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Genetic analysis of nephrogenic diabetes insipidus patients: A study on the Iranian population 肾源性糖尿病患者的遗传分析:对伊朗人口的研究
IF 2 4区 医学 Q4 GENETICS & HEREDITY Pub Date : 2024-04-15 DOI: 10.1002/mgg3.2421
Saeed Ghasemi, Marzieh Mojbafan, Saeed Talebi, Nakysa Hooman, Rozita Hoseini
Nephrogenic diabetes insipidus (NDI) is a rare genetic disease that causes water imbalance. The kidneys play a crucial role in regulating body fluids by controlling water balance through urine excretion. This highlights their essential function in managing the body's water levels, but individuals with NDI may have excess urine production (polyuria), that leads to excessive thirst (polydipsia). Untreated affected individuals may exhibit poor feeding and failure to thrive. This disease is caused by mutations in the AVPR2 and the AQP2 genes which have the X-linked and autosomal recessive/dominant inheritance, respectively. Both of these genes are expressed in the kidney.
肾源性糖尿病(NDI)是一种罕见的遗传疾病,会导致体内水分失衡。肾脏通过排泄尿液控制水分平衡,在调节体液方面发挥着至关重要的作用。这凸显了肾脏在管理体内水分含量方面的重要功能,但 NDI 患者可能会出现尿液分泌过多(多尿症),从而导致过度口渴(多饮症)。未经治疗的患者可能会表现出进食不良和无法茁壮成长。这种疾病是由 AVPR2 和 AQP2 基因突变引起的,这两种基因分别为 X 连锁遗传和常染色体隐性/显性遗传。这两个基因都在肾脏中表达。
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引用次数: 0
Congenital disorders of glycosylation with multiorgan disruption and immune dysregulation caused by compound heterozygous variants in MAN2B2 由MAN2B2复合杂合子变异引起的先天性糖基化紊乱,伴有多器官功能障碍和免疫功能失调
IF 2 4区 医学 Q4 GENETICS & HEREDITY Pub Date : 2024-04-15 DOI: 10.1002/mgg3.2422
Shiqi Fan, Huanhuan Wu, Rongrong Wang, Qian Chen, Xue Zhang
Congenital disorders of glycosylation (CDG) are a type of inborn error of metabolism (IEM) resulting from defects in glycan synthesis or failed attachment of glycans to proteins or lipids. One rare type of CDG is caused by homozygous or compound heterozygous loss-of-function variants in mannosidase alpha class 2B member 2 (MAN2B2). To date, only two cases of MAN2B2-CDG have been reported worldwide.
先天性糖基化紊乱(CDG)是一种先天性代谢错误(IEM),是由于聚糖合成缺陷或聚糖未能附着在蛋白质或脂质上造成的。一种罕见的 CDG 是由甘露糖苷酶α 2B 类成员 2(MAN2B2)的同基因或复合杂合功能缺失变异引起的。迄今为止,全世界仅报告了两例 MAN2B2-CDG 病例。
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引用次数: 0
Auriculocondylar syndrome 2 caused by a novel PLCB4 variant in a male Chinese neonate: A case report and review of the literature 一名中国男性新生儿因新型 PLCB4 变异导致的耳软骨综合征 2:病例报告和文献综述
IF 2 4区 医学 Q4 GENETICS & HEREDITY Pub Date : 2024-04-15 DOI: 10.1002/mgg3.2441
Yongli Zhang, Yuwei Zhao, Liying Dai, Yu Liu, Zifeng Shi
BackgroundAuriculocondylar syndrome (ARCND) is a rare congenital craniofacial developmental malformation syndrome of the first and second pharyngeal arches with external ear malformation at the junction between the lobe and helix, micromaxillary malformation, and mandibular condylar hypoplasia. Four subtypes of ARCND have been described so far, that is, ARCND1 (OMIM # 602483), ARCND2 (ARCND2A, OMIM # 614669; ARCND2B, OMIM # 620458), ARCND3 (OMIM # 615706), and ARCND4 (OMIM # 620457).MethodsThis study reports a case of ARCND2 resulting from a novel pathogenic variant in the PLCB4 gene, and summarizes PLCB4 gene mutation sites and phenotypes of ARCND2.ResultsThe proband, a 5‐day‐old male neonate, was referred to our hospital for respiratory distress. Micrognathia, microstomia, distinctive question mark ears, as well as mandibular condyle hypoplasia were identified. Trio‐based whole‐exome sequencing identified a novel missense variant of NM_001377142.1:c.1928C>T (NP_001364071.1:p.Ser643Phe) in the PLCB4 gene, which was predicted to impair the local structural stability with a result that the protein function might be affected. From a review of the literature, only 36 patients with PLCB4 gene mutations were retrieved.ConclusionAs with other studies examining familial cases of ARCND2, incomplete penetrance and variable expressivity were observed within different families' heterozygous mutations in PLCB4 gene. Although, motor and intellectual development are in the normal range in the vast majority of patients with ARCND2, long‐term follow‐up and assessment are still required.
背景咽喉髁状突综合征(ARCND)是一种罕见的先天性颅面发育畸形综合征,表现为第一和第二咽弓的外耳畸形、耳垂与螺旋交界处的外耳畸形、小颌畸形和下颌骨髁状突发育不良。目前已描述了四种亚型的 ARCND,即 ARCND1(OMIM # 602483)、ARCND2(ARCND2A,OMIM # 614669;ARCND2B,OMIM # 620458)、ARCND3(OMIM # 615706)和 ARCND4(OMIM # 620457)。方法本研究报告了一例由 PLCB4 基因新型致病变异导致的 ARCND2 病例,并总结了 PLCB4 基因的突变位点和 ARCND2 的表型。他患有小颌畸形、小口畸形、独特的问号耳以及下颌骨髁突发育不良。基于三重全外显子组测序确定了 PLCB4 基因中的一个新型错义变异 NM_001377142.1:c.1928C>T(NP_001364071.1:p.Ser643Phe),预计该变异会损害局部结构的稳定性,从而可能影响蛋白质的功能。结论 与其他研究 ARCND2 家族病例的结果一样,在不同家族的 PLCB4 基因杂合突变中观察到不完全的渗透性和不同的表达性。尽管绝大多数 ARCND2 患者的运动和智力发育均处于正常范围,但仍需进行长期随访和评估。
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引用次数: 0
RARS1‐related hypomyelinating leukodystrophy‐9 (HLD‐9) in two distinct Iranian families: Case report and literature review 两个不同伊朗家族中与 RARS1 相关的骨髓营养不良性白质营养不良症-9 (HLD-9):病例报告和文献综述
IF 2 4区 医学 Q4 GENETICS & HEREDITY Pub Date : 2024-04-15 DOI: 10.1002/mgg3.2435
Sajjad Biglari, Hassan Vahidnezhad, Mohammad Amin Tabatabaiefar, Hamid Reza Khorram Khorshid, Emran Esmaeilzadeh
BackgroundHypomyelinating leukodystrophy‐9 (HLD‐9) is caused by biallelic pathogenic variants in RARS1, which codes for the cytoplasmic tRNA synthetase for arginine (ArgRS). This study aims to evaluate the clinical, neuroradiological, and genetic characteristics of patients with RARS1‐related disease and determine probable genotype–phenotype relationships.MethodsWe identified three patients with RARS1 homozygous pathogenic variants. Furthermore, we performed a comprehensive review of the literature.ResultsHomozygous variants of RARS1 (c.2T>C (p.Met1Thr)) were identified in three patients with HLD‐9. Clinical symptoms were severe in all patients. Following the literature review, thirty HLD‐9 cases from eight studies were found. The 33 patients' main symptoms were hypomyelination, language delay, and intellectual disability or developmental delay. The mean age of onset for HLD9 in the group of 33 patients with a known age of onset was 5.8 months (SD = 8.1). The interquartile range of age of onset was 0–10 months. Of the 25 variants identified, c.5A>G (p.Asp2Gly) was identified in 11 patients.ConclusionPathogenic variants in RARS1 decrease ArgRS activity and cause a wide range of symptoms, from severe, early onset epileptic encephalopathy with brain atrophy to a mild condition with relatively maintained myelination. These symptoms include the classic hypomyelination presentation with nystagmus and spasticity. Furthermore, the pathogenicity of the variation c.2T>C (p.Met1Thr) has been shown.
背景骨髓营养不良性白质营养不良-9(HLD-9)是由RARS1的双倍性致病变体引起的,RARS1编码细胞质精氨酸tRNA合成酶(ArgRS)。本研究旨在评估 RARS1 相关疾病患者的临床、神经放射学和遗传学特征,并确定基因型与表型之间的可能关系。结果在三名 HLD-9 患者中发现了 RARS1 同源变体(c.2T>C (p.Met1Thr))。所有患者的临床症状都很严重。经过文献回顾,我们从 8 项研究中找到了 30 例 HLD-9 病例。这 33 例患者的主要症状是骨髓营养不良、语言发育迟缓、智力障碍或发育迟缓。在已知发病年龄的 33 例 HLD9 患者中,平均发病年龄为 5.8 个月(SD = 8.1)。发病年龄的四分位数范围为 0-10 个月。结论 RARS1 中的致病变体会降低 ArgRS 的活性并导致多种症状,从伴有脑萎缩的严重早发性癫痫性脑病到伴有相对维持的髓鞘化的轻症。这些症状包括伴有眼球震颤和痉挛的典型髓鞘功能减退表现。此外,c.2T>C(p.Met1Thr)变异的致病性已经得到证实。
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引用次数: 0
Reclassification of a spindle cell sarcoma after identification of a TFG-ROS1 fusion: A case demonstrating the clinical benefit of next-generation sequencing in sarcoma 发现 TFG-ROS1 融合后对纺锤细胞肉瘤进行重新分类:下一代测序技术在肉瘤临床治疗中的应用实例
IF 2 4区 医学 Q4 GENETICS & HEREDITY Pub Date : 2024-04-15 DOI: 10.1002/mgg3.2423
John J. Lim, Eleanor Y. Chen, Stephanie K. Schaub, Michael J. Wagner
Inflammatory myofibroblastic tumors (IMTs) are rare mesenchymal soft tissue sarcomas that often present diagnostic challenges due to their wide and varied morphology. A subset of IMTs have fusions involving ALK or ROS1. The role of next-generation sequencing (NGS) for classification of unselected sarcomas remains controversial.
炎性肌纤维母细胞瘤(IMT)是一种罕见的间叶软组织肉瘤,由于其形态广泛多样,常常给诊断带来困难。一部分 IMT 具有涉及 ALK 或 ROS1 的融合。下一代测序(NGS)在未经选择的肉瘤分类中的作用仍存在争议。
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引用次数: 0
Genotype and phenotype in patients with ACAN gene variants: Three cases and literature review ACAN 基因变异患者的基因型和表型:三个病例和文献综述
IF 2 4区 医学 Q4 GENETICS & HEREDITY Pub Date : 2024-04-13 DOI: 10.1002/mgg3.2439
Wei Tang, Ke‐Mi Wu, Qiong Zhou, Yan‐Fei Tang, Jun‐Fen Fu, Guan‐Ping Dong, Chao‐Chun Zou
ObjectiveTo characterize the phenotype spectrum, diagnosis, and response to growth‐promoting therapy in patients with ACAN variants causing familial short stature.MethodsThree families with ACAN variants causing short stature were reported. Similar cases in the literature were summarized, and the genotype and phenotype were analyzed.ResultsThree novel heterozygous variants, c.757+1G>A, (splicing), c.6229delG, p.(Asp2078Tfs*1), and c.6679C>T, p.(Gln2227*) in the ACAN gene were identified. A total of 314 individuals with heterozygous variants from 105 families and 8 individuals with homozygous variants from 4 families were confirmed to have ACAN variants from literature and our 3 cases. Including our 3 cases, the variants reported comprised 33 frameshift, 39 missense, 23 nonsense, 5 splicing, 4 deletion, and 1 translocation variants. Variation points are scattered throughout the gene, while exons 12, 15, and 10 were most common (25/105, 11/105, and 10/105, respectively). Some identical variants existing in different families could be hot variants, c.532A>T, p.(Asn178Tyr), c.1411C>T, p.(Gln471*), c.1608C>A, p.(Tyr536*), c.2026+1G>A, (splicing), and c.7276G>T, p.(Glu2426*). Short stature, early‐onset osteoarthritis, brachydactyly, midfacial hypoplasia, and early growth cessation were the common phenotypic features. The 48 children who received rhGH (and GnRHa) treatment had a significant height improvement compared with before (−2.18 ± 1.06 SD vs. −2.69 ± 0.95 SD, p < 0.001). The heights of children who received rhGH (and GnRHa) treatment were significantly improved compared with those of untreated adults (−2.20 ± 1.10 SD vs. −3.24 ± 1.14 SD, p < 0.001).ConclusionOur study achieves a new understanding of the phenotypic spectrum, diagnosis, and management of individuals with ACAN variants. No clear genotype–phenotype relationship of patients with ACAN variants was found. Gene sequencing is necessary to diagnose ACAN variants that cause short stature. In general, appropriate rhGH and/or GnRHa therapy can improve the adult height of affected pediatric patients caused by ACAN variants.
目的描述ACAN变异导致家族性身材矮小患者的表型谱、诊断和对促进生长治疗的反应。方法报告了三个ACAN变异导致身材矮小的家族。结果在 ACAN 基因中发现了 c.757+1G>A(剪接)、c.6229delG、p.(Asp2078Tfs*1) 和 c.6679C>T、p.(Gln2227*)三个新的杂合变异。共有来自105个家庭的314名杂合变异个体和来自4个家庭的8名同源变异个体从文献和我们的3个病例中被证实患有ACAN变异。包括我们的 3 个病例在内,报告的变异包括 33 个移框变异、39 个错义变异、23 个无义变异、5 个剪接变异、4 个缺失变异和 1 个易位变异。变异点散布在整个基因中,而外显子 12、15 和 10 最为常见(分别为 25/105、11/105 和 10/105)。不同家族中存在的一些相同变异可能是热变异,如 c.532A>T,p.(Asn178Tyr)、c.1411C>T,p.(Gln471*)、c.1608C>A,p.(Tyr536*)、c.2026+1G>A(剪接)和 c.7276G>T,p.(Glu2426*)。身材矮小、早发骨关节炎、手足畸形、中面部发育不全和早期生长停止是常见的表型特征。接受rhGH(和GnRHa)治疗的48名儿童的身高与治疗前相比有显著改善(-2.18 ± 1.06 SD vs. -2.69 ± 0.95 SD,p <0.001)。与未接受治疗的成人相比,接受 rhGH(和 GnRHa)治疗的儿童身高有明显改善(-2.20 ± 1.10 SD vs. -3.24 ± 1.14 SD,p < 0.001)。ACAN变体患者的基因型与表型之间没有明确的关系。要诊断导致身材矮小的 ACAN 变体,必须进行基因测序。一般来说,适当的rhGH和/或GnRHa疗法可改善由ACAN变异体引起的受影响儿童患者的成年身高。
{"title":"Genotype and phenotype in patients with ACAN gene variants: Three cases and literature review","authors":"Wei Tang, Ke‐Mi Wu, Qiong Zhou, Yan‐Fei Tang, Jun‐Fen Fu, Guan‐Ping Dong, Chao‐Chun Zou","doi":"10.1002/mgg3.2439","DOIUrl":"https://doi.org/10.1002/mgg3.2439","url":null,"abstract":"ObjectiveTo characterize the phenotype spectrum, diagnosis, and response to growth‐promoting therapy in patients with <jats:italic>ACAN</jats:italic> variants causing familial short stature.MethodsThree families with <jats:italic>ACAN</jats:italic> variants causing short stature were reported. Similar cases in the literature were summarized, and the genotype and phenotype were analyzed.ResultsThree novel heterozygous variants, c.757+1G&gt;A, (splicing), c.6229delG, p.(Asp2078Tfs*1), and c.6679C&gt;T, p.(Gln2227*) in the <jats:italic>ACAN</jats:italic> gene were identified. A total of 314 individuals with heterozygous variants from 105 families and 8 individuals with homozygous variants from 4 families were confirmed to have <jats:italic>ACAN</jats:italic> variants from literature and our 3 cases. Including our 3 cases, the variants reported comprised 33 frameshift, 39 missense, 23 nonsense, 5 splicing, 4 deletion, and 1 translocation variants. Variation points are scattered throughout the gene, while exons 12, 15, and 10 were most common (25/105, 11/105, and 10/105, respectively). Some identical variants existing in different families could be hot variants, c.532A&gt;T, p.(Asn178Tyr), c.1411C&gt;T, p.(Gln471*), c.1608C&gt;A, p.(Tyr536*), c.2026+1G&gt;A, (splicing), and c.7276G&gt;T, p.(Glu2426*). Short stature, early‐onset osteoarthritis, brachydactyly, midfacial hypoplasia, and early growth cessation were the common phenotypic features. The 48 children who received rhGH (and GnRHa) treatment had a significant height improvement compared with before (−2.18 ± 1.06 SD vs. −2.69 ± 0.95 SD, <jats:italic>p</jats:italic> &lt; 0.001). The heights of children who received rhGH (and GnRHa) treatment were significantly improved compared with those of untreated adults (−2.20 ± 1.10 SD vs. −3.24 ± 1.14 SD, <jats:italic>p</jats:italic> &lt; 0.001).ConclusionOur study achieves a new understanding of the phenotypic spectrum, diagnosis, and management of individuals with <jats:italic>ACAN</jats:italic> variants. No clear genotype–phenotype relationship of patients with <jats:italic>ACAN</jats:italic> variants was found. Gene sequencing is necessary to diagnose <jats:italic>ACAN</jats:italic> variants that cause short stature. In general, appropriate rhGH and/or GnRHa therapy can improve the adult height of affected pediatric patients caused by <jats:italic>ACAN</jats:italic> variants.","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"19 1","pages":""},"PeriodicalIF":2.0,"publicationDate":"2024-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140594487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Further delineation of phenotype and genotype of Kenny–Caffey syndrome type 2 (phenotype and genotype of KCS type 2) 进一步确定肯尼-卡菲综合征 2 型的表型和基因型(肯尼-卡菲综合征 2 型的表型和基因型)
IF 2 4区 医学 Q4 GENETICS & HEREDITY Pub Date : 2024-04-09 DOI: 10.1002/mgg3.2433
Xuefei Chen, Chaochun Zou
BackgroundKenny–Caffey syndrome type 2 (KCS2) is an extremely rare inherited disorder characterized by proportionate short stature, skeletal defects, ocular and dental abnormalities, and transient hypocalcemia. It is caused by variants in FAM111A gene. Diagnosis of KCS2 can be challenging because of its similarities to other syndromes, the absence of clear hallmarks and the deficient number of genetically confirmed cases. Here, we aimed to further delineate and summarize the genotype and phenotype of KCS2, in order to get a better understanding of this rare disorder, and promote early diagnosis and intervention.MethodsWe present clinical and genetic characteristics of eight newly affected individuals with KCS2 from six families, including one family with three individuals found to be a father‐to‐daughter transmission, adding to the limited literature. Furthermore, we performed a review of genetically confirmed KCS2 cases in PubMed, MEDLINE and CNKI databases.ResultsThere were six females and two males in our cohort. All the patients presented with short stature (100.0%). Clinical manifestations included ocular defects such as hypermetropia (5/8), dental problems such as defective dentition (3/8) and dental caries (3/8), skeletal and brain anomalies such as delayed closure of anterior fontanelle (6/8), cerebral calcification (3/8), cortical thickening (3/8) and medullary stenosis (4/8) of tubular bones. Endocrinologic abnormalities included hypoparathyroidism (5/8) and hypocalcemia (3/8). One male patient had micropenis and microorchidism. All cases harboured missense variants of FAM111A, and nucleotides c.1706 arose as a mutational hotspot, with seven individuals harbouring a c.1706G>A (p.Arg569His) variant, and one child harbouring a c.1531T>C (p.Tyr511His) variant. Literature review yielded a total of 46 patients from 20 papers. Data analysis showed that short stature, hypoparathyroidism and hypocalcemia, ocular and dental defects, skeletal features including cortical thickening and medullary stenosis of tubular bones, and seizures/spasms were present in more than 70% of the reported KCS2 cases.ConclusionWe provide detailed characteristics of the largest KCS2 group in China and present the first genetically confirmed instance of father‐to‐daughter transmission of KCS2. Our study confirms that Arg569His is the hot spot variant and summarizes the typical phenotypes of KCS2, which would help early diagnosis and intervention.
背景肯尼-卡菲综合征 2 型(KCS2)是一种极其罕见的遗传性疾病,以身材矮小、骨骼缺陷、眼部和牙齿异常以及一过性低钙血症为特征。它是由 FAM111A 基因变异引起的。由于 KCS2 与其他综合征相似,缺乏明确的特征,且遗传学确诊病例数量不足,因此诊断 KCS2 具有挑战性。在此,我们旨在进一步描述和总结 KCS2 的基因型和表型,以便更好地了解这种罕见疾病,促进早期诊断和干预。方法我们介绍了来自 6 个家庭的 8 名新患 KCS2 患者的临床和遗传特征,其中一个家庭的 3 名患者被发现是父女相传,为有限的文献资料增添了新的内容。此外,我们还查阅了 PubMed、MEDLINE 和 CNKI 数据库中经基因证实的 KCS2 病例。所有患者均表现为身材矮小(100.0%)。临床表现包括眼部缺陷(5/8)、牙齿问题(3/8)和龋齿(3/8)、骨骼和大脑异常(6/8)、大脑钙化(3/8)、皮质增厚(3/8)和管状骨髓狭窄(4/8)。内分泌异常包括甲状旁腺功能减退(5/8)和低钙血症(3/8)。一名男性患者患有小阴茎和小睾丸症。所有病例均携带FAM111A的错义变异,c.1706核苷酸是突变热点,其中7人携带c.1706G>A(p.Arg569His)变异,1名儿童携带c.1531T>C(p.Tyr511His)变异。文献综述共收集到 20 篇论文中的 46 名患者。数据分析显示,70%以上的KCS2病例存在身材矮小、甲状旁腺功能减退和低钙血症、眼部和牙齿缺陷、骨骼特征(包括皮质增厚和管状骨髓状狭窄)以及癫痫发作/痉挛。我们的研究证实 Arg569His 是热点变异,并总结了 KCS2 的典型表型,这将有助于早期诊断和干预。
{"title":"Further delineation of phenotype and genotype of Kenny–Caffey syndrome type 2 (phenotype and genotype of KCS type 2)","authors":"Xuefei Chen, Chaochun Zou","doi":"10.1002/mgg3.2433","DOIUrl":"https://doi.org/10.1002/mgg3.2433","url":null,"abstract":"BackgroundKenny–Caffey syndrome type 2 (KCS2) is an extremely rare inherited disorder characterized by proportionate short stature, skeletal defects, ocular and dental abnormalities, and transient hypocalcemia. It is caused by variants in <jats:italic>FAM111A</jats:italic> gene. Diagnosis of KCS2 can be challenging because of its similarities to other syndromes, the absence of clear hallmarks and the deficient number of genetically confirmed cases. Here, we aimed to further delineate and summarize the genotype and phenotype of KCS2, in order to get a better understanding of this rare disorder, and promote early diagnosis and intervention.MethodsWe present clinical and genetic characteristics of eight newly affected individuals with KCS2 from six families, including one family with three individuals found to be a father‐to‐daughter transmission, adding to the limited literature<jats:italic>.</jats:italic> Furthermore, we performed a review of genetically confirmed KCS2 cases in PubMed, MEDLINE and CNKI databases.ResultsThere were six females and two males in our cohort. All the patients presented with short stature (100.0%). Clinical manifestations included ocular defects such as hypermetropia (5/8), dental problems such as defective dentition (3/8) and dental caries (3/8), skeletal and brain anomalies such as delayed closure of anterior fontanelle (6/8), cerebral calcification (3/8), cortical thickening (3/8) and medullary stenosis (4/8) of tubular bones. Endocrinologic abnormalities included hypoparathyroidism (5/8) and hypocalcemia (3/8). One male patient had micropenis and microorchidism. All cases harboured missense variants of <jats:italic>FAM111A</jats:italic>, and nucleotides c.1706 arose as a mutational hotspot, with seven individuals harbouring a c.1706G&gt;A (p.Arg569His) variant, and one child harbouring a c.1531T&gt;C (p.Tyr511His) variant. Literature review yielded a total of 46 patients from 20 papers. Data analysis showed that short stature, hypoparathyroidism and hypocalcemia, ocular and dental defects, skeletal features including cortical thickening and medullary stenosis of tubular bones, and seizures/spasms were present in more than 70% of the reported KCS2 cases.ConclusionWe provide detailed characteristics of the largest KCS2 group in China and present the first genetically confirmed instance of father‐to‐daughter transmission of KCS2. Our study confirms that Arg569His is the hot spot variant and summarizes the typical phenotypes of KCS2, which would help early diagnosis and intervention.","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"19 1","pages":""},"PeriodicalIF":2.0,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140594327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The clinical value of optical genome mapping in the rapid characterization of RB1 duplication and 15q23q24.2 triplication, for more appropriate prenatal genetic counselling 光学基因组图谱在快速鉴定 RB1 复制和 15q23q24.2 三重复制方面的临床价值,以提供更适当的产前遗传咨询
IF 2 4区 医学 Q4 GENETICS & HEREDITY Pub Date : 2024-04-08 DOI: 10.1002/mgg3.2437
Malek Bouassida, Denise Molina‐Gomes, Fairouz Koraichi, Bérénice Hervé, Morgane Lhuilier, Clémence Duvillier, Jessica Le Gall, Marion Gauthier‐Villars, Valérie Serazin, Thibaud Quibel, Rodolphe Dard, François Vialard
BackgroundDespite recent advances in prenatal genetic diagnosis, medical geneticists still face considerable difficulty in interpreting the clinical outcome of copy‐number‐variant duplications and defining the mechanisms underlying the formation of certain chromosomal rearrangements.Optical genome mapping (OGM) is an emerging cytogenomic tool with proved ability to identify the full spectrum of cytogenetic aberrations.MethodsHere, we report on the use of OGM in a prenatal diagnosis setting. Detailed breakpoint mapping was used to determine the relative orientations of triplicated and duplicated segments in two unrelated foetuses harbouring chromosomal aberrations: a de novo 15q23q24.2 triplication and a paternally inherited 13q14.2 duplication that overlapped partially with the RB1 gene.ResultsOGM enabled us to suggest a plausible mechanism for the triplication and confirmed that the RB1 duplication was direct oriented and in tandem. This enabled us to predict the pathogenic consequences, refine the prognosis and adapt the follow‐up and familial screening appropriately.ConclusionAlong with an increase in diagnostic rates, OGM can rapidly highlight genotype–phenotype correlations, improve genetic counselling and significantly influence prenatal management.
背景尽管产前基因诊断取得了最新进展,但医学遗传学家在解释拷贝数变异重复的临床结果和确定某些染色体重排的形成机制方面仍面临相当大的困难。方法在此,我们报告了在产前诊断中使用光学基因组测绘(OGM)的情况。我们利用详细的断点图谱确定了两个无血缘关系胎儿染色体畸变的三倍段和重复段的相对方向:一个是新发的 15q23q24.2 三倍段,另一个是父系遗传的 13q14.2 重复段,该重复段与 RB1 基因部分重叠。结果OGM 使我们能够提出三倍段的合理机制,并证实 RB1 重复段是直接定向和串联的。结论随着诊断率的提高,OGM 可以迅速突出基因型与表型的相关性,改善遗传咨询,并对产前管理产生重大影响。
{"title":"The clinical value of optical genome mapping in the rapid characterization of RB1 duplication and 15q23q24.2 triplication, for more appropriate prenatal genetic counselling","authors":"Malek Bouassida, Denise Molina‐Gomes, Fairouz Koraichi, Bérénice Hervé, Morgane Lhuilier, Clémence Duvillier, Jessica Le Gall, Marion Gauthier‐Villars, Valérie Serazin, Thibaud Quibel, Rodolphe Dard, François Vialard","doi":"10.1002/mgg3.2437","DOIUrl":"https://doi.org/10.1002/mgg3.2437","url":null,"abstract":"BackgroundDespite recent advances in prenatal genetic diagnosis, medical geneticists still face considerable difficulty in interpreting the clinical outcome of copy‐number‐variant duplications and defining the mechanisms underlying the formation of certain chromosomal rearrangements.Optical genome mapping (OGM) is an emerging cytogenomic tool with proved ability to identify the full spectrum of cytogenetic aberrations.MethodsHere, we report on the use of OGM in a prenatal diagnosis setting. Detailed breakpoint mapping was used to determine the relative orientations of triplicated and duplicated segments in two unrelated foetuses harbouring chromosomal aberrations: a de novo 15q23q24.2 triplication and a paternally inherited 13q14.2 duplication that overlapped partially with the <jats:italic>RB1</jats:italic> gene.ResultsOGM enabled us to suggest a plausible mechanism for the triplication and confirmed that the <jats:italic>RB1</jats:italic> duplication was direct oriented and <jats:italic>in tandem</jats:italic>. This enabled us to predict the pathogenic consequences, refine the prognosis and adapt the follow‐up and familial screening appropriately.ConclusionAlong with an increase in diagnostic rates, OGM can rapidly highlight genotype–phenotype correlations, improve genetic counselling and significantly influence prenatal management.","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"53 1","pages":""},"PeriodicalIF":2.0,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140594510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A case of polyglucosan body myopathy caused by an RBCK1 gene variant and literature review 一例由 RBCK1 基因变异引起的多葡聚糖体肌病及文献综述
IF 2 4区 医学 Q4 GENETICS & HEREDITY Pub Date : 2024-04-08 DOI: 10.1002/mgg3.2432
Qiqing Sun, Zhenhua Xie, Lifang Song, Dapeng Fu
ObjectiveTo analyze the clinical and genetic characteristics of a patient with Polyglucosan body myopathy 1 (PGBM1) caused by a novel compound heterozygous variant in the RBCK1 gene.MethodsThe clinical data of the patient were collected, next‐generation sequencing technology was used to determine the exome sequence of the patient, and the suspected pathogenic locus was verified by Sanger sequencing.ResultsThrough whole‐exome sequencing, we found that there were c.919G>T; p. (Glu307*) and c.723_730dup; p. (Glu244fs) variants of the RBCK1 gene in the patient, inherited from his parents, constituting a compound heterozygous variation. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the two variants were rated as pathogenic, but there were no comparable cases. Previous literature reported 24 patients with RBCK1 gene variants, involving a total of 20 myocardial and 18 skeletal muscle cases.ConclusionsThe patient was twice diagnosed with cardiac insufficiency, neglecting the usual manifestations of muscle weakness, resulting in misdiagnosis. Later, novel variants in the RBCK1 gene were discovered through whole‐exome sequencing, and symptomatic treatment was given after diagnosis. The importance of whole‐exome sequencing technology in disease diagnosis and genetic counseling was emphasized.
方法 收集患者的临床资料,利用新一代测序技术测定患者的外显子组序列,并通过 Sanger 测序验证疑似致病位点。G>T;p.(Glu307*)和 c.723_730dup;p.(Glu244fs)变异,构成复合杂合变异。根据美国医学遗传学和基因组学学会(ACMG)的指南,这两个变异被评为致病性变异,但没有可比病例。结论该患者两次被诊断为心功能不全,忽视了肌无力的通常表现,导致误诊。后来,通过全外显子组测序发现了 RBCK1 基因的新型变异,并在确诊后给予了对症治疗。会议强调了全外显子组测序技术在疾病诊断和遗传咨询中的重要性。
{"title":"A case of polyglucosan body myopathy caused by an RBCK1 gene variant and literature review","authors":"Qiqing Sun, Zhenhua Xie, Lifang Song, Dapeng Fu","doi":"10.1002/mgg3.2432","DOIUrl":"https://doi.org/10.1002/mgg3.2432","url":null,"abstract":"ObjectiveTo analyze the clinical and genetic characteristics of a patient with Polyglucosan body myopathy 1 (PGBM1) caused by a novel compound heterozygous variant in the <jats:italic>RBCK1</jats:italic> gene.MethodsThe clinical data of the patient were collected, next‐generation sequencing technology was used to determine the exome sequence of the patient, and the suspected pathogenic locus was verified by Sanger sequencing.ResultsThrough whole‐exome sequencing, we found that there were c.919G&gt;T; p. (Glu307*) and c.723_730dup; p. (Glu244fs) variants of the <jats:italic>RBCK1</jats:italic> gene in the patient, inherited from his parents, constituting a compound heterozygous variation. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the two variants were rated as pathogenic, but there were no comparable cases. Previous literature reported 24 patients with <jats:italic>RBCK1</jats:italic> gene variants, involving a total of 20 myocardial and 18 skeletal muscle cases.ConclusionsThe patient was twice diagnosed with cardiac insufficiency, neglecting the usual manifestations of muscle weakness, resulting in misdiagnosis. Later, novel variants in the <jats:italic>RBCK1</jats:italic> gene were discovered through whole‐exome sequencing, and symptomatic treatment was given after diagnosis. The importance of whole‐exome sequencing technology in disease diagnosis and genetic counseling was emphasized.","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"50 1","pages":""},"PeriodicalIF":2.0,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140594515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Autism spectrum disorder profiles in RASopathies: A systematic review RAS病的自闭症谱系障碍特征:系统综述
IF 2 4区 医学 Q4 GENETICS & HEREDITY Pub Date : 2024-04-06 DOI: 10.1002/mgg3.2428
Edward Debbaut, Jean Steyaert, Mouna El Bakkali
BackgroundRASopathies are associated with an increased risk of autism spectrum disorder (ASD). For neurofibromatosis type 1 (NF1) there is ample evidence for this increased risk, while for other RASopathies this association has been studied less. No specific ASD profile has been delineated so far for RASopathies or a specific RASopathy individually.MethodsWe conducted a systematic review to investigate whether a specific RASopathy is associated with a specific ASD profile, or if RASopathies altogether have a distinct ASD profile compared to idiopathic ASD (iASD). We searched PubMed, Web of Science, and Open Grey for data about ASD features in RASopathies and potential modifiers.ResultsWe included 41 articles on ASD features in NF1, Noonan syndrome (NS), Costello syndrome (CS), and cardio‐facio‐cutaneous syndrome (CFC). Individuals with NF1, NS, CS, and CFC on average have higher ASD symptomatology than healthy controls and unaffected siblings, though less than people with iASD. There is insufficient evidence for a distinct ASD phenotype in RASopathies compared to iASD or when RASopathies are compared with each other. We identified several potentially modifying factors of ASD symptoms in RASopathies.ConclusionsOur systematic review found no convincing evidence for a specific ASD profile in RASopathies compared to iASD, or in a specific RASopathy compared to other RASopathies. However, we identified important limitations in the research literature which may also account for this result. These limitations are discussed and recommendations for future research are formulated.
背景RAS病与自闭症谱系障碍(ASD)风险增加有关。对于 1 型神经纤维瘤病 (NF1),有大量证据表明这种风险会增加,而对于其他 RAS 病,这种关联的研究较少。我们进行了一项系统性综述,以研究特定的 RAS 病是否与特定的 ASD 特征相关,或者与特发性 ASD(iASD)相比,RAS 病是否具有独特的 ASD 特征。我们在PubMed、Web of Science和Open Grey上搜索了有关RAS病的ASD特征和潜在修饰因素的数据。结果我们收录了41篇有关NF1、努南综合征(NS)、科斯特罗综合征(CS)和心-面-皮肤综合征(CFC)的ASD特征的文章。NF1、NS、CS和CFC患者的ASD症状平均高于健康对照组和未受影响的兄弟姐妹,但低于iASD患者。目前还没有足够的证据表明,与iASD相比,或当RAS病相互比较时,RAS病具有独特的ASD表型。结论我们的系统综述没有发现令人信服的证据表明,与 iASD 相比,或与其他 RAS 病相比,RAS 病具有特定的 ASD 特征。不过,我们也发现了研究文献中的一些重要局限性,这些局限性也可能是造成这一结果的原因。我们对这些局限性进行了讨论,并为今后的研究提出了建议。
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Molecular Genetics & Genomic Medicine
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