Journal of Human Genetics最新文献_第7页

Functional analysis of novel and recurrent RINT1 variants in patients with infantile liver dysfunction 新生儿肝功能不全患者新型和复发性RINT1变异的功能分析。

IF 2.5 3区生物学 Q2 GENETICS & HEREDITY

Journal of Human Genetics

Pub Date : 2025-09-12 DOI: 10.1038/s10038-025-01404-3

Taiga Aoki, Ayano Inui, Yoshiyasu Ogata, Arisa Igarashi, Kumiko Yanagi, Masahiko Yamamori, Takaya Iida, Yoshihiro H. Inoue, Yoichi Matsubara, Tadashi Kaname

Rad50-interacting protein (RINT1) interacts with the endoplasmic reticulum (ER) tethering and SNARE complex, playing a central role in membrane trafficking and lipid metabolism. Loss-of-function variants of RINT1 have been related to episodic severe transaminitis with skeletal dysplasia or spastic paraplegia. We report two unrelated patients with recurrent markedly elevated aminotransferase triggered by fever, accompanied by coagulopathy and hyperammonemia. Liver biopsy revealed liver steatosis and bridging fibrosis in one patient, while the other displayed mild hepatocyte enlargement. Trio-whole-exome sequencing identified biallelic pathogenic RINT1 variants in the two patients. A novel missense variant [c.662 A > C, p.(His221Pro)] and a recurrent splice-site variant (c.1333+1 G > A) were identified in the first case. In the second case, a recurrent pathogenic RINT1 homozygous missense variant [c.1102 G > A, p.(Ala368Thr)] was identified. We investigated the pathogenicity of these variants through immunoprecipitation. Recombinant proteins produced from the mutant RINT1 transcript (p.His221Pro or p.Ala368Thr) displayed disrupted ER tether and SNARE interactions. Since the inhibition of ER-Golgi transport is associated with ER-stress activation, unfolded protein response (UPR)-related gene expression was investigated by qPCR. TIP20, a RINT1 homolog in Saccharomyces cerevisiae, is needed for autophagosome formation; therefore, an LC3-II turnover assay was performed and revealed disrupted autophagic flux. In addition, we created a fat-body-specific Rint1 knockdown in Drosophila. In the mutant larva, tissue atrophy and decreased lipid droplets in the fat body were observed. These results indicated that a loss of RINT1 function activated the UPR, impairs autophagy, and led to lipid storage abnormalities, contributing to the pathogenesis of liver disease.

rad50相互作用蛋白（RINT1）与内质网（ER）系结和SNARE复合物相互作用，在膜运输和脂质代谢中起核心作用。RINT1的功能丧失变体与偶发性严重转氨炎伴骨骼发育不良或痉挛性截瘫有关。我们报告了两例不相关的患者，由发热引起的转氨酶复发性明显升高，并伴有凝血功能障碍和高氨血症。肝活检显示1例肝脂肪变性和桥性纤维化，另1例肝细胞轻度增大。三全外显子组测序鉴定了两名患者的双等位致病RINT1变异。一种新的错义变体[c]。在第一个病例中发现了662 A > C, p.(His221Pro)]和一个复发剪接位点变异（C .1333+ 1g > A）。在第二种情况下，复发致病性RINT1纯合错义变异[c]。1102 G > A, p.(Ala368Thr)]。我们通过免疫沉淀研究了这些变异的致病性。由RINT1突变体转录本（p.His221Pro或p.p ala368thr）产生的重组蛋白显示ER系链和SNARE相互作用被破坏。由于er -高尔基转运的抑制与er -应激激活有关，我们利用qPCR研究了未折叠蛋白反应（UPR）相关基因的表达。TIP20是酿酒酵母中RINT1的同源物，是自噬体形成所必需的；因此，LC3-II转换实验显示自噬通量被破坏。此外，我们在果蝇中创建了脂肪体特异性Rint1敲低。突变体幼虫组织萎缩，脂肪体脂滴减少。这些结果表明，RINT1功能的缺失激活了UPR，损害了自噬，导致脂质储存异常，参与了肝病的发病机制。

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引用次数: 0

Whole exome sequencing in Japanese spinocerebellar ataxia identifies novel variants 日本脊髓小脑共济失调的全外显子组测序鉴定出新的变异。

IF 2.5 3区生物学 Q2 GENETICS & HEREDITY

Journal of Human Genetics

Pub Date : 2025-09-12 DOI: 10.1038/s10038-025-01405-2

Tomoaki Watanabe, Kodai Kume, Ken Inoue, Masataka Nakamura, Shinji Yamamoto, Takashi Kurashige, Tomohiko Ohshita, Taku Tazuma, Misako Kaido, Yuta Maetani, Hirofumi Maruyama, Hideshi Kawakami

Spinocerebellar degeneration (SCD) is a clinically and genetically diverse group, and the dominant form of SCD (AD-SCD) is generally referred to as spinocerebellar ataxia (SCA) that primarily affects the cerebellum. Some patients do not have a definitive genetic diagnosis but may carry unknown variants of known causative genes. Here, we screened for known SCA-associated genes in patients with suspected SCA. We examined 174 patients with SCA lacking abnormal repeat expansion of known causative genes. Whole-exome sequencing (WES) was performed to screen for variants in SCA-associated genes. The identified variants were confirmed by Sanger sequencing, and their pathogenicity was determined using five web-based algorithms. WES revealed novel single-nucleotide variants (SNVs) in three genes, ELOVL4, ELOVL5, and GRM1. Patients presented with symptoms other than cerebellar symptoms. One patient with an ELOVL4 variant exhibited skin changes, a typical symptom of ELOVL4 SCA, whereas the other ELOVL4 SCA patient had no skin changes and exhibited mild parkinsonism and calcification in the globus pallidus and dentate nucleus. The patient with an ELOVL5 variant exhibited bladder and rectal disturbances. Finally, patients with GRM1 variants showed few common features beyond the cerebellar symptoms. One patient showed white matter lesions, cognitive decline, and no-no head tremors, whereas the other showed spasticity. The identification of novel SNVs in these known SCA-associated genes will expand our understanding of the genetic landscape of SCA and facilitate the diagnosis of previously undiagnosed patients.

脊髓小脑变性（Spinocerebellar degeneration， SCD）是一种临床和遗传多样化的群体，SCD的主要形式（AD-SCD）通常被称为脊髓小脑性共济失调（Spinocerebellar ataxia， SCA），主要影响小脑。有些患者没有明确的遗传诊断，但可能携带已知致病基因的未知变异。在这里，我们在疑似SCA患者中筛选已知SCA相关基因。我们检查了174例缺乏已知致病基因异常重复扩增的SCA患者。采用全外显子组测序（WES）筛选sca相关基因的变异。通过Sanger测序确认鉴定的变异，并使用五种基于网络的算法确定其致病性。WES在ELOVL4、ELOVL5和GRM1三个基因中发现了新的单核苷酸变异（SNVs）。患者表现为小脑症状以外的症状。一名ELOVL4变异患者表现出皮肤变化，这是ELOVL4 SCA的典型症状，而另一名ELOVL4 SCA患者没有皮肤变化，表现出轻度帕金森病和苍白球和齿状核钙化。ELOVL5变异的患者表现出膀胱和直肠紊乱。最后，GRM1变异患者除了小脑症状外，几乎没有其他共同特征。一名患者表现为白质病变、认知能力下降和头部震颤，而另一名患者表现为痉挛。在这些已知SCA相关基因中发现新的snv将扩大我们对SCA遗传格局的理解，并有助于对以前未确诊的患者进行诊断。

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引用次数: 0

Germline pathogenic variants detected by GenMineTOP: insight from a nationwide tumor/normal paired comprehensive genomic profiling test, in Japan GenMineTOP检测的种系致病变异：来自日本全国肿瘤/正常配对综合基因组分析测试的见解。

IF 2.5 3区生物学 Q2 GENETICS & HEREDITY

Journal of Human Genetics

Pub Date : 2025-09-09 DOI: 10.1038/s10038-025-01389-z

Eri Habano, Miho Ogawa, Kousuke Watanabe, Nana Akiyama, Hyangri Chang, Mirei Ka, Aya Shinozaki-Ushiku, Masahiko Tanabe, Masakazu Akahori, Toshimitsu Ichijo, Shuichi Tsutsumi, Kenji Tatsuno, Hiroyuki Aburatani, Hidenori Kage, Katsutoshi Oda

Comprehensive genomic profiling (CGP) expands treatment options for solid tumor patients and identifies hereditary cancers. However, in Japan, confirmatory tests have been conducted in only 31.6% of patients with presumed germline pathogenic variants (GPVs) detected through tumor-only testing. Paired tumor-normal analysis enables differentiation between somatic and germline variants. GenMineTOP, covered by Japan’s national health insurance since August 2023, analyzes paired samples and reports GPVs in 40 genes. This study provides an initial characterization of GPVs based on clinical findings collected during the first year of GenMineTOP implementation. We analyzed 1356 solid tumor patients who underwent GenMineTOP testing in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database between August 2023 and July 2024, focusing on GPV detection rates, gene distribution, and comparisons with other CGP tests. Among the analyzed cancer types, GenMineTOP had a higher proportion of CNS/brain, soft tissue, bone, and head and neck cancers compared to other CGP tests. GPVs were detected in 73 patients (5.4%), with 38.2% classified as off-tumor. HR-related GPVs (ATM, BRCA1, BRCA2, BRIP1, PALB2, RAD51C, RAD51D) were found in both males (median age: 69) and females (median age: 54). Among males, 57.9% were aged 65 or older. GPVs may be detected in any cancer patients, including those with off-tumor findings, particularly in older male patients, especially in HR-related genes. These findings support the use of paired CGP to improve the diagnosis of hereditary cancers that could otherwise remain undetected.

综合基因组分析（CGP）扩大了实体瘤患者的治疗选择，并确定了遗传性癌症。然而，在日本，仅对31.6%通过肿瘤检测检测到的推定种系致病变异（GPVs）患者进行了确证性检测。配对肿瘤-正常分析可以区分体细胞和种系变异。GenMineTOP自2023年8月起被日本国民健康保险覆盖，分析配对样本并报告40个基因的gpv。这项研究基于GenMineTOP实施第一年收集的临床结果，提供了gpv的初步特征。我们分析了2023年8月至2024年7月期间在癌症基因组学和高级治疗中心（C-CAT）数据库中接受GenMineTOP检测的1356例实体瘤患者，重点关注GPV检出率、基因分布以及与其他CGP检测的比较。在分析的癌症类型中，与其他CGP测试相比，GenMineTOP在中枢神经系统/脑、软组织、骨骼和头颈部癌症中的比例更高。在73例（5.4%）患者中检测到gpv，其中38.2%归类为肿瘤外。hr相关gpv （ATM、BRCA1、BRCA2、BRIP1、PALB2、RAD51C、RAD51D）在男性（中位年龄：69岁）和女性（中位年龄：54岁）中均被发现。男性中，年龄在65岁及以上的占57.9%。gpv可以在任何癌症患者中检测到，包括那些肿瘤外的发现，特别是在老年男性患者中，特别是在hr相关基因中。这些发现支持使用配对CGP来改善遗传性癌症的诊断，否则这些癌症可能仍未被发现。

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引用次数: 0

Augmenting cost-effectiveness in clinical diagnosis using extended whole-exome sequencing: SNVs, SVs, and beyond 使用扩展全外显子组测序提高临床诊断的成本效益：snv， SVs等。

IF 2.5 3区生物学 Q2 GENETICS & HEREDITY

Journal of Human Genetics

Pub Date : 2025-09-08 DOI: 10.1038/s10038-025-01403-4

Fuyuki Miya, Daisuke Nakato, Hisato Suzuki, Mamiko Yamada, Daisuke Watanabe, Toshiki Takenouchi, Kenjiro Kosaki

In standard short-read whole-exome sequencing (WES), capture probes are typically designed to target the protein-coding regions (CDS), and regions outside the exons—except for adjacent intronic sequences—are rarely sequenced. Although the majority of known pathogenic variants reside within the CDS as nonsynonymous variants, some disease-causing variants are located in regions that are difficult to detect by WES alone, such as deep intronic variants and structural variants, often requiring whole-genome sequencing (WGS) for detection. Moreover, WES has limitations in reliably identifying pathogenic variants within mitochondrial DNA or repetitive regions. Here, we propose a strategy to improve the diagnostic yield in a cost-effective manner by expanding the target design of WES beyond the CDS. As an illustrative example, we experimentally validated an extended WES approach covering intronic and untranslated regions (UTRs) of 188 genes listed in the Japanese public health insurance-covered multiple gene testing, intronic and UTRs of 81 genes listed in ACMG Secondary Findings (SF) v3.2, and 70 repeat regions associated with diseases. Additionally, the entire mitochondrial genome was targeted. We demonstrate the coverage of these extended regions based on experimental data and present case examples in which previously diagnosed pathogenic variants located outside the CDS were successfully detected using this approach. This strategy enables a substantial increase in the chance of achieving a definitive diagnosis for patients using WES alone, without requiring WGS, at a cost comparable to conventional WES. Our method has the potential to significantly shorten the diagnostic odyssey and represents a valuable approach in clinical genomics.

在标准的短读全外显子组测序（WES）中，捕获探针通常被设计用于靶向蛋白质编码区（CDS），而外显子区域（除了相邻的内含子序列）很少被测序。虽然大多数已知的致病变异作为非同义变异存在于CDS中，但一些致病变异位于仅通过WES难以检测的区域，例如深层内含子变异和结构变异，通常需要全基因组测序（WGS）进行检测。此外，WES在可靠地识别线粒体DNA或重复区域内的致病变异方面存在局限性。在这里，我们提出了一种策略，通过将WES的目标设计扩展到CDS之外，以经济有效的方式提高诊断率。为了举例说明，我们通过实验验证了一种扩展的WES方法，该方法涵盖了日本公共健康保险覆盖的多基因检测中列出的188个基因的内含子和非翻译区（UTRs）， ACMG Secondary Findings (SF) v3.2中列出的81个基因的内含子和非翻译区，以及70个与疾病相关的重复区域。此外，整个线粒体基因组都是目标。我们根据实验数据证明了这些扩展区域的覆盖范围，并提出了使用这种方法成功检测到位于CDS外的先前诊断的致病变异的病例示例。这一策略大大增加了单独使用WES而不需要WGS的患者获得明确诊断的机会，其成本与传统WES相当。我们的方法具有显著缩短诊断过程的潜力，代表了临床基因组学的一种有价值的方法。

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引用次数: 0

Molecular genetics and therapeutic development for GNE myopathy. GNE肌病的分子遗传学和治疗进展。

IF 2.5 3区生物学 Q2 GENETICS & HEREDITY

Journal of Human Genetics

Pub Date : 2025-09-05 DOI: 10.1038/s10038-025-01398-y

Wakako Yoshioka, Satoru Noguchi, Ichizo Nishino

GNE myopathy is an autosomal recessive distal myopathy resulting from biallelic pathogenic variants in the GNE gene, a key enzyme in sialic acid biosynthesis. Although most pathogenic variants are missense variants, recent advances have enabled the identification of copy number variations, deep intronic variants, and regulatory changes in the promoter region, significantly enhancing diagnostic accuracy. Progress in genetic diagnostics now allows detection of rare and complex variants. Studies of founder variants in specific populations have clarified that certain GNE genotypes are associated with distinct clinical features and disease progression, deepening our understanding of genotype-phenotype relationships in GNE myopathy. The development of approved therapies, such as aceneuramic acid extended-release tablets, as well as ongoing multicenter Phase 2 trials of ManNAc and promising pilot studies of 6'-sialyllactose, underscore the importance of timely and comprehensive genetic diagnosis. Additional approaches, including antioxidant and gene therapies, are also under investigation. Since genetic testing is currently the sole definitive diagnostic approach, continued efforts to identify challenging or novel variants are essential to ensure all affected individuals receive an accurate diagnosis and access to emerging therapies. Advances in molecular genetics and diagnostics are paving the way for precision medicine and improved outcomes in GNE myopathy.

GNE肌病是一种常染色体隐性远端肌病，由唾液酸生物合成的关键酶GNE基因的双等位致病变异引起。虽然大多数致病变异是错义变异，但最近的进展已经能够识别拷贝数变异、深层内含子变异和启动子区域的调节变化，显著提高了诊断的准确性。遗传诊断的进步现在可以检测到罕见和复杂的变异。对特定人群中奠基者变异的研究表明，某些GNE基因型与不同的临床特征和疾病进展相关，加深了我们对GNE肌病基因型-表型关系的理解。已获批准的治疗方法的发展，如乙酰胆酸缓释片，以及正在进行的ManNAc多中心ii期试验和有希望的6'-唾液酰基乳糖试点研究，都强调了及时和全面的遗传诊断的重要性。包括抗氧化和基因治疗在内的其他方法也在研究中。由于基因检测是目前唯一确定的诊断方法，因此继续努力识别具有挑战性或新颖的变异对于确保所有受影响的个体获得准确的诊断和获得新兴疗法至关重要。分子遗传学和诊断学的进步为精确医学和改善GNE肌病的预后铺平了道路。

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引用次数: 0

Congenital disorders caused by aberrations in the biosynthesis of chondroitin/dermatan sulfate. 由软骨素/硫酸皮肤素生物合成异常引起的先天性疾病。

IF 2.5 3区生物学 Q2 GENETICS & HEREDITY

Journal of Human Genetics

Pub Date : 2025-09-02 DOI: 10.1038/s10038-025-01396-0

Tadahisa Mikami, Shuji Mizumoto, Hiroshi Kitagawa, Shuhei Yamada

Chondroitin sulfate (CS)/dermatan sulfate (DS) proteoglycans that play indispensable roles in multiple physiological processes, including cell proliferation, cell adhesion, development, neuronal guidance, and cartilage formation. Depletion of CS/DS caused by biosynthetic enzyme loss of function impairs these processes and results in embryonic lethality. However, some individuals with mutant enzymes survive and exhibit severe phenotypes. These rare hereditary diseases have been discovered and characterized in recent decades because of marked advances in next-generation sequencing technology. In this review, CS/DS-related inherited diseases caused by aberrations in both CS/DS backbone synthesis, as well as their sulfation and/or epimerization, are comprehensively summarized and their pathogenesis discussed.

硫酸软骨素(CS)/硫酸皮肤聚糖（DS）蛋白聚糖在细胞增殖、细胞粘附、发育、神经元引导和软骨形成等多种生理过程中发挥着不可或缺的作用。由生物合成酶功能丧失引起的CS/DS耗竭会损害这些过程并导致胚胎致死。然而，一些具有突变酶的个体存活下来并表现出严重的表型。近几十年来，由于下一代测序技术的显著进步，这些罕见的遗传性疾病已经被发现和表征。本文综述了由CS/DS主链合成异常及其硫酸化和/或外聚异构化引起的CS/DS相关遗传病的研究进展，并对其发病机制进行了探讨。

引用次数: 0

A novel MCMDC2 variant causes meiotic arrest and non-obstructive azoospermia in a consanguineous Chinese family 一种新的MCMDC2变异在一个近亲中国家庭中引起减数分裂停止和非阻塞性无精子症。

IF 2.5 3区生物学 Q2 GENETICS & HEREDITY

Journal of Human Genetics

Pub Date : 2025-09-02 DOI: 10.1038/s10038-025-01397-z

Qi Fang, Lanxi Ran, Song Liu, Jianyong Di, Ye Liu, Fengqin Xu, Binbin Wang

Non-obstructive azoospermia (NOA) is often associated with genetic variants. Whole-exome sequencing (WES) has emerged as a powerful tool in studying the genetic diagnosis of NOA and to help identify novel causal gene variants. Minichromosome maintenance domain-containing 2 (MCMDC2), an atypical yet conserved MCM protein, plays a key role in meiotic recombination and the maintenance of fertility. To date, only a limited number of MCMDC2 variants have been reported. The current study identified a novel deleterious variant (c.G226T/p.Val76Phe) of MCMDC2 by WES in a patient with NOA from a consanguineous Chinese family. Bioinformatics analysis indicated that the altered amino acid is highly conserved, and the c.G226T/p.Val76Phe variant may affect the structure and function of the MCMDC2 protein. Our results provide new insights into the underlying etiology of NOA in humans, further expanding the mutant spectrum of MCMDC2.

非阻塞性无精子症（NOA）通常与遗传变异有关。全外显子组测序（WES）已成为研究NOA遗传诊断和帮助识别新的致病基因变异的有力工具。小染色体维持结构域2 （MCMDC2）是一种非典型但保守的MCM蛋白，在减数分裂重组和维持生育能力中起关键作用。迄今为止，仅报道了有限数量的MCMDC2变异。目前的研究在来自中国近亲家庭的NOA患者中通过WES发现了MCMDC2的一种新的有害变异（c.G226T/p.Val76Phe）。生物信息学分析表明，改变的氨基酸具有高度保守性，c.G226T/p。Val76Phe变异可能影响MCMDC2蛋白的结构和功能。我们的研究结果为人类NOA的潜在病因提供了新的见解，进一步扩大了MCMDC2的突变谱。

引用次数: 0

MYH2-associated myopathy caused by novel compound heterozygous mutations: a case report and literature review 新型复合杂合突变引起的myh2相关肌病1例报告及文献复习

IF 2.5 3区生物学 Q2 GENETICS & HEREDITY

Journal of Human Genetics

Pub Date : 2025-09-01 DOI: 10.1038/s10038-025-01400-7

Yulai Kang, Tong Yang, Xue Chen, Zhuo Min, Chunhua Tang, Lili Zhang, Lu Guo

MYH2-associated myopathy is a group of congenital heterogeneous diseases. Case reports with MYH2-associated myopathy due to compound heterozygous mutations are rare. We report a 63-year-old Asian female who presented with bilateral ptosis and limb weakness for over 10 years. The orbits magnetic resonance imaging showed no abnormalities. Muscle biopsy revealed characteristics consistent with congenital neuromuscular disease with uniform type 1 fibers. Genetic testing identified compound heterozygous mutations in the MYH2 gene: a heterozygous mutation in exon 30, c.4066G>T (chr17:10430037, p.E1356X) and a heterozygous mutation in exon 38, c.5473-1G>A (chr17:10426730, splicing). The novel gene mutations are considered potential pathogenic variants. MYH2-associated myopathy was diagnosed. Following treatment with cytidine diphosphate choline, coenzyme Q10, methylcobalamin, and idebenone, her ocular symptoms showed slight improvement before discharge. This case highlights the importance of genetic testing in diagnosing rare myopathies and expands the genetic spectrum of MYH2-associated myopathy.

myh2相关肌病是一组先天性异质性疾病。病例报告与myh2相关的肌病由于复合杂合突变是罕见的。我们报告了一位63岁的亚洲女性，她表现为双侧上睑下垂和肢体无力超过10年。眼眶核磁共振未见异常。肌肉活检显示的特征与先天性神经肌肉疾病一致，1型纤维均匀。基因检测在MYH2基因中发现了复合杂合突变：外显子30 c.4066G> a杂合突变（chr17:10430037, p.E1356X）和外显子38 c.5473-1G> a杂合突变（chr17:10426730，剪接）。新的基因突变被认为是潜在的致病变异。诊断为myh2相关肌病。经胞苷二磷酸胆碱、辅酶Q10、甲基钴胺素和依地苯酮治疗，出院前眼部症状略有改善。本病例强调了基因检测在诊断罕见肌病中的重要性，并扩大了myh2相关肌病的遗传谱。

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引用次数: 0

Identification of two novel pathogenic mutations in the SKOR2 gene linked to cerebellar hypoplasia and a broad spectrum of neurodevelopmental delay in two Iranian families 鉴定与两个伊朗家庭小脑发育不全和广谱神经发育迟缓相关的两个新的SKOR2基因致病性突变。

IF 2.5 3区生物学 Q2 GENETICS & HEREDITY

Journal of Human Genetics

Pub Date : 2025-09-01 DOI: 10.1038/s10038-025-01399-x

Mohammad Ali Farazi Fard, Zahra Tabatabaei, Mobarakeh Ajam-Hosseini, Pooneh Nikuei, Fatemeh Gila, Farshid Parvini, Payman Jamali

SKOR2 is a transcriptional repressor expressed in central nervous system tissues, mainly in the Purkinje cells (PCs). This is essential for the proper migration, development, and differentiation of PCs at embryonic stages, and its disruption can affect cerebellar function. SKOR2 protein has two DHD and SAND domains, which play an important role in the TGF-β signaling pathway by binding to Smad transcriptional regulators. Herein, we report nine patients from two unrelated Iranian families suffering from a distinctive combination of learning disability, facial dysmorphisms, and motor and speech impairments. Whole exome sequencing (WES) was employed to identify pathogenic variants in the probands. Sanger sequencing was conducted to confirm the mutations found in the patients, their healthy parents, and relatives. A range of bioinformatics tools was utilized to assess the impact of the identified mutations on the function and structure of the related proteins. WES identified two novel missense (c.374 G > C: p.Arg125Pro) and frameshift (c.1271_1274del: p.K424Rfs*71) mutations in exon 2 of the SKOR2 gene. After segregation and in-silico studies, autosomal recessive inheritance and pathogenic nature of the identified mutation were confirmed. In addition, the studied patients had distinct phenotypes such as clumsiness, dysarthria, and severe hypotonia compared to previous studies, which we named Skor2-related syndrome. These findings indicated a novel SKOR2-related syndrome characterized by neurodevelopmental delay and ataxia. Our findings, given the limited previous studies on the SKOR2 gene, expanded the pathogenic mutations and phenotypic spectrum of SKOR2-associated disorders, provided criteria facilitating early diagnosis and supported genetic counseling for prognosis and family planning.

SKOR2是一种在中枢神经系统组织中表达的转录抑制因子，主要在浦肯野细胞（PCs）中表达。这对于PCs在胚胎阶段的正常迁移、发育和分化至关重要，其破坏会影响小脑功能。SKOR2蛋白具有两个DHD和SAND结构域，通过与Smad转录调控因子结合，在TGF-β信号通路中发挥重要作用。在此，我们报告了来自两个不相关的伊朗家庭的9名患者，他们患有学习障碍、面部畸形、运动和语言障碍的独特组合。采用全外显子组测序（WES）鉴定先证者的致病变异。进行Sanger测序以确认在患者、其健康父母和亲属中发现的突变。利用一系列生物信息学工具来评估鉴定的突变对相关蛋白的功能和结构的影响。WES在SKOR2基因的外显子2上发现了两个新的错义突变（C .374 G > C: p.a g125pro）和移码突变（C .1271_1274del: p.K424Rfs*71）。经过分离和芯片研究，证实了所鉴定突变的常染色体隐性遗传和致病性。此外，与以往的研究相比，研究的患者具有明显的表型，如笨拙，构音障碍和严重的张力低下，我们将其命名为skor2相关综合征。这些发现提示了一种以神经发育迟缓和共济失调为特征的新型skor2相关综合征。鉴于以往对SKOR2基因的研究有限，我们的研究结果扩大了SKOR2相关疾病的致病突变和表型谱，为早期诊断提供了标准，并为预后和计划生育提供了遗传咨询。

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引用次数: 0

Heterozygous PRDM9 truncating variant in a patient with primary ovarian insufficiency 原发性卵巢功能不全患者的杂合子PRDM9截断变异。

IF 2.5 3区生物学 Q2 GENETICS & HEREDITY

Journal of Human Genetics

Pub Date : 2025-08-29 DOI: 10.1038/s10038-025-01394-2

Abdelkader Heddar, Juliette Fievez, Radoslava Saraeva, Thibaut Benquey, Guillaume Jouret

引用次数: 0