European Journal of Human Genetics最新文献

{"title":"Investigation of a pathogenic inversion in UNC13D and comprehensive analysis of chromosomal inversions across diverse datasets.","authors":"Tugce Bozkurt-Yozgatli, Ming Yin Lun, Jesse D Bengtsson, Ugur Sezerman, Ivan K Chinn, Zeynep Coban-Akdemir, Claudia M B Carvalho","doi":"10.1038/s41431-025-01817-w","DOIUrl":"10.1038/s41431-025-01817-w","url":null,"abstract":"<p><p>Inversions are known contributors to the pathogenesis of genetic diseases. Identifying inversions poses significant challenges, making it one of the most demanding structural variants (SVs) to detect and interpret. Recent advancements in sequencing technologies and the development of publicly available SV datasets have substantially enhanced our capability to explore inversions. However, a cross-comparison in those datasets remains unexplored. In this study, we reported a proband with familial hemophagocytic lymphohistiocytosis type-3 carrying a splicing variant (c.1389+1G>A) in trans with an inversion present in 0.006345% of individuals in gnomAD (v4.0) that disrupts UNC13D. Based on this result, we investigate the features of potentially pathogenic inversions in gnomAD which revealed 98.9% of them are rare and disrupt 5% of protein-coding genes associated with a phenotype in OMIM. We then conducted a comparative analysis of additional public datasets, including DGV, 1KGP, and two recent studies from the Human Genome Structural Variation Consortium which revealed common and dataset-specific inversion characteristics suggesting methodology detection biases. Next, we investigated the genetic features of inversions disrupting the protein-coding genes. Notably, we found that the majority of protein-coding genes in OMIM disrupted by inversions are associated with autosomal recessive phenotypes supporting the hypothesis that inversions in trans with other variants are potential hidden causes of monogenic diseases. This effort aims to fill the gap in our understanding of the molecular characteristics of inversions with low frequency in the population and highlight the importance of identifying them in rare disease studies.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Singleton rapid long-read genome sequencing as first tier genetic test for critically Ill children with suspected genetic diseases.","authors":"Wuttichart Kamolvisit, Chanatjit Cheawsamoot, Wanna Chetruengchai, Phawin Kor-Anantakul, Rungroj Thangpong, Chalurmpon Srichomthong, Adjima Assawapitaksakul, Kusuma Syananondh, Sineenat Kontun, Aayalida Buasong, Phichittra Od-Ek, Kanya Suphapeetiporn, Vorasuk Shotelersuk","doi":"10.1038/s41431-025-01818-9","DOIUrl":"https://doi.org/10.1038/s41431-025-01818-9","url":null,"abstract":"<p><p>Timely genetic testing is crucial for diagnosing pediatric patients in the intensive care units (ICUs) without known etiology. We aim to explore the benefits of singleton rapid long-read genome sequencing (rLR-GS) in critically ill children admitted to ICU with a suspected genetic etiology. Children younger than 18 years of age admitted to the ICU with a suspected genetic etiology at two tertiary hospitals in Thailand from August 2023 to May 2024 were included. rLR-GS was performed. The value of a molecular diagnosis for changing patient management outcomes was assessed. Eighteen patients were recruited. Singleton rLR-GS identified seventeen likely pathogenic (LP) or pathogenic (P) variants, resulting in the diagnosis of eleven distinct genetic disorders with autosomal recessive, autosomal dominant, and mitochondrial inheritance patterns. This yielded a diagnostic rate of 61% (11/18) with a median turnaround time of nine days. Specifically, rLR-GS identified three pathogenic structural variants (SVs), including large deletions of 19 kb, 2.4 kb, and 10.1 kb. Additionally, it provided phasing information for the two variants in each of the six patients with autosomal recessive disorders. Furthermore, the identification of two SVs and the phasing information led to the reclassification of three single nucleotide variants (SNV), one in each patient, from variants of unknown significance (VUS) to LP. The application of rLR-GS resulted in significant changes in the management of all eleven patients. This proof-of-concept study demonstrated the utility of singleton rLR-GS as a first-tier diagnostic approach for critically ill patients with unknown causes.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sociodemographic and health factors associated with genetic testing in Australia: insights from a cohort-based study of 45,061 participants.","authors":"David E Goldsbury, Yoon-Jung Kang, Catherine Tang, Hamzeh M Tanha, Amelia K Smit, Kate L A Dunlop, Lara Petelin, Preston Ngo, Harriet Hui, Nicola S Meagher, Melissa A Merritt, Marianne Weber, Anna DeFazio, Anne E Cust, Karen Canfell, Julia Steinberg","doi":"10.1038/s41431-025-01816-x","DOIUrl":"https://doi.org/10.1038/s41431-025-01816-x","url":null,"abstract":"<p><p>With increasing availability of genetic tests, it is important to consider differences in testing patterns between population subgroups. We examined self-reported genetic testing among 45,061 participants of the Australian population-based 45 and Up Study, testing for associations with sociodemographic and health characteristics (multivariable logistic regression). 9.2% of participants reported ever having genetic testing; 3.9% reported disease-related testing, 5.2% non-disease-related testing, 0.7% both disease-related and non-disease-related testing. Disease-related genetic testing was strongly associated with younger age, female sex, history of cancers and cardiovascular disease, and cancer family history. Disease-related testing was also strongly associated with higher education (university versus school certificate: adjusted OR [aOR] = 1.50 [95%CI:1.29-1.75]; certificate/diploma versus school certificate: aOR = 1.40 [95%CI:1.20-1.63]); there was suggestive evidence for association with higher household income ($AUD90,000+ versus <$AUD30,000: aOR = 1.22 [95%CI:1.02-1.46]), which strengthened when not adjusting for education (aOR = 1.34 [95%CI:1.13-1.60]). These results suggest further work on ensuring equitable access is needed to prevent potential health inequities.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding the mutational spectrum of ReNU syndrome: insights into 5’ Stem-loop variants","authors":"Alessandro Bruselles,&nbsp;Cecilia Mancini,&nbsp;Luigi Chiriatti,&nbsp;Mattia Carvetta,&nbsp;Maria Chiara Baroni,&nbsp;Camilla Cappelletti,&nbsp;Stefano Giuseppe Caraffi,&nbsp;Massimiliano Celario,&nbsp;Andrea Ciolfi,&nbsp;Viviana Cordeddu,&nbsp;Alessandro De Falco,&nbsp;Marco Ferilli,&nbsp;Livia Garavelli,&nbsp;Chiara Leoni,&nbsp;Camilla Meossi,&nbsp;Marcello Niceta,&nbsp;Roberta Onesimo,&nbsp;Francesca Peluso,&nbsp;Davide Politano,&nbsp;Manuela Priolo,&nbsp;Francesca Clementina Radio,&nbsp;Filippo Santorelli,&nbsp;Sabrina Signorini,&nbsp;Fabio Sirchia,&nbsp;Enza Maria Valente,&nbsp;Giuseppe Zampino,&nbsp;Marco Tartaglia","doi":"10.1038/s41431-025-01820-1","DOIUrl":"10.1038/s41431-025-01820-1","url":null,"abstract":"A narrow spectrum of heterozygous variants in RNU4-2, encoding the small nuclear RNA (snRNA) U4, underlies ReNU syndrome, a neurodevelopmental disorder (NDD) characterized by moderate to severe developmental delay (DD), intellectual disability (ID), a distinctive facial gestalt, and multisystem involvement. Pathogenic variants have primarily been reported within an 18-nt critical region contributing to stabilizing the U4/U6 snRNA duplex and proper spliceosome assembly. By combining whole genome sequencing reanalysis and targeted direct sequencing in 190 molecularly unexplained NDD cases, we report on five affected individuals carrying pathogenic/putative pathogenic RNU4-2 variants (2.6%). Three individuals harbored the recurrent pathogenic n.64_65insT variant, while two were heterozygous for private/rare maternally inherited variants (n.30 A &gt; T and n.43_44insT) within the 5’ Stem-loop region. Deep clinical phenotyping confirmed a homogeneous constellation of features in all individuals, with global DD, ID, brain malformations, and a recognizable facial gestalt representing core findings. Based on structural homology models and available cryo-EM data, n.30 A &gt; T and n.43_44insT were predicted to disrupt key intra- and inter-molecular interactions critical for spliceosome function. Our findings expand the mutational spectrum of ReNU syndrome, and confirm the 5’ Stem-loop as a second mutational hotspot in RNU4-2. We propose that a more complex genetics likely underlies the inheritance of a subset of disease-causing RNU4-2 variants from an apparently unaffected parent. We anticipate a relatively high proportion of pathogenic RNU4-2 variants among individuals with unclassified NDD despite extensive genomic testing, and propose a set of facial gestalt core features as a clinical screening tool to prioritize patients for RNU4-2 analysis.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 4","pages":"432-440"},"PeriodicalIF":3.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Another common genetic ataxia in South Korea: Spinocerebellar ataxia 36.","authors":"Jong Hyeon Ahn, Seungbok Lee, Jangsup Moon, Yoojung Han, Hyeshik Chang, Jinyoung Youn, Jin Whan Cho, Ja-Hyun Jang","doi":"10.1038/s41431-024-01783-9","DOIUrl":"https://doi.org/10.1038/s41431-024-01783-9","url":null,"abstract":"<p><p>Spinocerebellar ataxias (SCAs) represent a diverse group of neurodegenerative disorders characterized by progressive cerebellar ataxia. In South Korea, diagnostic laboratories typically focus on common SCA subtypes, leaving the prevalence of rare SCAs uncertain. This study aimed to explore the frequency of rarer forms of SCA, including SCA10, 12, 31, and 36 utilizing molecular techniques including long-read sequencing (LRS). Patients from ataxia cohorts who remained undiagnosed after testing for common genetic ataxias (SCA1, 2, 3, 6, 7, 8 17, and dentatorubral-pallidoluysian atrophy) were analyzed, along with unselected ataxia patients referred for screening of common SCAs. Expanded alleles for SCA10, 12, 31, and 36 were investigated through allele-length PCR, repeat-primed PCR, and LRS. Among 78 patients from 67 families with undiagnosed cerebellar ataxia, SCA36 was identified in 8 families (11.9%), while SCA10, 12, or 31 were not found. In unselected ataxia, SCA36 was present in 1.0% (1/99). Korean SCA36 patients exhibited clinical characteristics similar to global reports, with a higher incidence of hyperreflexia. The haplotype of expanded alleles identified in LRS was consistent among SCA36 patients. The findings indicate that SCA36 accounts for 11.9% of diagnoses after excluding common SCAs and 1.0% in unselected ataxia patients. The study underscores the prevalence of SCA36 in South Korea and emphasizes the potential of LRS as a diagnostic tool for this condition. Integrating LRS into diagnostic protocol could enhance diagnostic efficacy, particularly in populations with a high prevalence of SCA36 like South Korea. Further research is necessary to standardize LRS for routine clinical application.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotype of PAX2-related disorders correlates with kidney and ocular manifestations","authors":"Ji Hyun Kim,&nbsp;Yo Han Ahn,&nbsp;Yeonji Jang,&nbsp;Eujin Park,&nbsp;Hajeong Lee,&nbsp;Seong Heon Kim,&nbsp;Ji Yeon Song,&nbsp;Kyoung Hee Han,&nbsp;Jiwon Jung,&nbsp;Joo Hoon Lee,&nbsp;Hee Gyung Kang,&nbsp;Jae Ho Jung,&nbsp;Hae Il Cheong","doi":"10.1038/s41431-025-01822-z","DOIUrl":"10.1038/s41431-025-01822-z","url":null,"abstract":"PAX2-related disorders encompass renal coloboma syndrome (RCS) and hereditary focal segmental glomerulosclerosis (FSGS) type 7. We retrospectively analyzed 27 Korean patients with PAX2 pathogenic variants detected between 2004 and 2022 and conducted a literature review of 328 cases, including 301 previously reported. In our cohort, 19 had RCS, 4 had FSGS, and 4 had isolated congenital anomalies of the kidneys and urinary tract. Patients were classified by variant type into predicted loss of function (pLoF) and non-pLoF variant groups, and by variant location into paired domain and other sites group. pLoF variants were predominantly associated with RCS, observed in 82% of patients in both our data (18 of 22, P = 0.017) and the literature (140 of 171, P &lt; 0.001). Kidney failure developed in 52% of Korean patients at a median age of 14.5 years, with no difference in kidney survival between variant types. However, the literature review indicated faster progression to kidney failure in patients with pLoF variants (11.0 vs. 24.0 years; pLoF, n = 138 vs. non-pLoF, n = 71; P = 0.002), with no significant difference by variant location. Ocular manifestations were more common, had earlier onset, and were more severe in the pLoF variants group in our cohort (P = 0.038). The literature confirmed a higher prevalence of ocular involvement in patients with pLoF variants (pLoF, n = 175 vs. non-pLoF, n = 88; P &lt; 0.001) and in those with paired domain variants (P = 0.01). pLoF variants in PAX2 were associated with worse kidney and ocular outcomes. These findings support genotype-phenotype correlations, contributing to tailored management in patients with PAX2-related disorders.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 4","pages":"441-450"},"PeriodicalIF":3.7,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41431-025-01822-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preferences for genetic testing among populations underrepresented in genomic research: a systematic review.","authors":"Taylor Montgomery, Madison R Hickingbotham, Hadley Stevens Smith","doi":"10.1038/s41431-025-01819-8","DOIUrl":"https://doi.org/10.1038/s41431-025-01819-8","url":null,"abstract":"<p><p>Equitable implementation of genomic medicine requires understanding preferences of diverse populations. Stated preference methods, such as discrete choice experiments (DCEs) and conjoint analyses, allow empirical evaluation of whether and how preferences for aspects of genomic medicine tests and services differ according to demographic characteristics. We aimed to understand the extent to which stated preference research in genomic medicine includes respondents that are population representative and evidence regarding preference heterogeneity by race and ethnicity. We conducted a systematic review of the stated preference literature in genomic medicine. We searched Web of Science, CINAHL, PsycINFO, PubMed, Embase, Cochrane Library, and SCOPUS for articles published from February 2021 to November 2023, extending a previously published systematic review. We extracted information on whether demographic characteristics of respondents were reported, whether investigators tested for preference heterogeneity based on race and ethnicity, and whether preference heterogeneity by race and ethnicity was identified. We identified 138 newly published records in addition to the 38 articles included in the original review. In total, we included 18 articles that reported participants' race or ethnicity. Eight articles explicitly analyzed preferences by race and ethnicity, and preference heterogeneity was identified in two. Stated preference research in genomic medicine often does not include population representative samples, and preference heterogeneity is not frequently analyzed according to race and ethnicity. Improving the representativeness of respondent populations, which allows for better understanding of whether and how preferences may differ by population subgroups, is important to guide policy and implementation decisions in genomic medicine.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regional autozygosity association with albumin-to-creatinine ratio reveals a novel FTO region in an Indigenous Australian population.","authors":"Vignesh Arunachalam, Kim N Tran, Wendy Hoy, Rodney A Lea, Shivashankar H Nagaraj","doi":"10.1038/s41431-025-01799-9","DOIUrl":"https://doi.org/10.1038/s41431-025-01799-9","url":null,"abstract":"<p><p>The genetic distinctiveness of Indigenous Australian populations is well established, yet the Tiwi population remains underrepresented in genetic research. Due to their prolonged geographic isolation, these populations are prone to increased runs of homozygosity (ROH). We investigated the genetic diversity of the Tiwi population, isolated from mainland Australia for decades, based on ROH and their associations with clinical traits. We analyzed 455 whole genome sequences to identify population structure via PCA and performed a comparison with UK Biobank, Melanesian, and Polynesian cohorts. ROH assessment and genome-wide and regional measures of homozygosity were used to explore associations between clinical traits and autozygosity. Our analysis revealed distinct genetic characteristics of the Tiwi population that aligned closely with those of the Melanesian cohort. Tiwi individuals exhibited an increased burden of ROH, particularly in LINC0109, FMLN1, and RPL17P45 genes on chromosomes 2, 17, and 18, respectively, indicating prolonged isolation and genetic drift. A positive correlation was observed between genomic F_ROH and albumin-to-creatinine ratio (ACR) levels, suggesting a potential link between autozygosity and renal health markers. Furthermore, regional autozygosity association analysis revealed an association between elevated ACR and a region in FTO, implicating its role in obesity, kidney disease, and cardiovascular conditions. Importantly, we found that this association is strong under the recessive model. This research lays a robust foundation for further exploration of ROH mapping and its implications for disease susceptibility within Indigenous communities worldwide.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two distinct phenotypes in Snijders Blok-Campeau syndrome and characterization of the behavioral phenotype in a zebrafish model.","authors":"Yumi Enomoto, Takashi Shiromizu, Sakyo Yasojima, Junko Koiwa, Yukiko Kuroda, Hiroaki Ito, Mizuki Yuge, Momoka Ohkawa, Ryohei Shibata, Hiroaki Murakami, Takuya Naruto, Shizuka Shiiya, Naoko Omotani, Yuhei Nishimura, Kenji Kurosawa","doi":"10.1038/s41431-025-01815-y","DOIUrl":"https://doi.org/10.1038/s41431-025-01815-y","url":null,"abstract":"<p><p>Chromatin remodeling is an important system controlling gene expression. CHD3, which is a causative gene of Snijders Blok-Campeau syndrome (SNIBCPS), is a member of the chromodomain helicase DNA-binding (CHD) family related to chromatin remodeling. SNIBCPS is characterized by developmental delay (DD), intellectual disability (ID), macrocephaly, and facial features including a prominent forehead and hypertelorism. Hypersociability/overfriendliness is a notable behavioral feature in patients. Here, we describe five SNIBCPS patients with CHD3 variants from four families, including a sibling pair caused by parental gonosomal mosaicism. We observed two distinct phenotypes in our patients in accordance with previous observations. Phenotype 1: macrocephaly, hypertelorism, overgrowth, DD, and ID; and Phenotype 2: microcephaly, growth retardation, DD, and ID. Phenotype 1 was consistent with the typical SNIBCPS phenotype, while Phenotype 2 was distinct. To understand further the features of the patients with SNIBCPS, we generated chd3-knockout (KO) zebrafish using CRISPR-Cas9 genome editing. No morphological changes were observed in chd3-KO zebrafish. However, behavioral tests showed that chd3-KO zebrafish had strong and sustained interest in others, and were less aggressive toward others, suggesting a recapitulation of the hypersociability/overfriendliness phenotype in patients with SNIBCPS. Metabolomic analysis using whole brains showed changes in metabolites processed by specific mitochondrial enzymes in chd3-KO zebrafish. The administration of metformin, which reportedly ameliorates mitochondrial dysfunction and behavioral abnormalities, attenuated the abnormal behavior of chd3-KO zebrafish. Our study helps delineate the phenotypes of patients with SNIBCPS, provides insights into a characteristic behavior of the disease, and suggests a potential treatment to improve the behavioral symptoms of patients.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic TEDC1 variants cause a new syndrome with severe growth impairment and endocrine complications.","authors":"Noriko Miyake, Kentaro Shiga, Yuya Hasegawa, Chisato Iwabuchi, Kohei Shiroshita, Hiroshi Kobayashi, Keiyo Takubo, Fabien Velilla, Akiteru Maeno, Toshihiro Kawasaki, Yukiko Imai, Noriyoshi Sakai, Tomonori Hirose, Atsushi Fujita, Hidehisa Takahashi, Nobuhiko Okamoto, Mikako Enokizono, Shiho Iwasaki, Shuichi Ito, Naomichi Matsumoto","doi":"10.1038/s41431-025-01802-3","DOIUrl":"https://doi.org/10.1038/s41431-025-01802-3","url":null,"abstract":"<p><p>We encountered two affected male patients born to non-consanguineous parents, who presented with prenatal-onset severe growth impairment, primary microcephaly, developmental delay, adrenal insufficiency, congenital glaucoma, delayed bone aging, craniosynostosis, congenital tracheal stenosis, and primary hypogonadism. By exome sequencing, we identified compound heterozygous TEDC1 variants (NM_001134877.1 c.[104-5C>G];[787delG] p.[?];[(Ala263LeufsTer29)] in both affected siblings. We confirmed that the splice site variant, c.104-5C>G, leads to no TEDC1 protein production via nonsense-mediated mRNA decay. The frameshift variant located in the last coding exon, c.787delG, produces a C-terminally truncated protein, which impairs the binding with TEDC2. Thus, both variants are thought to be loss-of-function. TEDC1 and TEDC2 are both required for centriole stability and cell proliferation. Our in vitro experiments using patient-derived cells revealed cell cycle abnormality. Our in vivo study using tedc1^-/- zebrafish generated by CRISPR/Cas9 successfully recapitulated the growth impairment and cranial bone dysplasia as seen in our patients. The tedc1^-/- mutant zebrafish were sterile and did not have developed gonads. Furthermore, we showed that biallelic TEDC1 deletion causes cilia abnormalities through defective acetylated tubulins.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}