Journal of Human Genetics最新文献_第10页

Compound heterozygous variants of CACNA1H change channel properties and contribute to intractable epilepsy with myoclonic-atonic seizures CACNA1H的复合杂合变异体改变通道性质，有助于顽固性癫痫伴肌阵挛性失张力发作。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-11-22 DOI: 10.1038/s10038-025-01434-x

Ayumi Matsumoto, Go Kasuya, Suvd Tumurbaatar, Takuya Masuda, Kei Wakabayashi, Masako Kawada, Yasutomi Higashikuni, Kazuhiro Muramatsu, Koichi Nakajo, Hitoshi Osaka, Takayoshi Matsumura

{"title":"Compound heterozygous variants of CACNA1H change channel properties and contribute to intractable epilepsy with myoclonic-atonic seizures","authors":"Ayumi Matsumoto, Go Kasuya, Suvd Tumurbaatar, Takuya Masuda, Kei Wakabayashi, Masako Kawada, Yasutomi Higashikuni, Kazuhiro Muramatsu, Koichi Nakajo, Hitoshi Osaka, Takayoshi Matsumura","doi":"10.1038/s10038-025-01434-x","DOIUrl":"10.1038/s10038-025-01434-x","url":null,"abstract":"The CACNA1H gene, which encodes the T-type calcium channel Cav3.2, is known to confer susceptibility to childhood absence epilepsy (CAE) and has been implicated in various neurological disorders. However, its pathogenic significance, especially in childhood intractable epilepsies, has not been comprehensively explored. We performed whole-exome sequencing on a 4-year-old boy diagnosed with epilepsy with myoclonic–atonic seizures (EMAtS), and identified two missense variants in CACNA1H. One was a novel variant, p.D949H, inherited from the father, while the other was a known variant, p.R788C, inherited from the mother. Because the latter was previously reported to alter Cav3.2 channel function and contribute to the pathogenesis of CAE and idiopathic generalized epilepsy, we evaluated the former’s functional impact using two-electrode voltage clamp analysis in Xenopus laevis oocytes. While the current–voltage relationship of the D949H mutant channel was not significantly different from that of the wild-type channel, the time constant of recovery from inactivation was significantly prolonged in the D949H variant (671.7 ± 52.0 ms vs. 455.5 ± 28.2 ms), indicating moderately impaired properties of the mutant. Notably, neither the D949H nor the R788C variant was associated with epilepsy in either parent, suggesting that these variants were not sufficient to cause epilepsy on their own, and that the compound heterozygous state of CACNA1H contributed to the EMAtS phenotype in the proband. Our findings highlight the genetic complexity of EMAtS and underscore the importance of accumulated functional impacts of modifier variants in severe epileptic diseases, even when individual variants are not pathogenic.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 5","pages":"255-263"},"PeriodicalIF":2.5,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exploring socio-economic, biochemical, and genetic factors influencing thyroid status in Indian school-going adolescents 探讨影响印度学龄青少年甲状腺状况的社会经济、生化和遗传因素。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-11-17 DOI: 10.1038/s10038-025-01432-z

Janaki M. Nair, Khushdeep Bandesh, Anil K. Giri, Raman K. Marwaha, Analabha Basu, Nikhil Tandon, Shraddha Chakraborty, Dwaipayan Bharadwaj

{"title":"Exploring socio-economic, biochemical, and genetic factors influencing thyroid status in Indian school-going adolescents","authors":"Janaki M. Nair, Khushdeep Bandesh, Anil K. Giri, Raman K. Marwaha, Analabha Basu, Nikhil Tandon, Shraddha Chakraborty, Dwaipayan Bharadwaj","doi":"10.1038/s10038-025-01432-z","DOIUrl":"10.1038/s10038-025-01432-z","url":null,"abstract":"Thyroid hormones are central to regulating metabolism, growth, and development, yet their complex interactions with socioeconomic, metabolic, and genetic factors remain understudied in diverse populations. We compared thyroid profiles - free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) in Indian adolescents with anthropometric traits, metabolic markers, and socioeconomic status (SES). We observed that adolescents from higher SES backgrounds exhibited greater metabolic dysregulation, altered thyroid profiles, and abnormalities in lipid and adipokine levels. Subclinical (16.1%) and clinical hypothyroidism (1.1%) were found to be prevalent in this population but were not associated with obesity. Instead, they showed links with dyslipidemia and altered adipokine profiles. To investigate the genetic basis of thyroid traits, we conducted an exome-wide association study (ExWAS, N = 4324), and a two-staged genome-wide association study (GWAS, N = 4854). The ExWAS revealed two novel loci for TSH (GYS2 and CEP162) and fifteen novel loci for FT4, including ZNF467, P3H3, CRLF3, SPATA2L, MEFV, THNSL2, COL27A1, COL28A1, IGSF3, ZNF732, MOG, GABBR1, HPF1, LOC440563, and SPEG. The GWAS identified novel associations at near-genome-wide significance for TSH (ACTL7B) and FT4 (LINC00648, YTHDC1, and C2CD4B). We also replicated established associations in FOXE1 and IGFBP5. Our findings suggest that SES, metabolic health, and genetics jointly influence thyroid function in Indian adolescents. The identification of population-specific loci emphasizes the importance of ancestry-informed genetic studies and supports the development of precision interventions to enhance pediatric thyroid health.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 5","pages":"245-253"},"PeriodicalIF":2.5,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145540974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Biallelic variants in TNR cause neurodevelopmental disorders with variable expressivity TNR的双等位基因变异引起具有可变表达性的神经发育障碍。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-11-13 DOI: 10.1038/s10038-025-01431-0

Atsuhiro Ozaki, Masamune Sakamoto, Satoko Kumada, Keisuke Hamada, Kazuhiro Ogata, Jun Ikezawa, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Kohei Hamanaka, Atsushi Fujita, Satoko Miyatake, Takeshi Mizuguchi, Naomichi Matsumoto

{"title":"Biallelic variants in TNR cause neurodevelopmental disorders with variable expressivity","authors":"Atsuhiro Ozaki, Masamune Sakamoto, Satoko Kumada, Keisuke Hamada, Kazuhiro Ogata, Jun Ikezawa, Naomi Tsuchida, Yuri Uchiyama, Eriko Koshimizu, Kohei Hamanaka, Atsushi Fujita, Satoko Miyatake, Takeshi Mizuguchi, Naomichi Matsumoto","doi":"10.1038/s10038-025-01431-0","DOIUrl":"10.1038/s10038-025-01431-0","url":null,"abstract":"Tenascin-R (TNR) is an extracellular matrix glycoprotein that is essential for the formation of perineuronal nets in the central nervous system and is critical for neurite outgrowth, synaptic plasticity, and neural stem cell proliferation and differentiation. Biallelic TNR variants were reported to cause neurodevelopmental disorders with developmental delay, hypotonia, spasticity, and a variety of motor abnormalities. Here, we describe two Japanese siblings sharing novel compound heterozygous TNR missense variants (NM_003285.3:c.[1783 G > A];[3766 C > T] p.[(Asp595Asn)];[(Arg1256Cys)]) identified by exome and Sanger sequencing. The elder brother had dystonia, while the younger sister was asymptomatic except for adult-onset restless legs syndrome. Their development and intellect were normal. A total of 15 patients, including 13 previously reported patients, showed diverse phenotypic variability and severity, even among individuals sharing the same variants, indicating variable expressivity and reduced penetrance possibly influenced by genetic or environmental modifiers. Our findings extend the clinical spectrum of TNR-related disease and highlight the need for further accumulation of clinical cases and functional studies to understand genotype–phenotype correlations and the pathogenesis of diseases.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 4","pages":"231-237"},"PeriodicalIF":2.5,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145513013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction: Novel compound heterozygous ABCA2 variants cause IDPOGSA, a variable phenotypic syndrome with intellectual disability 更正：新的复合杂合ABCA2变异引起IDPOGSA，这是一种智力残疾的可变表型综合征。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-11-10 DOI: 10.1038/s10038-025-01422-1

Yuta Inoue, Naomi Tsuchida, Chong Ae Kim, Bruno de Oliveira Stephan, Matheus Augusto Araujo Castro, Rachel Sayuri Honjo, Debora Romeo Bertola, Yuri Uchiyama, Kohei Hamanaka, Atsushi Fujita, Eriko Koshimizu, Kazuharu Misawa, Satoko Miyatake, Takeshi Mizuguchi, Naomichi Matsumoto

引用次数: 0

Whole-genome sequencing of 3135 individuals representing the genetic diversity of the Japanese population 代表日本人口遗传多样性的3135个个体的全基因组测序。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-11-08 DOI: 10.1038/s10038-025-01430-1

Koichiro Higasa, Yoichiro Kamatani, Takahisa Kawaguchi, Shuji Kawaguchi, Saori Sakaue, Ta-yu Yang, Yukinori Okada, Yukihide Momozawa, Izumi Yamaguchi, Dominic Nelson, Simon Gravel, Yoshinori Murakami, Ryo Yamada, Keitaro Matsuo, Yoshihisa Yamano, Changhoon Kim, Jeong-sun Seo, Michiaki Kubo, Fumihiko Matsuda

{"title":"Whole-genome sequencing of 3135 individuals representing the genetic diversity of the Japanese population","authors":"Koichiro Higasa, Yoichiro Kamatani, Takahisa Kawaguchi, Shuji Kawaguchi, Saori Sakaue, Ta-yu Yang, Yukinori Okada, Yukihide Momozawa, Izumi Yamaguchi, Dominic Nelson, Simon Gravel, Yoshinori Murakami, Ryo Yamada, Keitaro Matsuo, Yoshihisa Yamano, Changhoon Kim, Jeong-sun Seo, Michiaki Kubo, Fumihiko Matsuda","doi":"10.1038/s10038-025-01430-1","DOIUrl":"10.1038/s10038-025-01430-1","url":null,"abstract":"Whole-genome sequence information currently available for large-scale sequencing studies is biased toward European descent populations. Such bias causes difficulties in identifying disease-associated genetic variations in non-European populations, including the Japanese. Here, to comprehensively identify genetic variants, we sequenced 3135 individuals representing the genetic diversity of the Japanese population. Of the 44,757,785 identified variants, 31.0% exhibiting a minor allele frequency of <1% were novel. Using these variants, we constructed a reference haplotype and graph-structured reference sequence to facilitate accurate imputation and variant characterization. Our findings suggest that integrating genetic variations from ethnically diverse populations into the prevailing catalogs is essential to achieve precision medicine for all populations.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 4","pages":"223-230"},"PeriodicalIF":2.5,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s10038-025-01430-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Long-read genomic analyses to elucidate hidden structural variations associated with MECP2 duplication syndrome 长读基因组分析阐明与MECP2重复综合征相关的隐藏结构变异。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-11-06 DOI: 10.1038/s10038-025-01419-w

Qiaowei Liang, Yuri Uchiyama, Rie Seyama, Ichiro Kuki, Kazuhiro Haginoya, Toshiyuki Shinozaki, Mitsuhiro Kato, Masamune Sakamoto, Naomi Tsuchida, Eriko Koshimizu, Atsushi Fujita, Satoko Miyatake, Takeshi Mizuguchi, Naomichi Matsumoto

{"title":"Long-read genomic analyses to elucidate hidden structural variations associated with MECP2 duplication syndrome","authors":"Qiaowei Liang, Yuri Uchiyama, Rie Seyama, Ichiro Kuki, Kazuhiro Haginoya, Toshiyuki Shinozaki, Mitsuhiro Kato, Masamune Sakamoto, Naomi Tsuchida, Eriko Koshimizu, Atsushi Fujita, Satoko Miyatake, Takeshi Mizuguchi, Naomichi Matsumoto","doi":"10.1038/s10038-025-01419-w","DOIUrl":"10.1038/s10038-025-01419-w","url":null,"abstract":"MECP2 duplication syndrome results from duplication of the MECP2 gene, encoding methyl-CpG-binding protein 2. Structural variations in this region can be detected by short-read next-generation sequencing, but resolving its precise genomic architecture remains challenging because of the involvement of complex and highly repetitive sequences. This study investigated the hidden structural variations using optical genome mapping and targeted long-read nanopore sequencing. We identified 14 breakpoints within the Xq28 regions encompassing MECP2 in four individuals from four families with MECP2 duplication syndrome. Combining the above methods enabled us to identify all the precise breakpoints, except for two inversions embedded within highly repetitive sequences. This also represents the most precise delineation to date of complex structural variants in MECP2 duplication syndrome. Notably, leveraging long nanopore reads (> 75 kb) allowed us to span low-copy repeat regions, including the approximately 72 kb J-group low-copy repeat which was difficult to be resolved, as well as GC-rich segments and dense clusters of short interspersed nuclear elements such as Alu, thus enhancing breakpoint-detection accuracy. We also detected previously underreported rare and complex rearrangement patterns. These findings highlight the power of integrating long-read sequencing with optical genome mapping for the delineation of complex genomic architectures, thus enhancing our understanding of the genomic structure underlying MECP2 duplication syndrome.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 4","pages":"209-221"},"PeriodicalIF":2.5,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PHOX2B deletion in congenital central hypoventilation syndrome: is this sufficient for pathogenesis? 先天性中枢性低通气综合征PHOX2B缺失：这足以说明发病机制吗？

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-11-05 DOI: 10.1038/s10038-025-01429-8

Kiyoshi Hayasaka, Ayako Sasaki, Yumiko Kishikawa, Yu Abiko, Haruka Arakaki, Madoka Yasukohchi, Jun Takayama, Gen Tamiya, Hisaya Hasegawa, Atsushi Ueda, Motoki Osawa, Tetsuo Mitsui

{"title":"PHOX2B deletion in congenital central hypoventilation syndrome: is this sufficient for pathogenesis?","authors":"Kiyoshi Hayasaka, Ayako Sasaki, Yumiko Kishikawa, Yu Abiko, Haruka Arakaki, Madoka Yasukohchi, Jun Takayama, Gen Tamiya, Hisaya Hasegawa, Atsushi Ueda, Motoki Osawa, Tetsuo Mitsui","doi":"10.1038/s10038-025-01429-8","DOIUrl":"10.1038/s10038-025-01429-8","url":null,"abstract":"Congenital central hypoventilation syndrome (CCHS) is primarily caused by dominant PHOX2B mutations, with recessive LBX1 or MYO1H mutations being rare. Among PHOX2B mutations, polyalanine repeat expansion mutations (PARMs) are common, whereas non-PARMs (NPARMs) are less frequent. PHOX2B mutations are believed to act through loss-of-function mechanisms combined with dominant-negative and/or toxic gain-of-function effects. However, the role of PHOX2B haploinsufficiency remains unclear. We investigated the role of PHOX2B deletion and other genetic modifiers in CCHS. Among 93 patients without PHOX2B mutations, four were found to carry PHOX2B deletions via multiplex ligation-dependent probe amplification. Two had typical CCHS, whereas two siblings presented with mild sleep hypoventilation following CCHS symptoms in infancy. After ruling out pathogenic variants in LBX1 and MYO1H, we explored potential modifiers by analyzing sequence and methylation changes in the wild-type PHOX2B promoter and 3′ untranslated region (3′UTR), and the coding regions of PHOX2A and MIR204. One female patient with CCHS carried a 3′UTR haplotype predicted to reduce PHOX2B expression via MIR204 interaction. To date, 15 informative cases with PHOX2B deletions (eight males, seven females) have been reported. Respiratory phenotypes included: CCHS (n = 5), CCHS with obstructive sleep apnea (OSA) (n = 1), OSA alone (n = 2), mild central sleep apnea (n = 1), mild central sleep hypoventilation or apnea following CCHS symptoms in infancy (n = 3), and asymptomatic (n = 3). These indicate that although a heterozygous PHOX2B deficiency alone is insufficient to cause CCHS, it may delay or impair the development of respiratory control.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 4","pages":"203-208"},"PeriodicalIF":2.5,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145444895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genome-wide functional annotation and interpretation of splicing variants: toward RNA-targeted therapies. 剪接变异的全基因组功能注释和解释：面向rna靶向治疗。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-11-05 DOI: 10.1038/s10038-025-01424-z

Tomonari Awaya, Ryo Kurosawa, Masatoshi Hagiwara

{"title":"Genome-wide functional annotation and interpretation of splicing variants: toward RNA-targeted therapies.","authors":"Tomonari Awaya, Ryo Kurosawa, Masatoshi Hagiwara","doi":"10.1038/s10038-025-01424-z","DOIUrl":"https://doi.org/10.1038/s10038-025-01424-z","url":null,"abstract":"Splice-disruptive variants represent an underrecognized yet critical category of disease-causing mutations. While canonical splice site disruptions have long been associated with genetic disorders, it is now increasingly evident that synonymous, deep-intronic, and regulatory variants can also perturb splicing events and contribute to diseases. As genomic diagnostics shift from phenotype-first to genome-first paradigms, there is an urgent need for systematic strategies to identify and interpret such variants-including those residing in noncoding regions that escape detection by traditional annotation pipelines. This review provides an integrative overview of current in silico approaches for the annotation and interpretation of splice-disruptive variants. We outline the mechanistic diversity of splicing aberrations and discuss recent advances in computational prediction frameworks, including both deep learning-based models and motif-oriented tools. In parallel, we summarize experimental strategies that are used to validate predicted splicing effects and assess their pathogenic relevance. Focusing on clinically relevant contexts, we discuss how splicing-aware variant interpretation enhances diagnostic yield, informs the reclassification of variants of uncertain significance, and uncovers targets for therapeutic intervention. Finally, we consider the implications of such interpretation for RNA-targeted strategies, including antisense oligonucleotides, small-molecule modulators, and emerging RNA-editing platforms, particularly in neuromuscular and other splicing-driven disorders. Together, these insights underscore the expanding role of in silico splicing prediction in precision medicine, offering new diagnostic and therapeutic avenues for rare and undiagnosed genetic diseases.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145444941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Elucidating the impact of a synonymous SEC24D variant on aberrant splicing in a patient with cole-carpenter syndrome 2 阐明同义SEC24D变异对cole-carpenter综合征患者异常剪接的影响2。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-11-05 DOI: 10.1038/s10038-025-01426-x

Suzan Süncak, Beyhan Tüysüz, Ravza Nur Yıldırım, Semra Gürsoy, Dilek Uludağ Alkaya, Ayhan Abacı, Emre Özzeybek, Tuğçe Batur, İnci Yaprak, Evin İşcan, Özlem Giray Bozkaya

{"title":"Elucidating the impact of a synonymous SEC24D variant on aberrant splicing in a patient with cole-carpenter syndrome 2","authors":"Suzan Süncak, Beyhan Tüysüz, Ravza Nur Yıldırım, Semra Gürsoy, Dilek Uludağ Alkaya, Ayhan Abacı, Emre Özzeybek, Tuğçe Batur, İnci Yaprak, Evin İşcan, Özlem Giray Bozkaya","doi":"10.1038/s10038-025-01426-x","DOIUrl":"10.1038/s10038-025-01426-x","url":null,"abstract":"SEC24D is a key component of the Coat Protein Complex II, which plays a critical role in the selective sorting and transport of cargo proteins from the endoplasmic reticulum. This function is particularly essential for the secretion of extracellular matrix proteins, including collagens. Biallelic pathogenic variants in SEC24D have been associated with Cole-Carpenter Syndrome 2, a rare skeletal dysplasia characterized by craniofacial abnormalities and recurrent fractures. We reported a 12-year-old male patient presenting with recurrent bone fractures, severe skeletal deformities, limb shortening, craniofacial dysmorphism and pseudoarthrosis, a feature not previously reported in this condition. Whole-exome sequencing identified a novel homozygous synonymous variant in SEC24D (c.2361C>T; p.Asn787=), located 16 bases upstream of the donor splice site of intron 18. Functional analyses revealed markedly reduced SEC24D expression and aberrant exon 18 skipping, supported by RNA-seq, qPCR, and Western blot. This case provided the first functional evidence for a synonymous variant in SEC24D causing disease via splicing disruption and expands both the phenotypic and genotypic spectrum of Cole-Carpenter Syndrome 2.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 4","pages":"195-202"},"PeriodicalIF":2.5,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145444883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genetic disruption of satellite cell function underlying congenital myopathies. 先天性肌病中卫星细胞功能的遗传破坏。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-11-05 DOI: 10.1038/s10038-025-01425-y

Shinichiro Hayashi

{"title":"Genetic disruption of satellite cell function underlying congenital myopathies.","authors":"Shinichiro Hayashi","doi":"10.1038/s10038-025-01425-y","DOIUrl":"https://doi.org/10.1038/s10038-025-01425-y","url":null,"abstract":"Congenital myopathies are a group of genetically heterogeneous neuromuscular disorders characterized by early-onset hypotonia and muscle weakness. While many congenital myopathies have historically been attributed to structural defects in muscle fibers, accumulating evidence reveals that dysfunction of satellite cells-the resident stem cells essential for muscle growth and regeneration-can also cause congenital myopathy. In this review, we focus on four genes critical for satellite cell biology: PAX7, MYOD1, MEGF10, and MYMK, and discuss how pathogenic variants in these genes contribute to muscle pathology. Mutations in PAX7, a transcription factor essential for satellite cell specification and maintenance, have been identified in patients with progressive congenital myopathy and scoliosis. MYOD1 variants affect the transcriptional regulation of myogenic differentiation and have been reported in individuals with congenital muscle hypoplasia. Loss-of-function variants in MEGF10, which mediates satellite cell proliferation, result in early-onset myopathy characterized by severe weakness and areflexia. Mutations in MYMK, essential for myoblast fusion, lead to congenital myopathy with facial and axial weakness. Together, these studies illustrate that distinct steps in satellite cell function-including specification, commitment, proliferation, and fusion-are critical for normal muscle development and maintenance. Recognizing that genetic defects affecting any of these processes can lead to congenital myopathies, redefining the disease spectrum beyond purely structural muscle disorders. Expanding our understanding of satellite cell biology will be key to elucidating the full spectrum of congenital myopathies and identifying targeted therapeutic strategies.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0