Molecular Genetics & Genomic Medicine最新文献

{"title":"A Novel Synonymous Variant of PAX2 in Monochorionic Diamniotic Twins With Bilateral Renal Agenesis: A Case Report and Literature Review.","authors":"Wencong Yao, Bocheng Xu, Hao Wang, Shanling Liu, He Wang, Jingqun Mai, Xihan Wang, Xin Chen, Zhu Zhang","doi":"10.1002/mgg3.70113","DOIUrl":"10.1002/mgg3.70113","url":null,"abstract":"<p><strong>Background: </strong>Paired Box 2 (PAX2, NM_000278.5) encodes paired box gene 2, one of many human homologs of the Drosophila melanogaster gene prd. PAX2-related disorder is an autosomal dominant disorder associated with renal and eye abnormalities.</p><p><strong>Methods: </strong>In this study, both monochorionic diamniotic twins presenting bilateral renal agenesis were subjected to investigation. The pregnancy was terminated and muscular tissue of the fetus was analyzed by trio whole exome sequencing (WES). The target sequence was verified by Sanger sequencing at the genome level. In vitro Minigene model was constructed and the transcribed cDNA was subjected to Sanger sequencing to explore the splicing effect of the suspected mutation.</p><p><strong>Results: </strong>The synonymous mutation PAX2 c.792G>A was detected in both twins, but not in the parents or the family's firstborn. Although this mutation did not alter the amin acid sequence, minigene splice analysis confirmed that c.792G>A resulted in exon 6 skipping, leading to aberrant mRNA splicing.</p><p><strong>Conclusion: </strong>PAX2 c.792G>A is the first pathogenic synonymous mutation ever documented. It has a significant impact on mRNA splicing and leads to developmental abnormalities. This case highlights the importance of clinical phenotyping as well as comprehensive genetic analysis during genetic testing, including evaluation of synonymous mutations.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 6","pages":"e70113"},"PeriodicalIF":1.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12166194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying a Novel Causal FAM83H Variant for Autosomal Dominant Amelogenesis Imperfecta Using Exome-Sequencing.","authors":"Rick Kamps, Herm Martens, Bart de Koning, Bert Smeets, Michel van Geel","doi":"10.1002/mgg3.70108","DOIUrl":"10.1002/mgg3.70108","url":null,"abstract":"<p><strong>Background: </strong>Amelogenesis imperfecta (AI) is a rare genetic disorder causing tooth enamel defects. AI has been classified into 14 different clinical subtypes with different modes of inheritance. In this study, we performed whole-exome sequencing to identify the causative gene defect in a large Dutch family with autosomal dominant hypocalcified AI (ADHCAI).</p><p><strong>Methods: </strong>Whole-exome sequencing (WES) was performed on genomic DNA of the proband with AI. We focused on eight candidate genes known to be involved in inherited autosomal dominant AI. Sanger sequencing was used to confirm the selected exome candidate variant. Additionally, genotype and phenotype analyses were performed in the selected affected and non-affected individuals and compared according to previously listed literature for this candidate gene of the proband.</p><p><strong>Results: </strong>The clinical phenotype of the affected individuals showed a generalized and extensive enamel defect of all teeth. In the exome dataset of the proband, a novel nonsense variant in FAM83H, c.1055C>A p.(Ser352*) was detected, which was verified by conventional Sanger sequencing. Co-segregation analysis confirmed that the variant was present in all affected individuals and not in unaffected individuals.</p><p><strong>Conclusion: </strong>A novel pathogenic, protein-truncating variant was detected in FAM83H, a gene with similar truncating variants known to be associated with ADHCAI.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 6","pages":"e70108"},"PeriodicalIF":1.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12162354/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole Exome Sequencing Identifies a Novel Frameshift Mutation of the WRN Gene in a Werner Syndrome Family and Functional Analysis.","authors":"Hao Xiong, Haiqing Gao, Jianji Wan, Jieping Xiao, Xiaoqun Luo, Xiuqin Dong, Yueheng Wu, Tao Liu","doi":"10.1002/mgg3.70118","DOIUrl":"10.1002/mgg3.70118","url":null,"abstract":"<p><strong>Introduction: </strong>Werner syndrome (WS) is a rare recessive disorder characterized by premature aging and metabolic abnormalities. WS is caused by mutations in the WS RecQ-like helicase gene (WRN), which encodes the WRN RecQ-like helicase protein. This study aimed to identify the deletion mutation in the WRN gene within the WS family and comprehensively analyze its regulatory role.</p><p><strong>Methods: </strong>We utilized whole exome sequencing to assess gene mutations in non-close relatives of two patients with WS. The mutation was further verified using Sanger sequencing. Subsequently, the pathophysiological characteristics of the mutation were examined using Western blotting, subcellular localization determination, conservative analysis, and three-dimensional (3D) protein structure prediction.</p><p><strong>Results: </strong>Whole exome sequencing revealed a previously unreported homozygous mutation c.3244delG (p.Val1082Tyrfs*17) within exon 27 of the WRN gene. Sanger sequencing confirmed the presence of a homozygous mutation in the two patients, while a heterozygous mutation was identified in the other six family members. Western blotting revealed that the c.3244delG mutation in the WRN gene resulted in a reduced molecular weight of the mutated WRN protein. Furthermore, subcellular localization experiments revealed that the mutant WRN protein could not be effectively transported to the nucleus. Some studies reported that the mutation exhibits a high conservation rate across various species. The three-dimensional structure prediction indicates that the mutant WRN protein exhibits a distinct structure compared to the wild-type protein.</p><p><strong>Conclusions: </strong>This study identified a frameshift mutation in the WRN gene, which was associated with WS. The subsequent functional analysis revealed the inefficiency of the mutated protein. This study broadens the spectrum of known WRN mutations and enhances the comprehension of WS pathogenesis.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 6","pages":"e70118"},"PeriodicalIF":1.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12175019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Compound Heterozygous Loss-of-Function Variants in CCM2L in a Fetus With Tetralogy of Fallot.","authors":"Dandan Ling, Wanqin Xie, Xiao Mao, Zhiyu Liu, Yabing Tang, Fanjuan Kong","doi":"10.1002/mgg3.70117","DOIUrl":"10.1002/mgg3.70117","url":null,"abstract":"<p><strong>Background: </strong>Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. However, our current understanding of the genetic etiology for TOF is limited.</p><p><strong>Methods: </strong>Whole exome sequencing (WES) and Sanger sequencing were applied to a family trio diagnosed with TOF by fetal prenatal ultrasound examination. A minigene assay was performed to confirm the splicing defects.</p><p><strong>Results: </strong>We identified compound heterozygous variants in the cerebral cavernous malformation 2-like (CCM2L) gene, namely the paternally inherited nonsense variant NM_001365692.1:c.741G>A p.(Trp247Ter) and the maternally inherited splice-site variant NM_001365692.1:c.1263+2T>A in a fetus with TOF featuring a ventricular septal defect associated with overriding aorta and pulmonary stenosis. Minigene assay showed that the c.1263+2T>A variant led to skipping of CCM2L exon8 during RNA splicing, which is thought to result in frameshift and premature termination of translation. Both variants were absent from the public population databases (Genome Aggregation Database [gnomAD], 1000 Genomes [1000G], Clinvar) and classified as likely pathogenic according to the ACMG guidelines (PVS1 + PM2 level evidence).</p><p><strong>Conclusion: </strong>To our knowledge, this is the first reported case of biallelic loss-of-function variants in human CCM2L. Our findings suggest a potential association of human CCM2L with TOF.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 6","pages":"e70117"},"PeriodicalIF":1.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12168162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"De Novo Variant in GBX1 Gene Associated With Developmental Delay and Focal Epilepsy.","authors":"Bingbing Zhang, Xiaohua Li, Xiao Qian, Jihong Tang","doi":"10.1002/mgg3.70114","DOIUrl":"10.1002/mgg3.70114","url":null,"abstract":"<p><strong>Background: </strong>The gastrulation brain homeobox (Gbx) family, including GBX1 and GBX2, is crucial for hindbrain development and contributes to the morphogenesis of the midbrain-hindbrain boundary (MHB). While the role of the GBX1 gene in the development of the human nervous system remains to be elucidated, its variant in humans has not previously been reported to be associated with disease.</p><p><strong>Methods: </strong>The patient presenting with sleep panic attacks underwent comprehensive clinical assessments, including electroencephalograph (EEG), magnetic resonance imaging (MRI), and genetic testing through whole exome sequencing (WES). Zebrafish models were generated through gbx1 gene crispants to investigate the functional impact of identified genetic variants.</p><p><strong>Results: </strong>The patient in our study was diagnosed with focal epilepsy through long-range EEG. WES revealed a de novo GBX1 gene variant [NM_001098834.3: c.910C>T (p.Gln304*)]. In zebrafish larvae with gbx1 gene disruption, significant abnormalities were observed in the morphology of the interocular area. Furthermore, these larvae exhibited an increased susceptibility to neurophysiological abnormalities associated with epileptiform activity.</p><p><strong>Conclusion: </strong>Our study is the first to identify an association between the GBX1 gene variant and focal epilepsy. The zebrafish models confirmed the presence of related phenotypes in the gbx1-Cas9. These findings underscore the significance of the GBX1 gene in neurological function.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 6","pages":"e70114"},"PeriodicalIF":1.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12168089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of De Novo Chromosomal Translocations Disrupting NIPBL in a Patient With Cornelia de Lange Syndrome by Full Genome Analysis.","authors":"Hsiao-Jung Kao, Elin H F Wang, Erh-Chan Yeh, Hsiao-Huei Chen, Feng-Jen Hsieh, Tsang-Ming Ko, Wuh-Liang Hwu, Pui-Yan Kwok, Ni-Chung Lee","doi":"10.1002/mgg3.70115","DOIUrl":"10.1002/mgg3.70115","url":null,"abstract":"<p><strong>Background: </strong>Cornelia de Lange syndrome (CdLS) is a rare genetic disorder characterized by congenital multiple anomalies, developmental delay, and distinctive facial features.</p><p><strong>Methods: </strong>We performed chromosomal microarray analysis (CMA), whole exome sequencing (WES), linked-read whole-genome sequencing (WGS) and optical genome mapping (OGM) to investigate an undiagnosed case of CdLS.</p><p><strong>Results: </strong>A male patient presented clinical features consistent with CdLS, including a short nose, synophrys, small hands, hearing impairment, refractory complex partial seizures, and developmental delay. Amniocentesis at 28 gestational weeks and karyotyping revealed a presumably balanced translocation between chromosome 5 and chromosome 6. CMA and WES failed to identify copy number variants or a molecular diagnosis. Further analysis using WGS and OGM identified two translocation events on chromosome 5, resulting in three derivative chromosomes: 46,XY, der(2)t(2;5)(q32.3;p13.2),der(5)t(5;6)(p13.1;q12),der(6)t(2;6)(q32.3;q12)ins(6;5)(q12;p13.1p13.2). These rearrangements disrupted the NIPBL gene, a key gene with CdLS, splitting it across derivative chromosomes 2 and 6. Phasing studies revealed that these translocations originated from the paternal lineage.</p><p><strong>Conclusions: </strong>This case highlights the intricate genetic underpinnings of CdLS in this patient and underscores the diagnostic value of high-resolution genomic analyses in elucidating complex chromosomal rearrangements.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 6","pages":"e70115"},"PeriodicalIF":1.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144310148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Japanese Case of Lenz-Majewski Syndrome With a Novel PTDSS1 Variant.","authors":"Yasuko Kobari, Non Miyata, Jun Takayama, Naoya Saijo, Tomohisa Suzuki, Shigeo Kure, Atsuo Kikuchi, Gen Tamiya, Takumi Takizawa","doi":"10.1002/mgg3.70112","DOIUrl":"10.1002/mgg3.70112","url":null,"abstract":"<p><strong>Background: </strong>Lenz-Majewski syndrome (LMS) is a rare genetic disorder characterized by osteosclerosis, intellectual disability, characteristic facies, and distinct craniofacial, dental, cutaneous, and distal-limb anomalies. Mutations in the PTDSS1 gene, which encodes one of the phosphatidylserines (PS) synthase enzymes, PSS1, have been identified as causative in LMS patients. These mutations make PSS1 insensitive to feedback inhibition by PS levels.</p><p><strong>Methods: </strong>Whole genome sequence (WGS) was performed on a patient with congenital cutis laxa and her parents. PS synthase activity was analyzed in PTDSS1 mutant cDNA clones to evaluate functional alterations.</p><p><strong>Results: </strong>A 5-year-old girl presented with congenital skin wrinkles and was initially diagnosed with congenital cutis laxa. She had bilateral inner ear hypoplasia, bilateral low-frequency hearing loss, attention-deficit/hyperactivity disorder, and mild intellectual disability. Physical examination revealed protruding ears, frontal bossing, and dental malalignment. A de novo heterozygous missense variant in the PTDSS1 gene, c.284G>A (p. Arg95Gln) was identified by WGS. Functional analysis indicated increased PS synthase activity, supporting the pathogenicity of this variant.</p><p><strong>Conclusions: </strong>The patient's cutis laxa and facial features were consistent with LMS, though radiographic findings did not reveal the characteristic sclerosing bone dysplasia reported in previous cases. This observation suggests that LMS may have a broader phenotypic spectrum than previously recognized.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 6","pages":"e70112"},"PeriodicalIF":1.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144310224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel EP300 Variant in an African American Girl With Global Developmental Delay and Leukemia.","authors":"Subit Barua, Vundavalli V Murty, Alejandro Iglesias, Jun Liao","doi":"10.1002/mgg3.70102","DOIUrl":"10.1002/mgg3.70102","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic germline missense and in-frame indel variants in exons 30 or 31 of the EP300 gene are associated with Menke-Hennekam syndrome-2 (MKHK2). The phenotypic spectrum associated with MKHK2 is variable, including neurodevelopmental, respiratory, skeletal, and immunological impairments. Based on their genetic, clinical, and DNA methylation profiles, a recent study proposed three domain-specific subtypes of MKHK: MKHK-ZZ, MKHK-TAZ2, and MKHK-ID4. In somatic cells, EP300 variants have been reported in lymphoma, leukemia, and various solid tumors. We present an African American girl with global developmental delay, failure to thrive, microcephaly, seizure, osteopenia, and T-cell acute lymphoblastic leukemia (T-ALL).</p><p><strong>Method: </strong>We performed karyotype, FISH, chromosomal microarray, and exome sequencing with probands bone marrow, blood, and buccal swab.</p><p><strong>Result: </strong>Comprehensive genetic studies using multiple tissues detected somatic complex cytogenomic changes in blood cells and a de novo germline missense variant (NM_001429.4: c.5258G>A, p.Cys1753Tyr) in the TAZ2 domain of EP300 from her buccal swab, which is consistent with a diagnosis of MKHK2. While in our patient we observed phenotypic overlaps with affected individuals harboring variants in the TAZ2 domain, some phenotypes such as osteopenia and alopecia have not been reported previously. The hematolymphoid malignancy of our patient also raises the question of whether germline EP300 variants are associated with a genetic predisposition to cancer.</p><p><strong>Conclusion: </strong>Together, this case expands the growing body of knowledge regarding the clinical and genetic spectrum of MKHK2. This is the first MKHK individual reported in the literature in an underrepresented population of African American ancestry.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 6","pages":"e70102"},"PeriodicalIF":1.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12107369/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144151288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Randomized, Double-Blind, 2-Treatment, 2-Period, Crossover Phase 1 Study to Compare the Pharmacokinetics, Safety and Tolerability of 60 IU/Kg of Abcertin and Cerezyme in Healthy Volunteers Following a Single Intravenous Administration.","authors":"Eungu Kang, Dohyung Kim, Soojin Hwang, Charlotte Lemech, Jessica Wharton, Yongyoon Lee, Han Wook Yoo, Beom Hee Lee","doi":"10.1002/mgg3.70111","DOIUrl":"10.1002/mgg3.70111","url":null,"abstract":"<p><strong>Background: </strong>Imiglucerase (Cerezyme; Sanofi, Paris, France), an analogue of β-glucocerebrosidase produced by recombinant DNA technology, has been a safe and effective treatment for Gaucher disease (GD) for over 25 years. A new imiglucerase, Abcertin (Seongnam-si, Gyeonggi-do, Republic of Korea) has shown a similar safety and efficacy profile in previous clinical studies. This study compared the pharmacokinetics, immunogenicity, safety, and tolerability to EU-sourced Cerezyme following a single 60 IU/kg dose.</p><p><strong>Methods: </strong>This phase 1, single-center, randomized, double-blind, two-way crossover study enrolled 36 healthy volunteers aged 18-45 years. Participants were randomly assigned to receive either Abcertin or Cerezyme in a predetermined sequence.</p><p><strong>Results: </strong>Abcertin reached peak plasma concentrations at a median t_max of 61 min (range: 40-121 min). The mean C_max, AUC_0-last, and AUC_0-inf were 115.4 mU/mL, 12,190 min·mU/mL, and 12,210 min mU/mL, respectively, indicating bioequivalence to Cerezyme. The mean t_½, CL, and V_z were 6.88 min, 376.7 mL/min, and 3.62 L, respectively, and were comparable between the two treatments. One participant in the Cerezyme group developed anti-drug antibodies, which were non-neutralizing A total of 24 subjects experienced treatment-emergent adverse event (TEAE). The most common TEAE was headache (3 in the Abcertin group and 5 in the Cerezyme group), followed by general disorders and administration site condition (3 in Abcertin group and 5 in Cerezyme group). Two participants in the Cerezyme sequence experienced severe TEAEs: one had a urinary tract infection, and the other developed urticaria, which leading to study withdrawal.</p><p><strong>Conclusion: </strong>Abcertin demonstrated pharmacokinetic equivalence to Cerezyme, with a comparable safety, immunogenicity, and tolerability profile. These findings support its potential as an affordable biosimilar for GD treatment.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 6","pages":"e70111"},"PeriodicalIF":1.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12166193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Germline PARN Variants in Telomere Biology Disorders and Challenges in Variant Curation.","authors":"Hasset T Nurelegne, Mone't B Thompson, Kelvin C de Andrade, Ashley S Thompson, Lisa J McReynolds, Marena R Niewisch, Sharon A Savage","doi":"10.1002/mgg3.70107","DOIUrl":"10.1002/mgg3.70107","url":null,"abstract":"<p><strong>Background: </strong>PARN encodes poly(A)-specific ribonuclease, a 3 exoribonuclease important in regulating RNA stability and maturation. Rare germline PARN variants have been reported in telomere biology disorders (TBDs) leading to its inclusion on gene panels for bone marrow failure syndromes and pulmonary diseases.</p><p><strong>Methods: </strong>To understand the extent of germline PARN variation in human disease, we conducted a comprehensive literature review, curated the TBD-associated PARN variants using AutoGVP and in silico prediction tools (MetaSVM, REVEL, and/or CADD) and assessed their frequency in the gnomAD database.</p><p><strong>Results: </strong>Ninety-three unique PARN variants were identified in the literature as present in individuals or families affected by TBDs, but clinical features were not consistently reported. Forty-one variants (44.1%) were classified as pathogenic or likely pathogenic. These variants were spread across the entire gene with no obvious clustering. gnomAD data were notable for a paucity of common variants and metrics suggesting PARN variation would be tolerated.</p><p><strong>Conclusion: </strong>The extent to which specific PARN variants can be associated with TBD etiology is limited due to incomplete literature, clinical data, lack of robust functional assays, and high frequency of rare variants.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 6","pages":"e70107"},"PeriodicalIF":1.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12120517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144173999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}