Journal of Human Genetics最新文献

{"title":"Novel susceptibility gene SLC23A2 functions via PI3K-AKT-mTOR pathway in etiology of non-syndromic cleft palate","authors":"Bin Yin, Mu-Jia Li, Jia-Lin Sun, Yue You, Si-Di Zhang, Qian-Xue Wan, Mei-Lin Yao, Cheng-Wei Yang, Hua-Qin Sun, Zi-Yuan Lin, Bing Shi, Zhong-Lin Jia","doi":"10.1038/s10038-025-01352-y","DOIUrl":"10.1038/s10038-025-01352-y","url":null,"abstract":"The biological interactions between genetic and environmental modifiers play critical roles in the etiology of non-syndromic orofacial cleft (NSOC), but it is rarely studied. This study selected 47 environmental related genes from the metabolic pathways of smoking, drinking, hypoxia, and vitamins (including vitamin A, vitamin B9 (folic acid), vitamin C (ascorbic acid), vitamin D, and vitamin E), and test their associations with NSOC and its subtypes. We found that a novel gene SLC23A2, the vitamin C transporter gene is significantly associated with non-syndromic cleft palate only (NSCPO) (p = 3.25E-07, OR = 8.45, 95%CI:3.73–19.17). SLC23A2 is expressed in the craniofacial region of zebrafish (24hpf to 120hpf), obvious craniofacial abnormalities appeared in zebrafish (48hpf) when knock down the slc23a2 (slc23a2-MO). Knock down SLC23A2 in human embryonic palatal mesenchymal cell line (HEPM) induced decreased intracellular ascorbic acid (AA), increased reactive oxygen species (ROS), inhibited cell proliferation and triggered apoptosis, activated the PI3K-AKT-mTOR signaling pathway and inhibited autophagy; ROS levels and apoptosis ratio significantly decreased when we supplemented AA to HEPM cells with high ROS levels induced by Sin-1 (an exogenous ROS mimic). Knocked down SLC23A2 in HEPM cells or zebrafish, they became more sensitive to Sin-1, and AA supplementation was ineffective. In conclusion, we identified a novel susceptibility gene SLC23A2 for NSCPO, it may function by decreasing AA level, increasing the ROS levels, inducing apoptosis, and inhibiting autophagy through the activation of the PI3K-AKT-mTOR pathway in etiology of cleft palate.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 9","pages":"443-452"},"PeriodicalIF":2.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208715","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}

{"title":"Bi-allelic KCTD19 variants associated with meiotic arrest and non-obstructive azoospermia in humans","authors":"Shuai Xu, Chenwang Zhang, Chencheng Yao, Wanze Ni, Dewei Qian, Zizhou Meng, Yifan Sun, Cunzhong Deng, Furong Bai, Jianxiong Zhang, Peng Li, Yuhua Huang, Zhi Zhou, Zheng Li, Na Li, Yuxiang Zhang","doi":"10.1038/s10038-025-01350-0","DOIUrl":"10.1038/s10038-025-01350-0","url":null,"abstract":"Non-obstructive azoospermia (NOA) represents the severe form of male infertility, affecting approximately 1% of men during their reproductive years. It is marked by the absence of sperm production caused by testicular dysfunction and has many genetic origins. However, the genetic factors underlying most NOA cases are still unclear. Meiosis, a crucial process ensuring accurate chromosome segregation and generating genetic diversity in gametes, is susceptible to genetic disruptions that may result in NOA. In this study, whole exome sequencing (WES) was conducted on 969 NOA patients, identifying six compound heterozygous KCTD19 variants in three Chinese pedigrees. KCTD19 has been demonstrated to interact with ZFP541 and HDAC1, thereby participating in the modulation of chromatin remodeling and transcriptional programs during meiosis in mice. Herein, our findings expand the phenotypic and mutational spectrum of KCTD19 in male infertility and provide further insights into its role during meiosis. This research underscores the importance of KCTD19 in meiotic progression and male fertility, highlighting the need for further investigation into the molecular mechanisms underlying gametogenic failure in NOA.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 8","pages":"427-437"},"PeriodicalIF":2.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132424","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}

{"title":"The impact of public insurance on RRSO for HBOC in Japan: a nationwide data study","authors":"Megumi Matsumoto, Hiroki Den, Shoko Miura, Ayumi Harada, Hiroyuki Nomura, Masami Arai, Hiraku Kumamaru, Seigo Nakamura, Masayuki Sekine, Kiyonori Miura","doi":"10.1038/s10038-025-01326-0","DOIUrl":"10.1038/s10038-025-01326-0","url":null,"abstract":"In Japan, risk management based on genetic disposition, such as risk-reducing surgery for hereditary breast and ovarian cancer (HBOC), is covered by public insurance only for some cancer patients. However, non-cancer clients are forced to pay a high co-payment. In this study, we examined the impact of risk-reducing salpingo-oophorectomy (RRSO), before and after the April 2020 public insurance coverage, using nationwide data from the Japanese Organization of Hereditary Breast and Ovarian Cancer. The period from March 2006 to March 2020 was defined as before insurance coverage (Pre), and the period from April 2020 to August 2021 was defined as after insurance coverage (Post). In addition, the period from April 2018 to March 2020 was designated as special (short-Pre) to coincide with the post-insurance coverage period. Of the 383 breast cancer patients who underwent genetic testing at Short-Pre, 42 (11.0%) underwent RRSO during that period. Of the 623 breast cancer patients who underwent genetic testing at Post, 142 (22.8%) underwent RRSO during that period. Significantly, this comparison shows an increase in RRSO rates in Post. Separating BRCA1 and BRCA2 also significantly increased RRSO in Post. This nationwide survey suggests that if RRSO is covered by insurance in Japan, the implementation rate will increase. As the number of cases increases in the future, the impact of insurance coverage will become clearer. If the insurance coverage for RRSO in Japan is determined to be useful, this information can be used to expand coverage for those who have not yet developed the disease.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 8","pages":"421-426"},"PeriodicalIF":2.5,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12289518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119841","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}

{"title":"ACMG secondary findings in the Brazilian rare genomes project: insights from 5402 genome sequencing","authors":"Eduardo Perrone, Luiza Virmond, Antonio Victor Campos Coelho, Marina De França, Carolina Araujo Moreno, Joana Rosa Marques Prota, Jessica Grasiela de Araujo Espolaor, Michele Migliavacca, Thiago Yoshinaga Tonholo Silva, Caio Robledo D’Angioli Costa Quaio, José Ricardo Magliocco Ceroni, Kelin Chen, Renata Moldenhauer Minillo, Anne Caroline Barbosa Teixeira, Renata Yoshiko Yamada, Vivian Pedigone Cintra, Lucas Santos de Santana, Gabriela Pereira Campilongo, Renata Martins Ribeiro da Silva, Karla de Oliveira Pelegrino, João Bosco de Oliveira Filho, Tatiana Ferreira de Almeida","doi":"10.1038/s10038-025-01349-7","DOIUrl":"10.1038/s10038-025-01349-7","url":null,"abstract":"Secondary findings (SF) are pathogenic or likely pathogenic variants in genes unrelated to the primary purpose of genetic testing. The American College of Medical Genetics (ACMG) provides guidelines on which SF should be reported, involving 81 genes linked to different conditions. With the increasing use of genome sequencing (GS), SF are more frequently detected, presenting challenges for healthcare systems. The Brazilian population is often underrepresented in genomic studies, which limits population-specific knowledge. This study aimed to outline the profile of SF in the Brazilian Rare Genomes Project (BRGP). We analyzed retrospectively SF (ACMG) data from GS of 5402 BRGP individuals. Of the 5316 cases who consented to receive SF, 3.6% (191 cases) had at least one SF. The most common genes identified were TTR, TTN, and BRCA2. SF were mainly related to cardiovascular conditions (40.2%) and cancer predisposition (37.6%). Some variants, such as TTR: c.424G>A; p. (Val142Ile) and TP53: c.1010G>A; p. (Arg337His), were recurrent, reflecting population-specific traits and founder effects. Novel variants were 10.6% of SF. SF rate varies across studies and populations. While SF can aid early diagnosis, their relevance is debated due to potential psychological and healthcare burdens. Effective genetic counseling and public health policies are essential.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 8","pages":"415-420"},"PeriodicalIF":2.5,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101823","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}

{"title":"Reclassification of variants of uncertain significance in neonatal genetic diseases: implications from a clinician’s perspective","authors":"Xiaojiao Wu, Jiancheng Jiao, Weicong Pu, Xiaotong Yan, Yaofang Xia, Weiwei Guo, Li Ma, Yanyan Cao","doi":"10.1038/s10038-025-01348-8","DOIUrl":"10.1038/s10038-025-01348-8","url":null,"abstract":"Although whole-exome sequencing (WES) is now widely used to diagnose neonatal genetic diseases, the genetic causes in over half of the cases remain unresolved, primarily due to variants of uncertain significance (VUS). Therefore, reclassifying VUS may be an effective strategy to improve WES’s diagnostic yield. However, not all reclassification approaches are suitable for clinicians. Patients in the neonatal unit of Hebei Provincial Children’s Hospital who underwent WES for suspected genetic diseases and demonstrated VUS were re-evaluated from January 2019 to December 2023 using user-friendly methods. A total of 676 individuals were tested, with 101 phenotype-associated VUS identified in 82 patients. Thirty (29.7%) VUS classifications were changed: 24 were upgraded to likely pathogenic or pathogenic, and 6 were downgraded to likely benign. VUS reclassification clarified the molecular diagnosis in 19 cases, increasing the WES diagnostic rate from 30.2% to 33.0%. Computational prediction contributed the most to reclassification, whereas clinical phenotype-related evidence was also particularly significant in upgrading variants. Moreover, phenotype-associated VUS with a score of ≥3 points are more likely to be classified as likely pathogenic or pathogenic, thus requiring more attention. This study provides a practical reference for clinicians in managing VUS reclassification.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 8","pages":"405-413"},"PeriodicalIF":2.5,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143999863","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}

{"title":"The usefulness of comprehensive genome profiling test in screening of Lynch syndrome independent of the conventional clinical screening or microsatellite instability tests","authors":"Mizuki Yamaguchi, Shintaro Akabane, Hiroaki Niitsu, Hikaru Nakahara, Asuka Toshida, Tetsuya Mochizuki, Takuya Yano, Yoshihiro Saeki, Hiroshi Okuda, Manabu Shimomura, Kazuhiro Sentani, Kiwamu Akagi, Hideki Ohdan, Takao Hinoi","doi":"10.1038/s10038-025-01345-x","DOIUrl":"10.1038/s10038-025-01345-x","url":null,"abstract":"Lynch syndrome (LS) is a hereditary cancer predisposition syndrome caused by germline pathogenic variants of DNA mismatch repair (MMR) genes. To diagnose LS, the microsatellite instability (MSI) test or immunohistochemistry of MMR enzymes is used as a conventional clinical screening method for all patients with colorectal and endometrial cancers. Recently, patients with advanced-stage cancers have undergone comprehensive genomic profiling (CGP), which is useful not only for the detection of molecularly targeted personalized therapies, but also for the screening of hereditary cancer syndromes by determining presumed germline pathogenic variants (PGPVs). Between January 2020 and April 2024, 1583 patients underwent CGP at our institute. PGPVs in MMR genes were detected in 19 patients. Although one patient died prior to the disclosure of the results and eight patients declined confirmatory genetic testing, the remaining ten patients underwent confirmatory genetic tests, of whom six were found to have a hereditary origin. Two additional patients were diagnosed with LS using tumor-normal paired CGP. Eventually, a total of eight patients were diagnosed with LS. Herein, we describe two patients with microsatellite-stable cancer who could not be diagnosed using conventional clinical screening or MSI testing. Furthermore, we showed that pathogenic variants of MMR genes do not always correlate with high MSI prediction scores in several cancer types in The Cancer Genome Atlas (TCGA) dataset analysis. These findings highlight the usefulness of CGP as a screening tool to identify individuals with possible LS, especially when conventional criteria and MSI/MMR testing fail.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 8","pages":"385-393"},"PeriodicalIF":2.5,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12289520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024133","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}

{"title":"Refining the detection of complex rearrangements in 15q15.3 region involving the STRC gene in hereditary hearing loss patients","authors":"Sara Alvaro, Daniel Castillo, Jordi Genovés, Erik D. Prados, Maurizio Levorato, Anna Albertí, Águeda Díaz, Sara Cardelús, Loreto Martorell","doi":"10.1038/s10038-025-01347-9","DOIUrl":"10.1038/s10038-025-01347-9","url":null,"abstract":"Hearing loss (HL) is the most common sensory disability worldwide, with GJB2-GJB6 connexin alterations (DFNB1) being the most frequent causes of non-syndromic hearing loss (NSHL). Recent studies have also highlighted the STRC gene as a significant contributor to NSHL, with its incidence potentially approaching that of connexin alterations. Despite advances in next-generation sequencing (NGS), molecular diagnosis remains challenging for many NSHL patients, often due to the complexity of analyzing the STRC gene. This is largely attributed to its location in a tandemly duplicated region and the presence of a homologous pseudogene (STRCP1), which complicates its accurate identification. The most common cause of DFNB16 is a homozygous large contiguous gene deletion at 15q15.3, but other copy number variants (CNVs), including both losses and gains, have been less well characterized. Through a combination of techniques we present new data on STRC variants and the diagnosis of 72 DFNB16 patients from 59 families. While the CKMT1B-STRC-CATSPER2 deletion is the most frequent alteration, the improvement of droplet-digital PCR (ddPCR) for refining CNV analysis in the first 16 exons of the gene (99,8% homologous with the pseudogene) has allowed us to identify and better define a higher incidence of previously unclarified complex rearrangements. Additionally, we have identified a direct cis association between the c.4837 G > T;p.(Glu1613*) pathogenic variant and the CATSPER2-CKMT1A-STRCP1 duplication. These findings underscore the important role of ddPCR in identifying CNVs that are difficult to detect through conventional NGS, significantly improving diagnosis and enabling precise genetic counseling for affected families.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 8","pages":"395-403"},"PeriodicalIF":2.5,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144029530","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}

{"title":"Autism and intellectual disability due to a novel gain-of-function mutation in UBE3A","authors":"Anna M. Gunelson, Kwang-Soo Kim, Connolly G. Steigerwald, Devorah Segal, Nicolas J. Abreu, Jason J. Yi","doi":"10.1038/s10038-025-01343-z","DOIUrl":"10.1038/s10038-025-01343-z","url":null,"abstract":"The loss of maternal UBE3A causes Angelman syndrome whereas its duplication is associated with a heterogeneous neurodevelopmental disorder. Here, we describe two affected brothers who possess a novel UBE3AL734S variant that is not present in two neurotypical siblings. The UBE3AL734S variant was confirmed to be maternally inherited, and the affected individuals exhibited early global developmental delay, ongoing learning difficulties, and autistic features. Their phenotypes were inconsistent with Angelman syndrome. Biochemical characterization showed the UBE3AL734S variant causes a dramatic increase in the activity of the UBE3A enzyme, suggesting that a gain in UBE3A activity is the driver of neurodevelopmental disease. Our observations document an emerging class of neurodevelopmental disorders caused by gain-of-function mutations in UBE3A.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 8","pages":"439-442"},"PeriodicalIF":2.5,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12289519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143999861","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}

{"title":"Hemizygous SMARCA1 variants cause X-linked intellectual disability","authors":"Naoto Nishimura, Takeshi Mizuguchi, Keisuke Hamada, Kotaro Yuge, Masamune Sakamoto, Naomi Tsuchida, Yuri Uchiyama, Atsushi Fujita, Eriko Koshimizu, Kazuharu Misawa, Satoko Miyatake, Yoriko Watanabe, Hitoshi Osaka, Koh-Ichiro Yoshiura, Kazuhiro Ogata, Naomichi Matsumoto","doi":"10.1038/s10038-025-01346-w","DOIUrl":"10.1038/s10038-025-01346-w","url":null,"abstract":"Pathogenic SNF2 related chromatin remodeling ATPase 1 (SMARCA1) variants have been reported in patients with X-linked intellectual disability (XLID) characterized by macrocephaly and variable neurological symptoms. Here, we report two unrelated male patients with XLID due to novel SMARCA1 variants detected by exome sequencing. Patient 1 showed macrocephaly, behavioral difficulty, and learning disability with a hemizygous SMARCA1 variant (NM_003069.5:c.1795 C > T p.[Gln599*]) leading to nonsense-mediated decay. Patient 2 had ataxia and speech delay with a hemizygous missense variant (NM_003069.5:c.1343 G > T p.[Arg448Leu]). Structural modeling suggested that the missense variant, p.(Arg448Leu) might destabilize interactions between SMARCA1 and nucleosomal DNA, thereby contributing to the abberant effect of mutant SMARCA1 protein. Both variants were inherited from their unaffected healthy mothers. This study suggests that hemizygous variants impairing SMARCA1 function can cause XLID with other variable features, such as macrocephaly and ataxia, in men.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 7","pages":"359-363"},"PeriodicalIF":2.5,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985295","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}

{"title":"Variant sub-tiering, disease-gene associations and strictness of clinical criteria improves the interpretation of variants of uncertain significance in hereditary cardiomyopathies and rhythm disorders","authors":"Marco Castori, Sandra Mastroianno, Andrea Fontana, Silvia Morlino, Grazia Nardella, Ester Di Muro, Pietro Palumbo, Maria Pia Leone, Riccardo Pracella, Orazio Palumbo, Antonio Petracca, Domenico Rosario Potenza, Massimo Carella, Giovanni De Luca, Carlo Coli, Raimondo Salvatore Massaro, Rosa De Santis, Lorenzo Vaccaro, Marcella Cesana, Davide Cacchiarelli, Massimiliano Copetti, Carmela Fusco, Giuseppe Di Stolfo","doi":"10.1038/s10038-025-01344-y","DOIUrl":"10.1038/s10038-025-01344-y","url":null,"abstract":"Besides the ClinGen’s efforts to standardize the ACMG/AMP criteria and European initiatives aimed at monitoring quality standards, molecular diagnostics of hereditary cardiomyopathies and heart rhythm disorders (HCHRDs) remains strongly influenced by the local strategies developed to overcome the variables in which genetic testing is requested. This is a monocentric study on the clinical and molecular findings of 363 pedigrees with various HCHRDs. ACMG/AMP criteria were adapted according to the ClinGen’s material and internal specifications. Phenotypes were reviewed according to known disease-gene associations and the concurrence of multiple variants in the same individual. Relatives were studied when available and the significance of selected variants was supported by RNA- studies before reporting. One or more (likely) pathogenic variants were found in 80 pedigrees (22.0%), while 96 (26.4%) displayed one or more variants of uncertain significance (VUS) only. The 132 identified VUS were sub-tiered according to the Bayesian score in three categories presenting distinguishable patterns of selected criteria. VUS_high showed profiles of key molecular criteria and resembled deleterious variants according to the combinations of assigned criteria, while the VUS_low category displayed a high chance of conflicting combinations of criteria and unsupported disease-gene associations. Reclassification to likely pathogenic by the application of applicable clinical criteria (PVS1_Strength, PP1 and PP4) was accessible to VUS_high and a few VUS_mid only. This work supports the combined need to (i) introduce VUS sub-tiering, (ii) consider known disease-gene associations, (iii) stringently apply clinical criteria and (iv) incorporate RNA data to improve the clinical significance of genetic testing in HCHRDs.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 7","pages":"349-358"},"PeriodicalIF":2.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143994829","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}