Molecular Genetics & Genomic Medicine最新文献

{"title":"Reporting a Homozygous Case of Neurodevelopmental Disorder Associated With a Novel PRPF8 Variant.","authors":"Mohammad Reza Mirinezhad, Farzaneh Mirzaei, Arash Salmaninejad, Reza Jafarzadeh Esfehani, Mohammad Reza Seyedtaghia, Sheyda Farahmand, Mehran Beiraghi Toosi, Somayyeh Hashemian, M E Suzzane Lewis","doi":"10.1002/mgg3.70084","DOIUrl":"10.1002/mgg3.70084","url":null,"abstract":"<p><strong>Background: </strong>While recently identified heterozygous PRPF8 variants have been linked to various human diseases, their role in neurodevelopmental disorders (NDDs) remains ambiguous. This study investigates the potential association between homozygous PRPF8 variants and NDDs. Most PRPF8 variants are primarily associated with retinal diseases; however, we analyze a family with multiple members diagnosed with NDDs.</p><p><strong>Methods: </strong>Using exome sequencing (ES), the cause of behavioral problems and intellectual disabilities (IDs) of two sisters from a consanguineous parents was solved, and the results confirmed by direct sanger sequencing method likewise protein modeling to assess the structural impact of the identified variant on the PRPF8 protein has been done.</p><p><strong>Results: </strong>ES identified a novel homozygous variant, PRPF8 c.257G>T, p.R86M. To the best of our knowledge at the time of writing this manuscript, the mentioned variant has not been reported in relation to NDDs. Protein modeling provided another line of evidence proving the pathogenicity of the novel variant.</p><p><strong>Conclusion: </strong>Our findings indicate that the p.R86M variant may disrupt normal protein function by changing its structure and probably its interaction, potentially leading to the observed neurodevelopmental phenotypes. This study highlights the first link between the PRPF8 variant and NDDs, suggesting a distinct role for specific PRPF8 variants in the etiology of NDDs. These results warrant further investigation into the mechanisms by which PRPF8 variants contribute to NDDs, emphasizing the need for comprehensive genetic screening in families with unexplained neurodevelopmental conditions.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 3","pages":"e70084"},"PeriodicalIF":1.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11894437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143597307","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":"Prevalence of Constitutional Pathogenic Variant in a Cohort of 348 Patients With Multiple Primary Cancer Addressed in Oncogenetic Consultation.","authors":"Mathis Lepage, Nancy Uhrhammer, Ioana Molnar, Maud Privat, Flora Ponelle-Chachuat, Mathilde Gay-Bellile, Yannick Bidet, Mathias Cavaillé","doi":"10.1002/mgg3.70086","DOIUrl":"10.1002/mgg3.70086","url":null,"abstract":"<p><strong>Introduction: </strong>Multiple primary malignancies (MPMs) refer to two or more primary malignant tumors in the same patient. MPMs are frequent: 18.4% of incident cancers represent a second or a higher primary cancer. In order to assess the value of genetic testing for patients with multiple cancers, studies are needed to accurately determine the prevalence of pathogenic variants for these patients.</p><p><strong>Methods: </strong>All families were seen in our oncogenetics consultation from 2010 to 2022. We compared clinical features and detection rates of pathogenic or likely pathogenic variants in a panel of up to 47 cancer predisposition genes in patients with ≥ 2 primary cancers (n = 348) versus a single primary cancer (n = 1422).</p><p><strong>Results: </strong>A pathogenic or likely pathogenic variant was diagnosed in 27.3% of patients with 348 index patients with MPM, concerning 21 genes: BRCA1 (n = 27), BRCA2 (n = 19), MSH2 (n = 9), ATM (n = 8), MLH1 (n = 5), MSH6 (n = 6), TP53 (n = 4), CHEK2 (n = 4), PALB2 (n = 3), APC (n = 2), MEN1 (n = 1), RAD51C (n = 1), NBN (n = 1), EPCAM (n = 1), PMS2 (n = 1), RB1 (n = 1), PTEN (n = 1), CYLD1 (n = 1), NF1 (n = 1), RAD51D (n = 1), and CDKN2A (n = 1). MPM index cases were more likely to carry a deleterious mutation than cases with a single cancer (27.3% vs. 11.39%, p < 0.001). Pathogenic variants were found more frequently in patients with a suggestive family history (34.2% vs. 20.1%, p < 0.05), with a younger age of cancer diagnosis related to the suspected syndrome (32.7% vs. 22%, p = 0.049). For the 208 index patients with ≥ 2 cancers pertaining to the same predisposition syndrome (HBOC, HNPCC…), the detection rate increased significantly to 36% (vs. 14.3% for MPM patients with unrelated cancers (n = 140), p < 0.001). Conversely, the detection rate for patients with unrelated cancers was not statistically different from the single-cancer population (14.3%-11.39%, p = 0.318).</p><p><strong>Conclusion: </strong>Patients referred for oncogenetic testing with MPM are more likely to carry pathogenic variants in cancer predisposition genes than patients with a single primary cancer (p < 0.05), especially if the cancers are related to the same predisposition syndrome. If the cancers are unrelated, no statistical difference in comparison to the single-cancer population was observed. For these latter patients, we recommend using the specific criteria of each tumor to propose appropriate genetic testing.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 3","pages":"e70086"},"PeriodicalIF":1.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531649","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 Variant in Dentin Sialophosphoprotein (DSPP) Gene Causes Dentinogenesis Imperfecta Type III: Case Report.","authors":"Yan Wang, Ximin Xu, Yuzhe Ding, Guohua Yuan","doi":"10.1002/mgg3.70087","DOIUrl":"10.1002/mgg3.70087","url":null,"abstract":"<p><strong>Background: </strong>Hereditary dentin defects are a group of autosomal dominant disorders characterized by developmental abnormalities in dentin formation and mineralization. They can be categorized into dentin dysplasia and dentinogenesis imperfecta.</p><p><strong>Methods: </strong>In this study, we report a Chinese family with dentinogenesis imperfecta type III (DGI-III). The proband, a 3-year-old girl, and her mother showed extremely rapid attrition and opalescent discoloration in their teeth. Besides, the primary teeth of the proband showed \"shell teeth\" radiographically, a phenotype characterized by abnormally enlarged pulp cavities and thin dentin, which are specific features of DGI-III. The clinical data was collected and the genomic DNA was extracted from their peripheral blood samples. Whole-exome sequencing and Sanger sequencing were performed to screen for variations. Then we preliminarily evaluated the secretion of the dentin sialophosphoprotein (DSPP) variant of this family and compared this variant with wild-type DSPP via western blot (WB) analysis in vitro.</p><p><strong>Results: </strong>The results revealed a novel variant (NM_014208: exon2: c.38C>A: p.A13E) in the signal peptide coding region of the DSPP gene in both the proband and her mother, but not in her father, who had normal teeth. The secretion of the variant DSPP protein was not detected in Human embryonic kidney 293E cells via WB analysis.</p><p><strong>Conclusion: </strong>Taken together, this study describes the clinical features and genetic etiology of a family with DGI-III, expanding the range of variants that cause DGI-III and enriching the phenotypes associated with variants in the signal peptide segment of DSPP. Functional analysis reveals that this variant disrupts DSPP protein secretion.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 3","pages":"e70087"},"PeriodicalIF":1.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11880773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557341","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 KCNQ4 Gene Variant (c.701A > G; p.His234Arg) in a Chinese Family With Nonsyndromic Deafness 2A.","authors":"Guo-Qing Gong, Cheng-Cheng Huang, Hui-Yu Jin, Zhao Zhang, Chang-Liang Yang, Guang Yang, Hui-Fang Lu, Yue-Bin Yang, Jing-Yuan Cao, Rui-Yao Chen, Li-Wang, Yi-Ming Ji, Yi Sun, Yu Lu","doi":"10.1002/mgg3.70075","DOIUrl":"10.1002/mgg3.70075","url":null,"abstract":"<p><strong>Background: </strong>KCNQ4 is a common genetic cause of nonsyndromic autosomal dominant hearing loss. We have identified the family in China with a KCNQ4 (c.701A>G; p.His234Arg) missense variation. In this study, a survey and analysis were performed to investigate the audiological and genetic characteristics of the Chinese family.</p><p><strong>Methods: </strong>The medical history of family members was collected, and the family members underwent pure tone audiometry, acoustic immittance, and physical examination. The proband was additionally examined by ABR (auditory brainstem response) and DPOAE (distortion product otoacoustic emission). DNA samples from family members were collected, and the possible causative gene of the proband was detected by whole-exome sequencing (WES), which was verified by Sanger sequencing in family members.</p><p><strong>Results: </strong>The inheritance pattern of the family was an autosomal dominant nonsyndromic type. The hearing loss was characterized by postlingual deafness, high-frequency hearing loss in the early stage, gradually involving the full frequency. About 32-40 years of age, the hearing gradually became stable, the decline rate slowed down, and the final degree of hearing loss was severe. WES results showed that the KCNQ4 gene had a missense variation (c.701A>G; p.His234Arg).</p><p><strong>Conclusion: </strong>This family has autosomal dominant nonsyndromic hereditary hearing loss caused by a variation in the KCNQ4 gene, characterized by high-frequency hearing loss.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 3","pages":"e70075"},"PeriodicalIF":1.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11886983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573001","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 Mutation in the ANK2 Gene Causing ASD and a Review of the Literature.","authors":"Lu Zhao, Zhi-Dong Qiao, Yue-Xin Jia, Jun-Xian Fu, Tian-Xia Li, Kai-Ru Jia, Hong Zhao, Jin-Ping Bao, Xiao-Fan Yang, Hao Pan, Guang-Lu Yang","doi":"10.1002/mgg3.70083","DOIUrl":"10.1002/mgg3.70083","url":null,"abstract":"<p><strong>Objective: </strong>To investigate the clinical and genetic characteristics of patients with ANK2(HGNC:493)-associated autism spectrum disorders (ASDs) and epilepsy (EP).</p><p><strong>Methods: </strong>We identified a novel ANK2 variant in a patient with ASD and EP and summarized the clinical and genetic characteristics of ANK2 gene variants in this patient and those in previous reports.</p><p><strong>Results: </strong>A novel nonsense variant, ANK2 (NM_001148.6):c.3007C>T/p.R1003* in exon 27, was identified in one patient. We described the clinical features and molecular genetics of this patient and previously reported patients. This was discovered at a follow-up visit to the pediatric neurology department where genetic testing based on condition identified this rare genetic variant. He mainly presents with language delay, intellectual disability, limited learning, and communication skills, and later develops seizures, combined with common childhood neurological disorders such as hyperactivity, behavioral abnormalities, and even self-injury. The patient cohort included 16 patients with a complex array of neurological disabilities: ASD (9 patients); EP (10 patients); ASD with EP (4 patients); intellectual disability and developmental delay (5 patients); poor language communication (11 patients); language and learning impairment (11 patients); anxiety/agitation mood disorder (6 patients); attention-deficit/hyperactivity disorder (5 patients); cognitive, memory, and adaptability deficits (1 patient); tic disorder (1 patient); electrocardiogram and cardiac damage (1 patient); and abnormal electroencephalography (EEG) (9 patients).</p><p><strong>Conclusion: </strong>For the first time, we identified a novel variant of the ANK2 gene in China, broadening the genetic spectrum of the ANK2 gene. ANK2 gene mutations can cause ASD, EP, ASD with EP, developmental delay and intellectual disability, poor language communication skills, language and learning disorders, anxiety/agitation mood disorder, and attention-deficit/hyperactivity disorder. Clinical ASD, EP, common EP should consider the ANK2 gene mutation.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 3","pages":"e70083"},"PeriodicalIF":1.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542727","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 Biallelic Variant in IHH Causing Acrocapitofemoral Dysplasia in a Pakistani Family.","authors":"Tayyaba Saeed, Nousheen Bibi, Ashfaq Ahmad, Saadullah Khan, Muhammad Ansar, Naveed Wasif, Umm-E- Kalsoom","doi":"10.1002/mgg3.70085","DOIUrl":"10.1002/mgg3.70085","url":null,"abstract":"<p><strong>Background: </strong>Acrocapitofemoral dysplasia (ACFD) is a rare autosomal recessive disorder, characterized by postnatal onset of disproportionate short stature with short limbs, brachydactyly, cone-shaped epiphysis, narrow thorax, and relatively large head. To date, only three homozygous missense mutations have been reported in the signaling amino terminal domain (201-308 amino acids) of the IHH gene in three ACFD families from Belgian, Dutch, and Turkish ethnicities.</p><p><strong>Methods: </strong>In the present study, we have investigated two patients in a Pakistani family affected with ACFD. Whole exome sequencing (WES) followed by Sanger sequencing was carried out for mutational screening. The variant was further validated by in silico modeling and molecular dynamics simulation analysis.</p><p><strong>Results: </strong>Data analysis revealed a novel homozygous missense variant [c.518C>A; p.(Ala173Asp)] in exon 2 of the IHH (NM_002181.4) gene. The variant segregated within the family and was not observed in unaffected ethnically matched controls. In silico modeling and dynamic simulation analysis revealed that the variant disturbed the core structure of the domain and destabilized the loop region and the region surrounding the variant.</p><p><strong>Conclusion: </strong>This study reports the first case of ACFD from Pakistan and identifies the fourth novel missense variant in the IHH gene that led to the broadening of the phenotypic and genotypic spectrum of ACFD.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 3","pages":"e70085"},"PeriodicalIF":1.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11883292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567308","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":"Genome-Wide Scan of Fifth Finger Clinodactyly.","authors":"Myoung Keun Lee, Noah Herrick, Mary L Marazita, John R Shaffer, Seth M Weinberg","doi":"10.1002/mgg3.70090","DOIUrl":"10.1002/mgg3.70090","url":null,"abstract":"<p><strong>Background: </strong>Fifth finger clinodactyly describes the conspicuous curvature of the fifth digit toward the other digits of the hand. Phenotypic expression can range from mild and almost imperceptible to severe, where function is impacted, and clinical intervention may be required. Although classically considered an autosomal dominant trait based on early family studies, no genes have been mapped for the trait. Further, there is epidemiological evidence that mild (typical-range) fifth finger clinodactyly may have a different etiology than more severe forms.</p><p><strong>Methods: </strong>In this retrospective cross-sectional study, we carried out genome-wide association mapping of common genetic variants for clinodactyly in three cohorts separately and combined results via meta-analysis, treating the trait as either a continuous quantitative variable (n_meta = 631) or a binary outcome (n_meta = 1647).</p><p><strong>Results: </strong>The vast majority of participants in these cohorts exhibited mild forms of clinodactyly. Both the individual cohort results and meta-analyses revealed no genome-wide significant loci. We identified several possible suggestive signals (p < 1 × 10^-6), but these showed no evidence of replication.</p><p><strong>Conclusion: </strong>While our results cannot definitively exclude the contribution of common variants to fifth finger clinodactyly due to the small sample size, they do suggest that the mild form of the trait is unlikely to be related to a major gene effect operating in a simple Mendelian manner.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 3","pages":"e70090"},"PeriodicalIF":1.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11897800/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605688","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":"Approaches to Evaluate Whole Exome Sequencing Data That Incorporate Genetic Intolerance Scores for Congenital Anomalies, Including Intronic Regions Adjacent to Exons.","authors":"Kosuke Taniguchi, Fuyuki Hasegawa, Yuka Okazaki, Asuka Hori, Hiroko Ogata-Kawata, Saki Aoto, Ohsuke Migita, Tomoko Kawai, Kazuhiko Nakabayashi, Kohji Okamura, Kana Fukui, Seiji Wada, Katsusuke Ozawa, Yushi Ito, Haruhiko Sago, Kenichiro Hata","doi":"10.1002/mgg3.70092","DOIUrl":"10.1002/mgg3.70092","url":null,"abstract":"<p><strong>Background: </strong>Whole exome sequencing (WES) aids in diagnosing monogenic diseases, yet > 50% of all cases remain undiagnosed. We aimed to improve diagnostic precision by developing an effective WES-based strategy for detecting congenital anomalies.</p><p><strong>Methods: </strong>Initially, 128 probands with congenital anomalies were assessed using trio-WES and copy number variation analysis-variant interpretation was for exons and splice sites. Thereafter, we reanalyzed the sequence data for undiagnosed cases using the following methods. First, we performed trio-WES analysis, adding genetic intolerance scores annotation. Second, we analyzed all exons, splicing sites, and intron variants for cases with phenotypes suggestive of specific causative genes using SpliceAI. Lastly, using SpliceAI, we analyzed all exons, splicing sites, and intron variants in genetically constrained genes filtered with genetic intolerance scores.</p><p><strong>Results: </strong>Initial analysis diagnosed 51 of 128 cases (39.8%). In the reanalysis, first, we identified novel likely pathogenic variants in MED12 and CCDC22 associated with X-linked diseases. Second, a novel TMEM67 intron variant associated with Meckel syndrome was detected. Finally, a de novo hemizygous pathogenic intronic variant in CASK was identified in a case of intrauterine fetal death.</p><p><strong>Conclusions: </strong>WES analysis, including intronic regions and utilizing genetic intolerance scores, has the potential to efficiently improve diagnostic yield.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 3","pages":"e70092"},"PeriodicalIF":1.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143616254","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":"Two Nonsense GLI3 Variants Are Identified in Two Chinese Families With Polydactyly.","authors":"Yongzhen Qi, Kai Liu, Yuda Wei, Xiaxia Liu, Liangqian Jiang, Juan Teng, Baoqiang Chong, Shuqi Zheng, Xiangyu Zhao, Lin Li","doi":"10.1002/mgg3.70088","DOIUrl":"10.1002/mgg3.70088","url":null,"abstract":"<p><strong>Background: </strong>Polydactyly is a prevalent limb deformity with an autosomal dominant inheritance pattern, manifesting in both syndromic and nonsyndromic forms. It exhibits significant etiological and clinical diversity. This study aims to identify the pathogenic cause in two patients with sub-PHS (sub-Pallister-Hall Syndrome) and PAP (postaxial polydactyly), respectively, from two Chinese pedigrees.</p><p><strong>Methods: </strong>Exome sequencing was performed on patients to screen for potential pathogenic variants. Subsequently, these variants were validated by Sanger sequencing. The c.3342dupC and c.4431dupT mutant plasmids were transfected into HEK293T cells, and the effects of GLI3 mutations on transcription and protein levels were analyzed via qRT-PCR and Western blot. Additionally, Swiss Model was utilized to predict the effects of mutations on protein tertiary structure.</p><p><strong>Results: </strong>The mutations of GLI3 (NM_000168.6: c.3342dupC; p. A1115Rfs*14) (NM_000168.6: c.4431dupT; p. Glu1478Ter) were identified in affected individuals. These mutations were present exclusively in the patients and absent in the healthy individuals. No significant difference in transcription levels between the mutations and wild type was observed. Functional analysis revealed that the truncated variants p. A1115Rfs*14 and p. Glu1478Ter exhibited reduced molecular weight and potential functional impairment due to protein retention.</p><p><strong>Conclusion: </strong>The mutations p. A1115Rfs*14 and p. Glu1478Ter in GLI3 may account for sub-PHS and PAP in the two patients, respectively. This finding expands the mutation and phenotype spectrum associated with GLI3, providing valuable insights for the clinical diagnosis of polysyndactyly.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 3","pages":"e70088"},"PeriodicalIF":1.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11886411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573143","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":"Incomplete Trisomy Rescue Reveals the Mechanism Underlying Discordance Between Noninvasive Prenatal Screening and Prenatal Diagnosis.","authors":"Yanan Wang, Yong Zhou, Yuqiong Chai, Weiwei Zang, Hongchao Wang, Fan Yin, Qianqian Tan, Zhigang Chen","doi":"10.1002/mgg3.70091","DOIUrl":"10.1002/mgg3.70091","url":null,"abstract":"<p><strong>Background: </strong>Uniparental disomy (UPD) is a specific type of chromosomal variation in which both chromosomes of a homologous pair are inherited from the same parent. It is responsible for a wide range of disorders. Monosomy rescue and trisomy rescue are the two main hypotheses of UPD generation.</p><p><strong>Methods: </strong>An older parturient woman with a positive noninvasive prenatal screening (NIPS) test but a negative prenatal diagnosis was referred to the hospital. Trio whole exome sequencing (trio-WES) and ddPCR were further performed.</p><p><strong>Results: </strong>Utilizing Trio-WES analysis, our research identified a maternal segmental UPD on chromosome 16, characterized by isodisomic genomic segments at the ends of the chromosome arms and heterodisomic genomic segments near the centromere. Moreover, several nuanced signs pointing to the paternal chromosome 16 were discovered, suggesting a low level of trisomy 16 mosaicism. A homozygous missense mutation (c.1499C>T; p.Ala500Val) was also detected in the fetal TBC1D24 gene, passed down from the heterozygous carrier mother. Furthermore, ddPCR analysis verified a 3% mosaic level of trisomy 16.</p><p><strong>Conclusion: </strong>We have quantitatively verified for the first time a combination of trisomy 16 mosaicism and maternal segmental UPD 16 due to incomplete trisomy rescue, illuminating the cause of the mismatch between positive NIPS and negative prenatal diagnoses.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 3","pages":"e70091"},"PeriodicalIF":1.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625298","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}