Pub Date : 2024-02-28DOI: 10.1186/s43042-024-00497-3
Rosa Catapano, Filippo Russo, Marco Rosetti, Giovanni Poletti, Silvia Trombetti, Raffaele Sessa, Tommaso Fasano, Sauro Maoggi, Sante Roperto, Michela Grosso
Dear Editor,
Acquired alpha-thalassemia mental retardation X-linked (ATRX) mutations are associated with the onset of α-thalassemia in several hematological malignancies including myelodysplasia, acute lymphoblastic leukemia, myelofibrosis, essential thrombocythemia, and acute myeloid leukemia (acquired α-thalassemia myelodisplastic syndrome, ATMDS) [1]. The ATRX gene (NM_000489.6) is located at Xq21.1 and encodes a chromatin remodeling protein which contributes to regulate the structure and function of chromatin in centromeric heterochromatin and telomeric domains to control different cellular pathways including DNA damage response and senescence mechanisms [2, 3]. ATRX is also involved in the epigenetic regulation of α-globin genes: loss-of-function mutations in the ATRX gene cause the transcriptional repression of the α-globin gene (HBA), thus resulting in a decreasing production of α-globin chains [4]. In this regard, mutations of the ATRX gene have been reported in association with a rare inherited pathology called X-linked α-thalassemia and mental retardation syndrome (or ATR-X syndrome) characterized by mental retardation, facial and urogenital abnormalities along with an α-thalassemia trait with elevated levels of β-globin or γ-globin tetramers (HbH or Barts' hemoglobin), the amount of which is directly related to the severity of the α-globin chain deficiency [5].
Here we report a novel single-nucleotide variant (SNV) in the ATRX gene, found by Next-Generation Sequencing (NGS) analysis in a 77-year-old Italian man previously healthy who had been hospitalized for myelofibrosis and was referred to our Centre to investigate the possible genetic cause of an acquired form of α-thalassemia with elevated levels of HbH. The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the University of Naples Federico II (project approval number 443/21). Genomic DNA was extracted using the Nucleon BACC3 kit (GE Healthcare, Life Sciences, Chicago, IL, USA) and analyzed by a customized NGS gene panel recently developed by our group to identify acquired or inherited mutations associated with thalassemic disorders. The DNA libraries were prepared with the SureSelectXT HS Target Enrichment System kit (Agilent Technologies, Santa Clara, CA, USA) after enzymatic fragmentation and according to the manufacturer’s protocol. Library quality and quantity were checked with the TapeStation system (Agilent Technologies) and Qubit dsDNA High Sensitivity assay kit on Qubit Fluorometer (Thermo Fisher Scientific, Waltham, MA, USA), respectively. Libraries were sequenced with MiSeq Reagent Kit v2 (300-cycles) by loading a concentrated pool (9 pM) and 1% Phix on a MiSeq Illumina® instrument (Illumina; San Diego, CA, USA). To exclude any kind of contamination, a blank negative control was included, and it followed all procedure’s steps, from DNA extraction to sequencing. Data analysis
{"title":"Identification of a novel ATR-X mutation causative of acquired α-thalassemia in a myelofibrosis patient","authors":"Rosa Catapano, Filippo Russo, Marco Rosetti, Giovanni Poletti, Silvia Trombetti, Raffaele Sessa, Tommaso Fasano, Sauro Maoggi, Sante Roperto, Michela Grosso","doi":"10.1186/s43042-024-00497-3","DOIUrl":"https://doi.org/10.1186/s43042-024-00497-3","url":null,"abstract":"<p><b>Dear Editor,</b></p><p>Acquired alpha-thalassemia mental retardation X-linked (ATRX) mutations are associated with the onset of α-thalassemia in several hematological malignancies including myelodysplasia, acute lymphoblastic leukemia, myelofibrosis, essential thrombocythemia, and acute myeloid leukemia (acquired α-thalassemia myelodisplastic syndrome, ATMDS) [1]. The ATRX gene (NM_000489.6) is located at Xq21.1 and encodes a chromatin remodeling protein which contributes to regulate the structure and function of chromatin in centromeric heterochromatin and telomeric domains to control different cellular pathways including DNA damage response and senescence mechanisms [2, 3]. ATRX is also involved in the epigenetic regulation of α-globin genes: loss-of-function mutations in the ATRX gene cause the transcriptional repression of the α-globin gene (HBA), thus resulting in a decreasing production of α-globin chains [4]. In this regard, mutations of the ATRX gene have been reported in association with a rare inherited pathology called X-linked α-thalassemia and mental retardation syndrome (or ATR-X syndrome) characterized by mental retardation, facial and urogenital abnormalities along with an α-thalassemia trait with elevated levels of β-globin or γ-globin tetramers (HbH or Barts' hemoglobin), the amount of which is directly related to the severity of the α-globin chain deficiency [5].</p><p>Here we report a novel single-nucleotide variant (SNV) in the <i>ATRX</i> gene, found by Next-Generation Sequencing (NGS) analysis in a 77-year-old Italian man previously healthy who had been hospitalized for myelofibrosis and was referred to our Centre to investigate the possible genetic cause of an acquired form of α-thalassemia with elevated levels of HbH. The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the University of Naples Federico II (project approval number 443/21). Genomic DNA was extracted using the Nucleon BACC3 kit (GE Healthcare, Life Sciences, Chicago, IL, USA) and analyzed by a customized NGS gene panel recently developed by our group to identify acquired or inherited mutations associated with thalassemic disorders. The DNA libraries were prepared with the SureSelect<sup>XT HS</sup> Target Enrichment System kit (Agilent Technologies, Santa Clara, CA, USA) after enzymatic fragmentation and according to the manufacturer’s protocol. Library quality and quantity were checked with the TapeStation system (Agilent Technologies) and Qubit dsDNA High Sensitivity assay kit on Qubit Fluorometer (Thermo Fisher Scientific, Waltham, MA, USA), respectively. Libraries were sequenced with MiSeq Reagent Kit v2 (300-cycles) by loading a concentrated pool (9 pM) and 1% Phix on a MiSeq Illumina® instrument (Illumina; San Diego, CA, USA). To exclude any kind of contamination, a blank negative control was included, and it followed all procedure’s steps, from DNA extraction to sequencing. Data analysis","PeriodicalId":39112,"journal":{"name":"Egyptian Journal of Medical Human Genetics","volume":null,"pages":null},"PeriodicalIF":1.3,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140008449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Despite substantial advancements in gastric cancer treatment in recent years, our understanding of the disease’s pathophysiology and progression processes remains limited, and the prognosis for gastric cancer patients remains poor. This study investigated potential prognostic indicators based on m7G-associated long non-coding RNA (lncRNA) and its relationship with gastric cancer (STAD). The researchers used RNA-seq and prognostic data from TCGA, employing Cox regression, co-expression network analysis, and multivariate Cox regression to identify relevant lncRNAs. We compiled four m7G-related lncRNAs into a single signature. We found it may be used as a prognostic indicator for gastric cancer. The m7G-related lncRNA profile had an area under the curve of 0.710, significantly more diagnostic than clinicopathological markers. The study also found that the TMB and tumor microenvironment were associated with gastric cancer risk, highlighting their signature’s potential utility for personalized treatment and disease monitoring. This study provides a novel signature of m7G-related lncRNAs that can be used as a prognostic indicator for gastric cancer and may help guide the development of targeted immunotherapy for the condition.
{"title":"A novel N7-methylguanosine-associated feature predicts prognosis in gastric cancer","authors":"Shixing Zhao, Wenbo Zhao, Chunxia Yao, Yunxiao Tian","doi":"10.1186/s43042-024-00495-5","DOIUrl":"https://doi.org/10.1186/s43042-024-00495-5","url":null,"abstract":"Despite substantial advancements in gastric cancer treatment in recent years, our understanding of the disease’s pathophysiology and progression processes remains limited, and the prognosis for gastric cancer patients remains poor. This study investigated potential prognostic indicators based on m7G-associated long non-coding RNA (lncRNA) and its relationship with gastric cancer (STAD). The researchers used RNA-seq and prognostic data from TCGA, employing Cox regression, co-expression network analysis, and multivariate Cox regression to identify relevant lncRNAs. We compiled four m7G-related lncRNAs into a single signature. We found it may be used as a prognostic indicator for gastric cancer. The m7G-related lncRNA profile had an area under the curve of 0.710, significantly more diagnostic than clinicopathological markers. The study also found that the TMB and tumor microenvironment were associated with gastric cancer risk, highlighting their signature’s potential utility for personalized treatment and disease monitoring. This study provides a novel signature of m7G-related lncRNAs that can be used as a prognostic indicator for gastric cancer and may help guide the development of targeted immunotherapy for the condition.","PeriodicalId":39112,"journal":{"name":"Egyptian Journal of Medical Human Genetics","volume":null,"pages":null},"PeriodicalIF":1.3,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139978775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-25DOI: 10.1186/s43042-024-00491-9
Anam Farooqui, Naaila Tamkeen, Safia Tazyeen, Sher Ali, Romana Ishrat
Turner syndrome (TS) is a rare disorder associated either with complete or partial loss of one X chromosome in women. The information on the genotype–phenotype relationship in TS is inadequate. Comparing the healthy and Turner syndrome patients may help elucidate the mechanisms involved in TS pathophysiology. Gene expression differences between healthy and individuals with Turner syndrome were characterized using the systems-biology approach of weighted gene coexpression network analysis (WGCNA) on 182 microarray peripheral mononuclear blood samples (PBMC). The coexpression networks of healthy and TS had scale-free topology that ensures network robustness. In the process, five modules were preserved between healthy and TS, which carry several genes common in each module. Two of them, SMCHD1 and PGK1, have already been reported to be involved in TS. Previously reported genes of TS, specifically, PTPN22, RPS4X, CSF2RA, and TIMP1, were missing in their respective modules. Dysfunction, differential expression, or absence of these genes could lead to a progressive disruption of molecular pathways leading to the pathophysiology of TS. Indeed, we observed a significant difference in the functions of these modules when compared within and across the healthy and TS samples. We identified four clusters in the PPI network constructed from the top 15 KME enriched in significant functions. Overall, our work highlights the potential molecular functions, pathways, and molecular targets of TS that can be exploited therapeutically in the human healthcare system.
{"title":"System biology approach to delineate expressional difference in the blood mononuclear cells between healthy and Turner syndrome individuals","authors":"Anam Farooqui, Naaila Tamkeen, Safia Tazyeen, Sher Ali, Romana Ishrat","doi":"10.1186/s43042-024-00491-9","DOIUrl":"https://doi.org/10.1186/s43042-024-00491-9","url":null,"abstract":"Turner syndrome (TS) is a rare disorder associated either with complete or partial loss of one X chromosome in women. The information on the genotype–phenotype relationship in TS is inadequate. Comparing the healthy and Turner syndrome patients may help elucidate the mechanisms involved in TS pathophysiology. Gene expression differences between healthy and individuals with Turner syndrome were characterized using the systems-biology approach of weighted gene coexpression network analysis (WGCNA) on 182 microarray peripheral mononuclear blood samples (PBMC). The coexpression networks of healthy and TS had scale-free topology that ensures network robustness. In the process, five modules were preserved between healthy and TS, which carry several genes common in each module. Two of them, SMCHD1 and PGK1, have already been reported to be involved in TS. Previously reported genes of TS, specifically, PTPN22, RPS4X, CSF2RA, and TIMP1, were missing in their respective modules. Dysfunction, differential expression, or absence of these genes could lead to a progressive disruption of molecular pathways leading to the pathophysiology of TS. Indeed, we observed a significant difference in the functions of these modules when compared within and across the healthy and TS samples. We identified four clusters in the PPI network constructed from the top 15 KME enriched in significant functions. Overall, our work highlights the potential molecular functions, pathways, and molecular targets of TS that can be exploited therapeutically in the human healthcare system.","PeriodicalId":39112,"journal":{"name":"Egyptian Journal of Medical Human Genetics","volume":null,"pages":null},"PeriodicalIF":1.3,"publicationDate":"2024-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139969083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-14DOI: 10.1186/s43042-024-00484-8
Farhana Siddiqi Mitu, Md. Murad Hossain, Shuvo Chandra Das, Md. Mafizul Islam, Dhirendra Nath Barman, Shipan Das Gupta
Type 2 diabetes mellitus (T2DM) is considered to be a polygenic disorder that emerges as a result of complicated gene-environment interactions. Several investigations revealed that SLC30A8 rs13266634 polymorphism elevates T2DM risk. T2DM and hypertension (HTN) are often found to be coexist. Compared to normotensive non-diabetic controls, T2DM patients with HTN have a fourfold increased risk of cardiovascular disease (CVD). The average age of T2DM diagnosis is decreasing, and ‘early onset of T2DM’ in adolescents and young adults is an emerging worldwide health concern. The objective of this study was to examine the potential correlations of SLC30A8 rs13266634 polymorphism with T2DM and T2DM-related CVD and HTN as well as ‘early onset of T2DM’ in the Noakhali region. This case–control study involved 163 T2DM patients and 75 healthy controls for analysis of SLC30A8-rs13266634 polymorphism. Genotyping of this polymorphism was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) method. MedCalc and Gene Calc programs were used for statistical analysis. A statistically significant association of SLC30A8 rs13266634 (P < 0.05) with T2DM was found in dominant, over dominant and allele models. But this study found no evidence of a connection between SLC30A8-rs13266634 with CVD, HTN, or ‘early onset of T2DM’ in any models. Furthermore, T2DM patients had higher total cholesterol (TC) and triglyceride (TG) levels than non-diabetics individuals. This study revealed a substantial association between the variation in SLC30A8-rs13266634 and the increased risk of developing T2DM within a sample of the Noakhali population in Bangladesh. However, no significant associations were observed between SLC30A8-rs13266634 and T2DM-related cardiovascular disease (CVD), hypertension (HTN), or the early onset of T2DM within this specific population.
{"title":"Association of SLC30A8 rs13266634 gene polymorphism with type 2 diabetes mellitus (T2DM) in a population of Noakhali, Bangladesh: a case–control study","authors":"Farhana Siddiqi Mitu, Md. Murad Hossain, Shuvo Chandra Das, Md. Mafizul Islam, Dhirendra Nath Barman, Shipan Das Gupta","doi":"10.1186/s43042-024-00484-8","DOIUrl":"https://doi.org/10.1186/s43042-024-00484-8","url":null,"abstract":"Type 2 diabetes mellitus (T2DM) is considered to be a polygenic disorder that emerges as a result of complicated gene-environment interactions. Several investigations revealed that SLC30A8 rs13266634 polymorphism elevates T2DM risk. T2DM and hypertension (HTN) are often found to be coexist. Compared to normotensive non-diabetic controls, T2DM patients with HTN have a fourfold increased risk of cardiovascular disease (CVD). The average age of T2DM diagnosis is decreasing, and ‘early onset of T2DM’ in adolescents and young adults is an emerging worldwide health concern. The objective of this study was to examine the potential correlations of SLC30A8 rs13266634 polymorphism with T2DM and T2DM-related CVD and HTN as well as ‘early onset of T2DM’ in the Noakhali region. This case–control study involved 163 T2DM patients and 75 healthy controls for analysis of SLC30A8-rs13266634 polymorphism. Genotyping of this polymorphism was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) method. MedCalc and Gene Calc programs were used for statistical analysis. A statistically significant association of SLC30A8 rs13266634 (P < 0.05) with T2DM was found in dominant, over dominant and allele models. But this study found no evidence of a connection between SLC30A8-rs13266634 with CVD, HTN, or ‘early onset of T2DM’ in any models. Furthermore, T2DM patients had higher total cholesterol (TC) and triglyceride (TG) levels than non-diabetics individuals. This study revealed a substantial association between the variation in SLC30A8-rs13266634 and the increased risk of developing T2DM within a sample of the Noakhali population in Bangladesh. However, no significant associations were observed between SLC30A8-rs13266634 and T2DM-related cardiovascular disease (CVD), hypertension (HTN), or the early onset of T2DM within this specific population.","PeriodicalId":39112,"journal":{"name":"Egyptian Journal of Medical Human Genetics","volume":null,"pages":null},"PeriodicalIF":1.3,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139770057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-12DOI: 10.1186/s43042-024-00494-6
Hala T. El-Bassyouni, Engy A. Ashaat, Khaled Hamed, Maha Rashed, Azza E. Abd-Elnaby, Marwa Shehab
The hallmarks of Emanuel syndrome are pre- and postnatal growth retardation, microcephaly, global developmental delay, ear anomalies, and in males, heart, kidney, and genital abnormalities. This study describes the atypical features of Emanuel syndrome, a rare chromosomal disorder. The patient had several physical features that are common in Emanuel syndrome, such as microcephaly, hypotonia, and ear anomalies. However, he exhibited certain unusual characteristics, including the lack of a prominent forehead, epicanthic folds, and a downward slanting palpebral fissure. There was infratentorial brain involution with a minor infarction in the left cerebral hemisphere and cerebellar hypoplasia on the magnetic resonance imaging (MRI) scan of the brain. Additionally, the patient had bilateral mild hearing loss and an aberrant epileptogenic pattern on the electroencephalogram (EEG). Orodental examination showed a long philtrum, everted fissured thick lower lip, highly attached labial frenum, and prominent median palatine raphe. The karyotype revealed 45XY t(11;22)(p15.5;q11.22), which is different from the typical karyotype of Emanuel syndrome. This case sheds light on the possibility of alternative genetic mechanisms, beyond chromosomal abnormalities, in patients presenting with multiple congenital anomalies and facial dysmorphism.
{"title":"Emanuel syndrome due to unusual pattern","authors":"Hala T. El-Bassyouni, Engy A. Ashaat, Khaled Hamed, Maha Rashed, Azza E. Abd-Elnaby, Marwa Shehab","doi":"10.1186/s43042-024-00494-6","DOIUrl":"https://doi.org/10.1186/s43042-024-00494-6","url":null,"abstract":"The hallmarks of Emanuel syndrome are pre- and postnatal growth retardation, microcephaly, global developmental delay, ear anomalies, and in males, heart, kidney, and genital abnormalities. This study describes the atypical features of Emanuel syndrome, a rare chromosomal disorder. The patient had several physical features that are common in Emanuel syndrome, such as microcephaly, hypotonia, and ear anomalies. However, he exhibited certain unusual characteristics, including the lack of a prominent forehead, epicanthic folds, and a downward slanting palpebral fissure. There was infratentorial brain involution with a minor infarction in the left cerebral hemisphere and cerebellar hypoplasia on the magnetic resonance imaging (MRI) scan of the brain. Additionally, the patient had bilateral mild hearing loss and an aberrant epileptogenic pattern on the electroencephalogram (EEG). Orodental examination showed a long philtrum, everted fissured thick lower lip, highly attached labial frenum, and prominent median palatine raphe. The karyotype revealed 45XY t(11;22)(p15.5;q11.22), which is different from the typical karyotype of Emanuel syndrome. This case sheds light on the possibility of alternative genetic mechanisms, beyond chromosomal abnormalities, in patients presenting with multiple congenital anomalies and facial dysmorphism.","PeriodicalId":39112,"journal":{"name":"Egyptian Journal of Medical Human Genetics","volume":null,"pages":null},"PeriodicalIF":1.3,"publicationDate":"2024-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139769818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anterior segment dysgenesis (ASD) disorders comprises of spectrum of developmental conditions affecting the structures of angle of anterior chamber including cornea, iris, and lens. These conditions are characterized by both autosomal dominant and recessive patterns of inheritance often with incomplete penetrance/variable expressivity. A significant overlap among phenotypes attributed to mutations in different ASD genes is well recognized. We present a case involving a 29-year-old pregnant woman referred for genetic screening and counseling. She had a 7-year-old male child with congenital bilateral corneal opacity, and his elder sister also exhibited similar findings. Exome sequencing identified a novel variant in the CYP1B1 gene in a homozygous state, which was associated with anterior segment dysgenesis. Both parents were found to be carriers of the same variant, while the sister had the same variant in a homozygous state. Genotype–phenotype correlation was performed, and it was concluded that the novel variant could be responsible for the eye changes in both siblings. The parents sought prenatal diagnosis for the current pregnancy, which was deemed possible. This case underscores the importance of genetic testing in such rare diseases, as it can assist in early diagnosis, management, and prognosis. It also aids clinicians and parents in making decisions regarding the continuation of the pregnancy at the appropriate time.
{"title":"Novel mutation as a cause of anterior segment dysgenesis leading to blindness in progeny: the genetics decoded!","authors":"Kumari Pritti, Vineet Mishra, Somesh Aggarwal, Mehul Mistri, Manisha Chhetry","doi":"10.1186/s43042-024-00493-7","DOIUrl":"https://doi.org/10.1186/s43042-024-00493-7","url":null,"abstract":"Anterior segment dysgenesis (ASD) disorders comprises of spectrum of developmental conditions affecting the structures of angle of anterior chamber including cornea, iris, and lens. These conditions are characterized by both autosomal dominant and recessive patterns of inheritance often with incomplete penetrance/variable expressivity. A significant overlap among phenotypes attributed to mutations in different ASD genes is well recognized. We present a case involving a 29-year-old pregnant woman referred for genetic screening and counseling. She had a 7-year-old male child with congenital bilateral corneal opacity, and his elder sister also exhibited similar findings. Exome sequencing identified a novel variant in the CYP1B1 gene in a homozygous state, which was associated with anterior segment dysgenesis. Both parents were found to be carriers of the same variant, while the sister had the same variant in a homozygous state. Genotype–phenotype correlation was performed, and it was concluded that the novel variant could be responsible for the eye changes in both siblings. The parents sought prenatal diagnosis for the current pregnancy, which was deemed possible. This case underscores the importance of genetic testing in such rare diseases, as it can assist in early diagnosis, management, and prognosis. It also aids clinicians and parents in making decisions regarding the continuation of the pregnancy at the appropriate time.","PeriodicalId":39112,"journal":{"name":"Egyptian Journal of Medical Human Genetics","volume":null,"pages":null},"PeriodicalIF":1.3,"publicationDate":"2024-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139769910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-09DOI: 10.1186/s43042-024-00489-3
Safa Meshaal, Rabab El Hawary, Dalia Abd Elaziz, Alia Eldash, Rania Darwish, Aya Erfan, Sohilla Lotfy, Mai M. Saad, Engy Chohayeb, Radwa Alkady, Jeannette Boutros, Nermeen Galal, Aisha Elmarsafy
Caspase recruitment domain family, member 11 (CARD11) is an important protein which plays a fundamental role in the activation of NF-κβ pathway in lymphocytes. CARD11 deficiency can be inherited in either autosomal dominant or autosomal recessive forms and present with different phenotypes including combined immunodeficiency, atopic dermatitis, and other variable manifestations. The present report describes clinical phenotypes and immunological defects of two unrelated patients with missense homozygous variants in CARD11 presenting with combined immunodeficiency (CID) and atopic skin disease resembling that reported in dominant negative CARD11 deficiency. The patients underwent next generation sequencing, immunophenotyping of T and B subsets by flow cytometry, T cell stimulation, and evaluation of CARD11 expression. Both patients had features suggesting CID including repeated pneumoniae with ICU admissions, chronic diarrhea, and itchy atopic skin disease. Patient-1 has homozygous missense variant in the C terminal domain (c.2839G > A, p.Glu947Lys), and patient-2 has homozygous variant in the inhibitory domain (c.1073C > G, p.Pro568Arg). Both have profound defects in Tregs with normal recent thymic emigrants, memory, and naïve CD4+ T cells. However, in response to stimulation, T cells failed to upregulate the expression of CD25. CARD11 expression by flow cytometry was decreased rather than abolished as previously described in patients with autosomal recessive CARD11 deficiency. B cells showed marked deficiency of switched memory and increase in transitional B cells. Missense variants causing CARD11 deficiency may affect the protein function rather than the expression and can result in a phenotype combining the atopic skin disease and the features of CID.
Caspase 募集结构域家族成员 11（CARD11）是一种重要的蛋白质，在淋巴细胞激活 NF-κβ 通路的过程中发挥着重要作用。CARD11 缺乏症可为常染色体显性遗传或常染色体隐性遗传，并表现出不同的表型，包括联合免疫缺陷、特应性皮炎和其他可变表现。本报告描述了两名无亲属关系的 CARD11 错义同源变异患者的临床表型和免疫缺陷，他们表现为联合免疫缺陷症（CID）和特应性皮肤病，类似于已报道的显性阴性 CARD11 缺乏症。患者接受了新一代测序、流式细胞术对 T 和 B 亚群进行免疫分型、T 细胞刺激和 CARD11 表达评估。这两名患者都有提示 CID 的特征，包括反复肺炎并住进 ICU、慢性腹泻和瘙痒性特异性皮肤病。患者-1 的 C 端结构域存在同源错义变异（c.2839G > A，p.Glu947Lys），患者-2 的抑制结构域存在同源变异（c.1073C > G，p.Pro568Arg）。二者的Tregs均存在严重缺陷，近期胸腺移入者、记忆和幼稚CD4+T细胞均正常。然而，在刺激下，T 细胞不能上调 CD25 的表达。通过流式细胞术检测，CARD11的表达减少了，而不是像以前在常染色体隐性CARD11缺乏症患者中描述的那样消失了。B 细胞表现出明显的切换记忆缺陷，过渡性 B 细胞增多。导致 CARD11 缺乏症的错义变体可能会影响蛋白质的功能而不是表达，并可能导致结合特应性皮肤病和 CID 特征的表型。
{"title":"Novel homozygous CARD11 variants in two patients with combined immunodeficiency and atopic skin disease","authors":"Safa Meshaal, Rabab El Hawary, Dalia Abd Elaziz, Alia Eldash, Rania Darwish, Aya Erfan, Sohilla Lotfy, Mai M. Saad, Engy Chohayeb, Radwa Alkady, Jeannette Boutros, Nermeen Galal, Aisha Elmarsafy","doi":"10.1186/s43042-024-00489-3","DOIUrl":"https://doi.org/10.1186/s43042-024-00489-3","url":null,"abstract":"Caspase recruitment domain family, member 11 (CARD11) is an important protein which plays a fundamental role in the activation of NF-κβ pathway in lymphocytes. CARD11 deficiency can be inherited in either autosomal dominant or autosomal recessive forms and present with different phenotypes including combined immunodeficiency, atopic dermatitis, and other variable manifestations. The present report describes clinical phenotypes and immunological defects of two unrelated patients with missense homozygous variants in CARD11 presenting with combined immunodeficiency (CID) and atopic skin disease resembling that reported in dominant negative CARD11 deficiency. The patients underwent next generation sequencing, immunophenotyping of T and B subsets by flow cytometry, T cell stimulation, and evaluation of CARD11 expression. Both patients had features suggesting CID including repeated pneumoniae with ICU admissions, chronic diarrhea, and itchy atopic skin disease. Patient-1 has homozygous missense variant in the C terminal domain (c.2839G > A, p.Glu947Lys), and patient-2 has homozygous variant in the inhibitory domain (c.1073C > G, p.Pro568Arg). Both have profound defects in Tregs with normal recent thymic emigrants, memory, and naïve CD4+ T cells. However, in response to stimulation, T cells failed to upregulate the expression of CD25. CARD11 expression by flow cytometry was decreased rather than abolished as previously described in patients with autosomal recessive CARD11 deficiency. B cells showed marked deficiency of switched memory and increase in transitional B cells. Missense variants causing CARD11 deficiency may affect the protein function rather than the expression and can result in a phenotype combining the atopic skin disease and the features of CID.","PeriodicalId":39112,"journal":{"name":"Egyptian Journal of Medical Human Genetics","volume":null,"pages":null},"PeriodicalIF":1.3,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139769903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Breast cancer (BC) is the most common female cancers in many countries including Syria. Familial breast cancer or previous family cancer history are considered significant risk factors. Therefore, detecting the prevalence and founder mutations in the population facilitates genetic counselling, risk assessment and the development of a cost-effective screening strategy. In this study, we investigated the three germ-line founder mutations in the BRCA1/2 genes: [NM_007294.4 (BRCA1):c.68_69del (p.Glu23fs), NM_007294.4 (BRCA1):c.5266dup (p.Gln1756fs) and NM_000059.4 (BRCA2):c.5946del (p.Ser1982fs)], to examine their incidence and frequency in early-onset breast cancer cases and determine if they are connected to familial breast cancer. One hundred early diagnosed BC females (≤ 40 years old) with no other type of cancer were recruited. Genomic DNA was isolated from peripheral blood samples, and mutations were investigated using the Amplification-Created Restriction Site (ACRS) method. The family history of cancer was observed in 61% of the cases, of which 35% were breast cancer; however, none of the screened mutations were detected among BC patients. The investigated germ-line mutations were not common among Syrian female patients with early-onset BC and were not associated with familial BC. Other mutations in the BRCA1/2 genes or other genes may have a contributing role. Future studies and the need to launch nationwide mutation screening tests for BRCA 1/BRCA2 in the Syrian population are recommended.
{"title":"BRCA mutations: screening for germ-line founder mutations among early-onset Syrian breast cancer patients","authors":"Salma Wahabi Alzahabi, Maher Saifo, Ghalia Abou Alchamat","doi":"10.1186/s43042-024-00492-8","DOIUrl":"https://doi.org/10.1186/s43042-024-00492-8","url":null,"abstract":"Breast cancer (BC) is the most common female cancers in many countries including Syria. Familial breast cancer or previous family cancer history are considered significant risk factors. Therefore, detecting the prevalence and founder mutations in the population facilitates genetic counselling, risk assessment and the development of a cost-effective screening strategy. In this study, we investigated the three germ-line founder mutations in the BRCA1/2 genes: [NM_007294.4 (BRCA1):c.68_69del (p.Glu23fs), NM_007294.4 (BRCA1):c.5266dup (p.Gln1756fs) and NM_000059.4 (BRCA2):c.5946del (p.Ser1982fs)], to examine their incidence and frequency in early-onset breast cancer cases and determine if they are connected to familial breast cancer. One hundred early diagnosed BC females (≤ 40 years old) with no other type of cancer were recruited. Genomic DNA was isolated from peripheral blood samples, and mutations were investigated using the Amplification-Created Restriction Site (ACRS) method. The family history of cancer was observed in 61% of the cases, of which 35% were breast cancer; however, none of the screened mutations were detected among BC patients. The investigated germ-line mutations were not common among Syrian female patients with early-onset BC and were not associated with familial BC. Other mutations in the BRCA1/2 genes or other genes may have a contributing role. Future studies and the need to launch nationwide mutation screening tests for BRCA 1/BRCA2 in the Syrian population are recommended.","PeriodicalId":39112,"journal":{"name":"Egyptian Journal of Medical Human Genetics","volume":null,"pages":null},"PeriodicalIF":1.3,"publicationDate":"2024-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139769820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-06DOI: 10.1186/s43042-024-00476-8
Vandit Sevak, Rathika Chinniah, Sasiharan Pandi, K. Sampathkumar, T. Dinakaran, Balakrishnan Karuppiah
The present study was undertaken to examine the role of IL-4 (− 590 C/T) (rs2243250) and IL-6 (− 174G/C) (rs1800795) polymorphism and the serum levels of IL-4 and IL-6 in chronic kidney disease (CKD). The IL-4 (− 590C/T) and IL-6 (− 174 G/C) polymorphisms were genotyped in 132 CKD patients and 161 controls using PCR–RFLP. Serum IL-4 and IL-6 quantifications were performed by ELISA. Significant susceptible associations of CT genotype (OR = 4.56; p < 1.84 × 10–9) and T allele (OR = 1.56; p < 0.010) of IL-4 (− 590C/T) and CC genotype (OR = 2.63; p < 0.032) of IL-6 (− 174G/C) were observed for CKD. The CC genotype (OR = 0.27; p < 9.314 × 10–7) and C allele (OR = 0.63; p < 0.010) of IL-4 (− 590 C/T) revealed strong protective associations. Five-fold increased levels were observed for both IL-6 (p < 0.0001) and IL-4 (p < 0.0043) cytokines in CKD patients than the controls. The IL-4 serum levels (pg/ml) increased significantly in patients with CT and TT genotypes of IL-4 (− 590 C/T) than the controls (6.18 ± 1.80 vs. 3.33 ± 0.48 and 6.14 ± 1.96 vs. 3.21 ± 0.56 respectively). For IL-6 (− 174 G/C) polymorphism, the patients with CC genotype (6.50 ± 1.30 vs. 3.49 ± 1.39) revealed with higher IL-6 serum levels followed by GC genotype (5.00 ± 1.91 vs. 4.01 ± 1.74). The genotypes of IL-4 (590 C/T) and IL-6 (174 G/C) polymorphisms contribute differential susceptibility in south Indian CKD patients. A fivefold increased serum levels of IL-4 (anti-inflammatory) and IL-6 (pro- and anti-inflammatory) cytokines were documented in CKD patients. There observed an opposite trend in disease association for these two cytokines and associated SNPs with CKD in south India.
{"title":"Association of IL-4 (− 590 C/T) and IL-6 (− 174 G/C) gene polymorphism in South Indian CKD patients","authors":"Vandit Sevak, Rathika Chinniah, Sasiharan Pandi, K. Sampathkumar, T. Dinakaran, Balakrishnan Karuppiah","doi":"10.1186/s43042-024-00476-8","DOIUrl":"https://doi.org/10.1186/s43042-024-00476-8","url":null,"abstract":"The present study was undertaken to examine the role of IL-4 (− 590 C/T) (rs2243250) and IL-6 (− 174G/C) (rs1800795) polymorphism and the serum levels of IL-4 and IL-6 in chronic kidney disease (CKD). The IL-4 (− 590C/T) and IL-6 (− 174 G/C) polymorphisms were genotyped in 132 CKD patients and 161 controls using PCR–RFLP. Serum IL-4 and IL-6 quantifications were performed by ELISA. Significant susceptible associations of CT genotype (OR = 4.56; p < 1.84 × 10–9) and T allele (OR = 1.56; p < 0.010) of IL-4 (− 590C/T) and CC genotype (OR = 2.63; p < 0.032) of IL-6 (− 174G/C) were observed for CKD. The CC genotype (OR = 0.27; p < 9.314 × 10–7) and C allele (OR = 0.63; p < 0.010) of IL-4 (− 590 C/T) revealed strong protective associations. Five-fold increased levels were observed for both IL-6 (p < 0.0001) and IL-4 (p < 0.0043) cytokines in CKD patients than the controls. The IL-4 serum levels (pg/ml) increased significantly in patients with CT and TT genotypes of IL-4 (− 590 C/T) than the controls (6.18 ± 1.80 vs. 3.33 ± 0.48 and 6.14 ± 1.96 vs. 3.21 ± 0.56 respectively). For IL-6 (− 174 G/C) polymorphism, the patients with CC genotype (6.50 ± 1.30 vs. 3.49 ± 1.39) revealed with higher IL-6 serum levels followed by GC genotype (5.00 ± 1.91 vs. 4.01 ± 1.74). The genotypes of IL-4 (590 C/T) and IL-6 (174 G/C) polymorphisms contribute differential susceptibility in south Indian CKD patients. A fivefold increased serum levels of IL-4 (anti-inflammatory) and IL-6 (pro- and anti-inflammatory) cytokines were documented in CKD patients. There observed an opposite trend in disease association for these two cytokines and associated SNPs with CKD in south India.","PeriodicalId":39112,"journal":{"name":"Egyptian Journal of Medical Human Genetics","volume":null,"pages":null},"PeriodicalIF":1.3,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139769900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-03DOI: 10.1186/s43042-024-00480-y
Tamer H. A. Ammar, Ghada M. M. Al-Ettribi, Maha M. A. Abo Hashish, Tarek M. Farid, Amany A. Abou-Elalla, Manal M. Thomas
Isolated growth hormone deficiency (IGHD) is a hereditary disorder that causes significant short stature. GHD has a reported incidence of 1/4000–1/10,000 births. It is caused by mutations in the major somatotroph axis genes, involving GH1, codes for growth hormone, GHSR, and GHRHR, codes for growth hormone secretagogue receptor and growth hormone-releasing hormone receptor, respectively. The present study aims to examine the clinical phenotype and investigate the genetic etiology of ten Egyptian patients with type I isolated growth hormone insufficiency. Patients recruited for the study were clinically diagnosed by two provocation tests and were subjected to a thorough history, clinical examination, and anthropometric measurements. Sanger sequencing and mutational analysis of the three genes, GH1, GHSR, and GHRHR, was our approach, performed in all enrolled IGHD patients. The variants identified were analyzed using the biological, population, sequence variants, and clinical genetics databases. Prediction of the pathogenicity of the novel variants was done by in silico prediction tools following the American College of Medical Genetics and Genomics (ACMG) guidelines. Sanger sequencing revealed a previously reported pathogenic mutation (NM_000823.4: c.1069C > T; p.Arg357Cys) in the GHRHR gene in one patient and a novel frameshift variant (NM_198407.2: c.1043dup; Ser349Leu fs*6) in the GHSR gene in another patient. This is the fourth report highlighting the autosomal dominant inheritance of the GHSR mutation as a cause of isolated growth hormone deficiency. A number of previously reported variants, but of rare frequency, were identified in this study. In our IGHD cases, 90% of the patients were underweight, 50% had anemia, and 80% showed hypovitaminosis D. Our findings broaden the mutational spectrum underlying the IGHD in Egyptian patients and point out the importance of mutation screening of the GHSR and GHRHR genes. This study also acknowledges the autosomal dominant mode of inheritance of the GHSR mutation as a cause for dwarfism.
{"title":"Screening of GHSR, GHRHR, GH1 genes in isolated growth hormone deficiency disease in Egyptian patients","authors":"Tamer H. A. Ammar, Ghada M. M. Al-Ettribi, Maha M. A. Abo Hashish, Tarek M. Farid, Amany A. Abou-Elalla, Manal M. Thomas","doi":"10.1186/s43042-024-00480-y","DOIUrl":"https://doi.org/10.1186/s43042-024-00480-y","url":null,"abstract":"Isolated growth hormone deficiency (IGHD) is a hereditary disorder that causes significant short stature. GHD has a reported incidence of 1/4000–1/10,000 births. It is caused by mutations in the major somatotroph axis genes, involving GH1, codes for growth hormone, GHSR, and GHRHR, codes for growth hormone secretagogue receptor and growth hormone-releasing hormone receptor, respectively. The present study aims to examine the clinical phenotype and investigate the genetic etiology of ten Egyptian patients with type I isolated growth hormone insufficiency. Patients recruited for the study were clinically diagnosed by two provocation tests and were subjected to a thorough history, clinical examination, and anthropometric measurements. Sanger sequencing and mutational analysis of the three genes, GH1, GHSR, and GHRHR, was our approach, performed in all enrolled IGHD patients. The variants identified were analyzed using the biological, population, sequence variants, and clinical genetics databases. Prediction of the pathogenicity of the novel variants was done by in silico prediction tools following the American College of Medical Genetics and Genomics (ACMG) guidelines. Sanger sequencing revealed a previously reported pathogenic mutation (NM_000823.4: c.1069C > T; p.Arg357Cys) in the GHRHR gene in one patient and a novel frameshift variant (NM_198407.2: c.1043dup; Ser349Leu fs*6) in the GHSR gene in another patient. This is the fourth report highlighting the autosomal dominant inheritance of the GHSR mutation as a cause of isolated growth hormone deficiency. A number of previously reported variants, but of rare frequency, were identified in this study. In our IGHD cases, 90% of the patients were underweight, 50% had anemia, and 80% showed hypovitaminosis D. Our findings broaden the mutational spectrum underlying the IGHD in Egyptian patients and point out the importance of mutation screening of the GHSR and GHRHR genes. This study also acknowledges the autosomal dominant mode of inheritance of the GHSR mutation as a cause for dwarfism.","PeriodicalId":39112,"journal":{"name":"Egyptian Journal of Medical Human Genetics","volume":null,"pages":null},"PeriodicalIF":1.3,"publicationDate":"2024-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139665670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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