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A Novel Missense Heterozygous Mutation in NKX2-5 Gene in a Family with Congenital Septal Defects and Cardiomyopathy: Case Series and Literature Review 一个先天性房间隔缺损和心肌病家族中的 NKX2-5 基因新型缺义杂合突变:病例系列和文献综述
IF 0.4 Q4 PEDIATRICS Pub Date : 2024-07-10 DOI: 10.1055/s-0044-1788252
Abdulqader Al Zubaidi, Aisha M Al-Shamsi
Single-gene mutations are important causes of congenital heart defects in children. Mutations in the NKX2-5 gene have been recently described in the literature as a cause of septal defects and cardiomyopathy. However, the spectrum of cardiac disease associated with NKX2-5 gene mutations is variable, ranging from asymptomatic septal defects to cardiomyopathy and sudden death. In this case report, we describe a case of 2-year-old child, along with two other family members, with a novel missense heterozygous (c.544G > T p.[Val182Phe]) mutation in NKX2-5 gene consistent with the diagnosis of autosomal dominant atrial septal defects with cardiomyopathy. This report can contribute to the understanding of genotype–phenotype correlations; it emphasizes the significant clinical relevance of NKX2-5 gene defects for congenital heart defects, sudden death, and cardiomyopathy, especially in multiple affected family members. It also suggests that individuals with NKX2-5 mutations are at risk of lethal arrhythmias and conduction disorders, that is why they should be evaluated routinely to assess the need for implantable cardioverter-defibrillator or pacemaker implantation.
单基因突变是导致儿童先天性心脏缺陷的重要原因。最近有文献描述,NKX2-5 基因突变是室间隔缺损和心肌病的病因之一。然而,与 NKX2-5 基因突变相关的心脏疾病谱是多变的,从无症状的房间隔缺损到心肌病和猝死。在本病例报告中,我们描述了一例两岁儿童和另外两名家庭成员的 NKX2-5 基因新型错义杂合(c.544G > T p. [Val182Phe])突变,与常染色体显性心房隔膜缺损伴心肌病的诊断一致。该报告有助于人们了解基因型与表型的相关性;它强调了 NKX2-5 基因缺陷与先天性心脏缺陷、猝死和心肌病的重大临床意义,尤其是在多个受影响的家庭成员中。该研究还表明,NKX2-5 基因突变的个体存在致命性心律失常和传导障碍的风险,因此应该对他们进行常规评估,以评估植入式心律转复除颤器或起搏器的必要性。
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引用次数: 0
Erratum: Corrigendum: A Severe Case of Spondylometaphyseal Dysplasia Algerian Type with Two Mutations in COL2A1. 勘误:更正:一例严重的脊柱软骨发育不良阿尔及利亚型病例伴有两种 COL2A1 基因突变。
IF 0.4 Q4 PEDIATRICS Pub Date : 2024-07-09 eCollection Date: 2023-12-01 DOI: 10.1055/s-0044-1788343
Francisco Cammarata-Scalisi, Uta Matysiak, Colin E Willoughby, Gunda Ruzaike, Antonio Cárdenas Tadich, Maykol Araya Castillo, Carmen Zara-Chirinos, Ana Bracho, Andrea Avendaño, Houweyda Jilani, Michele Callea

[This corrects the article DOI: 10.1055/s-0041-1732474.].

[此处更正了文章 DOI:10.1055/s-0041-1732474]。
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引用次数: 0
Contributing Reviewers in 2023. 2023 年的特约评论员。
IF 0.4 Pub Date : 2024-04-01 eCollection Date: 2024-03-01 DOI: 10.1055/s-0044-1782623
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引用次数: 0
A Novel Autosomal Recessive Candidate Gene Responsible for RASopathy-Like Phenotype and Bone Marrow Failure: RASA3 一种新的常染色体隐性候选基因负责ras病样表型和骨髓衰竭:RASA3
Pub Date : 2023-10-26 DOI: 10.1055/s-0043-1771526
Akif Ayaz, Zeynep Doğru, Kıvanç Kök, Nihan Bayram, Yöntem Yaman, Abdullah Hüseyin Köseoğlu, Türkan Yiğitbaşı, Aslı Güner Öztürk Demir, Elçin Yüksel, Burcu Dundar, Erdal Fırat Çaralan, Serdar Nepesov, Murat Elli
Abstract Although many genetic etiologies, such as Fanconi anemia, Shwachman–Diamond syndrome, dyskeratosis congenita, and Diamond–Blackfan anemia, from hereditary bone marrow failure are known today, the responsible gene remains unknown in a significant part of these patients. A 6-year-old girl, whose parents were first-cousin consanguineous, was referred to the pediatric hematology department due to growth retardation, thrombocytopenia, neutropenia, and anemia. The patient had low-set ears, pectus excavatum inferiorly, and cafe-au-lait spots. In whole-exome analysis, p.K385T (c.1154A > C) variant in the RASA3 gene was detected as homozygous. The amino acid position of the alteration is located in the conserved and ordered region, corresponding to the Ras GTPase activation domain (Ras-GAP) in the center of the protein. Importantly, most of in silico prediction tools of pathogenicity predicts the variant as damaging. RASopathies, which are characterized by many common clinical findings, such as atypical facial features, growth delays, and heart defects, are a group of rare genetic diseases caused by mutations in the genes involved in the Ras-MAPK pathway. The findings in this patient were consistent with the RASopathy-like phenotype and bone marrow failure. Interestingly, enrichment of RASopathy genes was observed in the RASA3 protein–protein interaction network. Furthermore, the subsequent topological clustering revealed a putative function module, which further implicates RASA3 in this disease as a novel potential causative gene. In this context, the detected RASA3 mutation could be manifesting itself clinically as the observed phenotype by disrupting the functional cooperation between the RASA3 protein and its interaction partners. Relatedly, current literature also supports the obtained findings. Overall, this study provides new insights into RASopathy and put forward the RASA3 gene as a novel candidate gene for this disease group.
虽然目前已知遗传性骨髓衰竭的许多遗传病因,如Fanconi贫血、Shwachman-Diamond综合征、先天性角化不良症和Diamond-Blackfan贫血,但在这些患者中,很大一部分的致病基因仍然未知。1例6岁女童因发育迟缓、血小板减少症、中性粒细胞减少症和贫血被转至儿科血液科。患者双耳低置,下漏斗胸,咖啡色斑点。在全外显子组分析中,p.K385T (c.1154A >C)检测到RASA3基因的变异为纯合子。该改变的氨基酸位置位于保守有序区域,对应于蛋白质中心的Ras GTPase激活域(Ras- gap)。重要的是,大多数计算机预测致病性的工具预测变异是有害的。RASopathies是一组罕见的遗传病,由Ras-MAPK通路相关基因突变引起,其特征是许多常见的临床表现,如非典型面部特征、生长迟缓和心脏缺陷。该患者的发现与rasopathy样表型和骨髓衰竭一致。有趣的是,在RASA3蛋白-蛋白相互作用网络中观察到ras病变基因的富集。此外,随后的拓扑聚类揭示了一个假定的功能模块,这进一步表明RASA3在该疾病中是一个新的潜在致病基因。在这种情况下,检测到的RASA3突变可能通过破坏RASA3蛋白与其相互作用伙伴之间的功能合作而在临床上表现为观察到的表型。相关的,目前的文献也支持我们的发现。总的来说,本研究为RASopathy提供了新的见解,并提出RASA3基因作为该疾病组的新的候选基因。
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引用次数: 0
rs1800890 Polymorphism of IL-10 and Susceptibility to Idiopathic Thrombocytopenic Purpura IL-10多态性与特发性血小板减少性紫癜易感性的关系
Pub Date : 2023-09-29 DOI: 10.1055/s-0043-1775558
Fatemeh Zeylabi, Mohammad Taha Jalali, Gholam-Abbas Kaydani, Kaveh Jaseb, Najmaldin Saki
Abstract Immune thrombocytopenic purpura (ITP) is an immune bleeding disorder that is reported in approximately 2 out of every 100,000 adults with a mean age of 50 years. Several factors such as various genetic backgrounds are associated with the pathogenesis of ITP. Interleukin (IL)-10 is a complicated cytokine that has a role in tumor progression, antitumor immunity, and immune system regulation. rs1800890 is an IL-10 single nucleotide polymorphism linked to lower levels of IL-10. A total of 67 patients with ITP and 70 healthy individuals (controls) were considered in this study. The IL-10 polymorphism was detected by the amplification refractory mutation system–polymerase chain reaction technique. According to our analysis, individual carriers of the AA genotype were less likely to develop ITP. The AT genotype was more common in patients with ITP in comparison to the control group. However, there was no significant association between rs1800890 genotypes (p = 0.775, odds ratio =1.517, 95%) in the acute and chronic groups. We observed that women had a higher mean frequency of this polymorphism (p = 0.0012). The rs1800890 AA genotype was associated with the highest platelet counts. However, the mean platelet volume and platelet distribution width values among alleles of the polymorphisms did not vary significantly. The IL-10 rs1800890 polymorphism may have a role in idiopathic thrombocytopenic purpura etiology. As a result, more research with a larger number of sample sizes is suggested.
免疫性血小板减少性紫癜(ITP)是一种免疫性出血性疾病,据报道,每10万成人中约有2例,平均年龄为50岁。多种遗传背景等因素与ITP的发病机制有关。白细胞介素(IL)-10是一种复杂的细胞因子,在肿瘤进展、抗肿瘤免疫和免疫系统调节中发挥作用。rs1800890是IL-10单核苷酸多态性,与较低水平的IL-10相关。本研究共纳入67例ITP患者和70例健康个体(对照)。采用扩增难解突变系统-聚合酶链反应技术检测IL-10多态性。根据我们的分析,单个AA基因型携带者发生ITP的可能性较小。与对照组相比,AT基因型在ITP患者中更为常见。然而,急性组和慢性组rs1800890基因型之间无显著相关性(p = 0.775,优势比=1.517,95%)。我们观察到女性具有更高的这种多态性的平均频率(p = 0.0012)。rs1800890 AA基因型与血小板计数最高相关。然而,多态性等位基因间血小板平均体积和血小板分布宽度值无显著差异。IL-10 rs1800890多态性可能在特发性血小板减少性紫癜病因学中起作用。因此,建议进行更多的研究,样本量更大。
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引用次数: 0
Novel Pathogenic DNAH5 Variants in Primary Ciliary Dyskinesia: Association with Visceral Heterotaxia and Neonatal Cholestasis. 原发性纤毛运动障碍的新型致病DNAH5变异:与内脏异位和新生儿胆汁淤积有关。
IF 0.4 Pub Date : 2023-09-01 DOI: 10.1055/s-0041-1733940
Hong T Lin, Anita Gupta, Kevin E Bove, Sara Szabo, Fang Xu, Anthony Krentz, Amelle L Shillington

The dynein axonemal heavy chain 5 gene codes for a subunit of axonemal dynein necessary for ciliary motor function. Though research has elucidated the consequences of some variants in this gene, it is still unclear whether many variants in the DNAH5 locus are benign or pathogenic due to the rarity of primary ciliary dyskinesia (PCD, of which Kartagener's syndrome is a subset). Here, we introduce the case of an infant boy presenting with the classical findings of PCD along with visceral heterotaxia and neonatal cholestasis. Genetic testing indicated that the patient is a compound heterozygote with a pathogenic c.8498G > A (known as pathogenic) on the maternally derived allele and two variants of uncertain significance, c.1206T > A and c.7800T > G, on the paternally derived allele. As PCD is autosomal recessive, we conclude that one, or both, of these paternally derived variants are pathogenic. To our knowledge, this is the first time that the clinical implications of c.1206T > A (p.Asn402Lys) and c.7800T > G (p.Ile2600Met) are documented. Furthermore, we use this case as an example to recommend clinicians to assess for PCD and laterality defects when presented with severe infantile cholestasis. While the association of cholestasis with PCD is relatively uncommon, PCD is a risk factor for increased prevalence of biliary atresia and infections, both of which are known causes of cholestasis in early infancy.

动力蛋白轴突重链5基因编码一个轴突动力蛋白亚基,是纤毛运动功能所必需的。尽管研究已经阐明了该基因的一些变异的后果,但由于原发性纤毛运动障碍(PCD, Kartagener综合征是其中的一个子集)的罕见性,尚不清楚DNAH5位点的许多变异是良性的还是致病的。在这里,我们介绍一个男婴的病例,表现为典型的PCD,同时伴有内脏异位和新生儿胆汁淤积。基因检测表明该患者为复合杂合子,母源性等位基因c.8498G > a(称为致病性),父源性等位基因c.1206T > a和c.7800T > G两个意义不确定的变异。由于PCD是常染色体隐性遗传,我们得出结论,一个,或两个,这些父亲衍生的变异是致病的。据我们所知,这是第一次记录c.1206T > A (p.Asn402Lys)和c.7800T > G (p.Ile2600Met)的临床意义。此外,我们以这个病例为例,建议临床医生在出现严重的婴儿胆汁淤积时评估PCD和侧侧缺陷。虽然胆汁淤积与PCD的关联相对不常见,但PCD是胆道闭锁和感染患病率增加的危险因素,这两种情况都是婴儿早期胆汁淤积的已知原因。
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引用次数: 0
Transient Neonatal Diabetes Mellitus and Seizure with an Unknown Etiology. 病因不明的新生儿短暂性糖尿病和癫痫发作。
IF 0.4 Pub Date : 2023-09-01 DOI: 10.1055/s-0041-1727175
Sevinc Odabasi Gunes, Erhan Calisici, Mutluay Arslan, Onur Akin, Belma Saygili Karagol

Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes, usually occurring in the first 6 months of life. Here, we present a newborn, which was admitted with epileptic seizure on the postnatal second day of life. Sepsis and meningitis were ruled out. Cranial imaging and electroencephalography revealed normal. She developed transient NDM on the follow-up and was diagnosed to carry an ABCC8 mutation. Although the neurological features are more common in patients with KCJN11 mutations, patients with ABCC8 mutations could also represent with subtle neurodevelopmental changes or even with epileptic seizures. The genetic testing and appropriate therapy is important in this patient group for predicting clinical course and possible additional features.

新生儿糖尿病(NDM)是一种单基因型糖尿病,通常发生在生命的前6个月。在这里,我们提出一个新生儿,这是入院与癫痫发作在出生后的第二天的生活。败血症和脑膜炎已被排除。颅脑显像及脑电图显示正常。她在随访中出现了短暂性NDM,并被诊断为携带ABCC8突变。尽管这些神经学特征在kcnn11突变患者中更为常见,但ABCC8突变患者也可能表现为微妙的神经发育变化,甚至癫痫发作。基因检测和适当的治疗对于预测临床过程和可能的其他特征是重要的。
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引用次数: 2
Infantile Systemic Hyalinosis Presenting as Pseudo-Paralysis in Infancy: Study of Six Cases. 以婴儿期假性麻痹表现的婴儿全身性透明质病6例分析。
IF 0.4 Pub Date : 2023-09-01 DOI: 10.1055/s-0041-1736558
Vykuntaraju K Gowda, Sahana M Srinivas, Priya Gupta, Varunvenkat M Srinivasan, Sanjay K Shivappa, Gurudatta B Vishwanathan

Infantile systemic hyalinosis is a very rare fatal autosomal recessive genetic disorder with a mutation in capillary morphogenesis gene-2- CMG2 /Human anthrax toxin-2 ANTXR2 resulting in spindle cell proliferation, altered collagen metabolism along with extensive deposition of hyaline material in the skin and several tissues. To date only a few cases have been reported in the literature, hence we reported this series. This study is a retrospective chart review of infants diagnosed with infantile systemic hyalinosis from January 2015 through December 2020 at a tertiary care children's hospital in South India. The mean age of presentation was 9.4 months, with a male to female ratio of 1:5. All children were born of consanguineous marriage except one child. All children had symptoms at birth, painful limb movements, multiple joint stiffness, gingival thickening, skin lesions around perianal, perioral areas, and frog-like position. Three (50%) children had stiff skin. Routine tests including complete blood count, liver function test, renal function test, creatine phosphokinase, nerve conduction studies, and metabolic tests were normal in all children. Skin biopsy showed hyalinized collagenous tissue in the dermis. Genetic study results of two cases revealed pathogenic variants in ANTXR2 gene. Infantile systemic hyalinosis should be considered in infants presenting with painful limb movements. The diagnosis helped in avoiding unnecessary investigations and prognostications. The genetic information from proband mutation helped in prenatal diagnosis in two families.

婴儿全身性透明质病是一种非常罕见的致命性常染色体隐性遗传病,毛细血管形态发生基因-2- CMG2 /人炭疽毒素-2 ANTXR2突变导致梭形细胞增殖,胶原代谢改变以及透明质物质在皮肤和一些组织中的广泛沉积。迄今为止,文献中仅报道了少数病例,因此我们报道了本系列。本研究是对印度南部一家三级儿童医院2015年1月至2020年12月诊断为婴儿全身性透明质病的婴儿进行回顾性图表回顾。平均发病年龄9.4个月,男女比例为1:5。除了一个孩子外,所有的孩子都是近亲结婚生的。所有患儿出生时均有症状,肢体运动疼痛,多关节僵硬,牙龈增厚,肛周、口周周围皮肤病变,体位呈蛙状。3例(50%)患儿皮肤僵硬。常规检查包括全血细胞计数、肝功能检查、肾功能检查、肌酸磷酸激酶、神经传导检查和代谢检查均正常。皮肤活检显示真皮内有透明胶原组织。2例病例的遗传分析结果显示ANTXR2基因存在致病性变异。出现肢体运动疼痛的婴儿应考虑为婴儿全身性透明质病。诊断有助于避免不必要的调查和预测。先证者突变的遗传信息有助于两个家庭的产前诊断。
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引用次数: 0
X-Linked Myotubular Myopathy: A Novel Mutation Expanding the Genotypic Spectrum of a Phenotypically Heterogeneous Myopathy. x连锁肌小管肌病:一种扩大表型异质性肌病基因型谱的新突变。
IF 0.4 Pub Date : 2023-09-01 DOI: 10.1055/s-0041-1728745
Andreia Carvalho, Carmen Costa, Miguel Pinto, Ricardo Taipa, Ana Gonçalves, Márcia E Oliveira, Sofia Ferreira, Joana Afonso Ribeiro

X-linked myotubular myopathy (XLMTM), a centronuclear congenital myopathy secondary to pathogenic variants in the MTM1 gene encoding myotubularin, is typically recognized for its classic and severe phenotype which includes neonatal hypotonia, severe muscle weakness, long-term ventilator dependence, markedly delayed gross motor milestones with inability to independently ambulate, and a high neonatal and childhood mortality. However, milder congenital forms of the condition and other phenotypes are recognized. We describe a 6-year-old boy with a mild XLMTM phenotype with independent gait and no respiratory insufficiency even in the neonatal period. The child has a hemizygous novel splice site variant in the MTM1 gene (c.232-25A > T) whose pathogenicity was confirmed by cDNA studies (exon 5 skipping) and muscle biopsy findings. We also compared the phenotype of our patient with the few reported cases that presented a mild XLMTM phenotype and no respiratory distress at birth, and discussed the potential mechanisms underlying this phenotype such as the presence of residual expression of the normal myotubularin transcript.

x连锁肌小管肌病(XLMTM)是一种继发于编码肌小管蛋白的MTM1基因致病性变异的核中心性先天性肌病,其典型的严重表型包括新生儿张力低下、严重肌肉无力、长期呼吸机依赖、明显延迟的大运动里程碑,无法独立行走,以及新生儿和儿童的高死亡率。然而,温和的先天性形式的条件和其他表型是公认的。我们描述了一个6岁的男孩与轻度XLMTM表型独立的步态,没有呼吸功能不全,甚至在新生儿期。该患儿MTM1基因(c.232-25A > T)具有半合子剪接位点变异,其致病性经cDNA研究(外显子5跳脱)和肌肉活检结果证实。我们还将该患者的表型与少数报道的出生时表现为轻度XLMTM表型且无呼吸窘迫的病例进行了比较,并讨论了这种表型的潜在机制,如正常肌小管蛋白转录物的残留表达。
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引用次数: 0
The Efficacy of Whole Genome Sequencing and RNA-Seq in the Diagnosis of Whole Exome Sequencing Negative Patients with Complex Neurological Phenotypes. 全基因组测序和RNA-Seq在复杂神经表型全外显子组测序阴性患者诊断中的作用
IF 0.4 Pub Date : 2023-09-01 DOI: 10.1055/s-0041-1736610
Bianca Blake, Lauren I Brady, Nicholas A Rouse, Peter Nagy, Mark A Tarnopolsky

Whole-genome sequencing (WGS) is being increasingly utilized for the diagnosis of neurological disease by sequencing both the exome and the remaining 98 to 99% of the genetic code. In addition to more complete coverage, WGS can detect structural variants (SVs) and intronic variants (SNVs) that cannot be identified by whole exome sequencing (WES) or chromosome microarray (CMA). Other multi-omics tools, such as RNA sequencing (RNA-Seq), can be used in conjunction with WGS to functionally validate certain variants by detecting changes in gene expression and splicing. The objective of this retrospective study was to measure the diagnostic yield of duo/trio-based WGS and RNA-Seq in a cohort of 22 patients (20 families) with pediatric onset neurological phenotypes and negative or inconclusive WES results in lieu of reanalysis. WGS with RNA-Seq resulted in a definite diagnosis of an additional 25% of cases. Sixty percent of these solved cases arose from the identification of variants that were missed by WES. Variants that could not be unequivocally proven to be causative of the patients' condition were identified in an additional 5% of cases.

全基因组测序(WGS)通过对外显子组和其余98%至99%的遗传密码进行测序,越来越多地用于神经系统疾病的诊断。除了更全面的覆盖范围外,WGS还可以检测全外显子组测序(WES)或染色体微阵列(CMA)无法识别的结构变异(SVs)和内含子变异(snv)。其他多组学工具,如RNA测序(RNA- seq),可以与WGS结合使用,通过检测基因表达和剪接的变化,从功能上验证某些变异。本回顾性研究的目的是在22名儿童发病神经表型患者(20个家庭)中测量基于二/三的WGS和RNA-Seq的诊断率,这些患者的WES结果为阴性或不确定,以代替重新分析。带有RNA-Seq的WGS对另外25%的病例进行了明确诊断。在这些已解决的病例中,有60%是由于发现了WES未发现的变异。在另外5%的病例中发现了不能明确证明是导致患者病情的变异。
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引用次数: 0
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Journal of pediatric genetics
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