosomal rearrangements and the risk of having another affected child, as well as to provide prenatal and/or preimplantation diagnostics. Case presentation DNA samples were obtained from the proband (a 2-year-old boy) and his two healthy parents. Molecular analysis revealed a 977.065 kb deletion that removed loci of the ELP4, PAX6, and RCN1 genes but did not affect the coding sequence of the WT1 gene. The deletion occurred de novo on the paternal allele. The patient had normal karyotype 46,XY and a de novo pericentric inversion of chromosome 11, inv(11)(p13q14). Conclusions We confirmed the diagnosis of congenital aniridia at the molecular level. For the patient, the risk of developing Wilms’ tumor is similar to that in the general population. The recurrence risk for sibs in the family is low, but considering the possibility of gonadal mosaicism, it is higher than in the general population.

scholarly journals Maternal DNMT3A-dependent de novo methylation of the paternal genome inhibits gene expression in the early embryo

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Julien Richard Albert ◽  
Wan Kin Au Yeung ◽  
Keisuke Toriyama ◽  
Hisato Kobayashi ◽  
Ryutaro Hirasawa ◽  
...  
Keyword(s):  
De Novo ◽  
Cpg Islands ◽  
Blastocyst Stage ◽  
Early Embryo ◽  
Mass Spectrometry Analysis ◽  
Paternal Allele ◽  
Sequencing Data ◽  
Cell Stage ◽  
Paternal Genome ◽  
Spectrometry Analysis

Abstract De novo DNA methylation (DNAme) during mammalian spermatogenesis yields a densely methylated genome, with the exception of CpG islands (CGIs), which are hypomethylated in sperm. While the paternal genome undergoes widespread DNAme loss before the first S-phase following fertilization, recent mass spectrometry analysis revealed that the zygotic paternal genome is paradoxically also subject to a low level of de novo DNAme. However, the loci involved, and impact on transcription were not addressed. Here, we employ allele-specific analysis of whole-genome bisulphite sequencing data and show that a number of genomic regions, including several dozen CGI promoters, are de novo methylated on the paternal genome by the 2-cell stage. A subset of these promoters maintains DNAme through development to the blastocyst stage. Consistent with paternal DNAme acquisition, many of these loci are hypermethylated in androgenetic blastocysts but hypomethylated in parthenogenetic blastocysts. Paternal DNAme acquisition is lost following maternal deletion of Dnmt3a, with a subset of promoters, which are normally transcribed from the paternal allele in blastocysts, being prematurely transcribed at the 4-cell stage in maternal Dnmt3a knockout embryos. These observations uncover a role for maternal DNMT3A activity in post-fertilization epigenetic reprogramming and transcriptional silencing of the paternal genome.

scholarly journals Processes of de novo duplication of human  -globin genes

2007 ◽  
Vol 104 (26) ◽  
pp. 10950-10955 ◽  
Author(s):  
K.-W. G. Lam ◽  
A. J. Jeffreys
Keyword(s):  
De Novo ◽  
Globin Genes

scholarly journals Chromosomal rearrangements in the 11p15 imprinted region: 17 new 11p15.5 duplications with associated phenotypes and putative functional consequences

2017 ◽  
Vol 55 (3) ◽  
pp. 205-213 ◽  
Author(s):  
Solveig Heide ◽  
Sandra Chantot-Bastaraud ◽  
Boris Keren ◽  
Madeleine D Harbison ◽  
Salah Azzi ◽  
...  
Keyword(s):  
De Novo ◽  
Chromosomal Rearrangements ◽  
Paternal Allele ◽  
Parental Origin ◽  
Imprinted Genes ◽  
Phenotype Correlation ◽  
Growth Disturbance ◽  
Correlation Studies ◽  
Functional Consequences

BackgroundThe 11p15 region contains two clusters of imprinted genes. Opposite genetic and epigenetic anomalies of this region result in two distinct growth disturbance syndromes: Beckwith-Wiedemann (BWS) and Silver-Russell syndromes (SRS). Cytogenetic rearrangements within this region represent less than 3% of SRS and BWS cases. Among these, 11p15 duplications were infrequently reported and interpretation of their pathogenic effects is complex.ObjectivesTo report cytogenetic and methylation analyses in a cohort of patients with SRS/BWS carrying 11p15 duplications and establish genotype/phenotype correlations.MethodsFrom a cohort of patients with SRS/BWS with an abnormal methylation profile (using ASMM-RTQ-PCR), we used SNP-arrays to identify and map the 11p15 duplications. We report 19 new patients with SRS (n=9) and BWS (n=10) carrying de novo or familial 11p15 duplications, which completely or partially span either both telomeric and centromeric domains or only one domain.ResultsLarge duplications involving one complete domain or both domains are associated with either SRS or BWS, depending on the parental origin of the duplication. Genotype-phenotype correlation studies of partial duplications within the telomeric domain demonstrate the prominent role of IGF2, rather than H19, in the control of growth. Furthermore, it highlights the role of CDKN1C within the centromeric domain and suggests that the expected overexpression of KCNQ1OT1 from the paternal allele (in partial paternal duplications, excluding CDKN1C) does not affect the expression of CDKN1C.ConclusionsThe phenotype associated with 11p15 duplications depends on the size, genetic content, parental inheritance and imprinting status. Identification of these rare duplications is crucial for genetic counselling.

scholarly journals Usefulness of NGS for Diagnosis of Dominant Beta-Thalassemia and Unstable Hemoglobinopathies in Five Clinical Cases

2021 ◽  
Vol 12 ◽  
Author(s):  
Valeria Rizzuto ◽  
Tamara T. Koopmann ◽  
Adoración Blanco-Álvarez ◽  
Barbara Tazón-Vega ◽  
Amira Idrizovic ◽  
...  
Keyword(s):  
De Novo ◽  
Globin Gene ◽  
Clinical Manifestations ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Beta Globin ◽  
Alpha Globin ◽  
Abnormal Hemoglobin ◽  
High Index Of Suspicion ◽  
Clinical Cases

Unstable hemoglobinopathies (UHs) are rare anemia disorders (RADs) characterized by abnormal hemoglobin (Hb) variants with decreased stability. UHs are therefore easily precipitating, causing hemolysis and, in some cases, leading to dominant beta-thalassemia (dBTHAL). The clinical picture of UHs is highly heterogeneous, inheritance pattern is dominant, instead of recessive as in more prevalent major Hb syndromes, and may occur de novo. Most cases of UHs are not detected by conventional testing, therefore diagnosis requires a high index of suspicion of the treating physician. Here, we highlight the importance of next generation sequencing (NGS) methodologies for the diagnosis of patients with dBTHAL and other less severe UH variants. We present five unrelated clinical cases referred with chronic hemolytic anemia, three of them with severe blood transfusion dependent anemia. Targeted NGS analysis was performed in three cases while whole exome sequencing (WES) analysis was performed in two cases. Five different UH variants were identified correlating with patients’ clinical manifestations. Four variants were related to the beta-globin gene (Hb Bristol—Alesha, Hb Debrousse, Hb Zunyi, and the novel Hb Mokum) meanwhile one case was caused by a mutation in the alpha-globin gene leading to Hb Evans. Inclusion of alpha and beta-globin genes in routine NGS approaches for RADs has to be considered to improve diagnosis’ efficiency of RAD due to UHs. Reducing misdiagnoses and underdiagnoses of UH variants, especially of the severe forms leading to dBTHAL would also facilitate the early start of intensive or curative treatments for these patients.

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