Molecular Genetics & Genomic Medicine最新文献

{"title":"Spastic Paraplegia Type 78 Associated With ATP13A2 Gene Variants in Compound Heterozygosity.","authors":"R Bermejo Ramírez, N Villena Gascó, L Ruiz Palmero, G A Ribes Bueno, E Seiti Yamanaka, J D Arroyo Andújar","doi":"10.1002/mgg3.70073","DOIUrl":"10.1002/mgg3.70073","url":null,"abstract":"<p><strong>Background: </strong>Spastic Paraplegia Type 78 (SPG78) is a rare form of hereditary spastic paraplegia (HSP), mainly characterized by late-onset lower-limb spasticity, muscle weakness, and in some cases cerebellar dysfunction and cognitive impairment. Understanding its genetic background is essential to distinguish it from other autosomal recessive types of HSP.</p><p><strong>Methods: </strong>A pathogenic variant screening in a Spanish HSP patient was carried out by whole-exome sequencing, followed by a software filtering process and validation of candidate variants by Sanger sequencing. The pathogenicity of the selected variants was evaluated by In Silico predictions and a segregation analysis including the proband and 16 family members.</p><p><strong>Results: </strong>Two variants in the ATP13A2 gene, predicted to have damaging effects by In Silico analyses, were considered potentially pathogenic: NM022089.4:c.649G>A (rs199961048), previously associated with SPG78 but with uncertain clinical significance, and NM_022089.4:c.2097delC, an unreported variant. The segregation analysis revealed that both variants were present in compound heterozygosity in the proband and two affected siblings, while unaffected relatives carried only one or none of the variants.</p><p><strong>Conclusion: </strong>These findings suggest that the two variants are pathogenic when occurring in compound heterozygosity and, therefore, should be included in the genetic spectrum of SPG78 diagnosis.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 2","pages":"e70073"},"PeriodicalIF":1.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11814479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399456","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 Korean Patient With Leber Congenital Amaurosis and a Homozygous RPE65 Variant Originating From a Paternal Uniparental Isodisomy.","authors":"Hane Lee, Dongseok Moon, Rin Khang, Go Hun Seo, Chang Ki Yoon, Un Chul Park, Kyu Hyung Park, Eun Kyoung Lee","doi":"10.1002/mgg3.70060","DOIUrl":"10.1002/mgg3.70060","url":null,"abstract":"<p><strong>Background: </strong>Leber congenital amaurosis (LCA), the most severe form of inherited retinal dystrophy, is a rare, heterogeneous, genetic eye disease associated with severe congenital visual impairment. RPE65, one of the causative genes for LCA, encodes retinoid isomerohydrolase, an enzyme that plays a critical role in regenerating visual pigment in photoreceptor cells.</p><p><strong>Methods: </strong>Exome sequencing (ES) was performed on a patient with suspected LCA.</p><p><strong>Results: </strong>Here, we report a 33-year-old male patient diagnosed with RPE65-related LCA caused by uniparental isodisomy (UPiD) who received gene therapy as treatment, fourth patient to receive it in Korea. His fundus examinations showed salt-and-pepper retinal dystrophy, with diffuse extinguished signal on fundus autofluorescence and attenuated amplitude on electroretinogram. A homozygous frameshift variant NM_000329.3:c.1067del (p.Asn356MetfsTer17) in RPE65 was identified by ES with the entire chromosome 1 proving to be paternal UPiD. Within 5 months after the molecular diagnosis, the patient was treated with subretinal voretigene neparvovec (VN) therapy and is being followed up for prognosis.</p><p><strong>Conclusions: </strong>To our knowledge, this patient is the first UPiD case to receive VN treatment. Performing ES as a first-tier test was favourable because it allowed to identify UPiD that needed to be detected in addition to the disease-causing variant.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 1","pages":"e70060"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008523","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":"Influence of the Sex of Translocation Carrier on Clinical Outcomes of Couples Undergoing Preimplantation Genetic Testing.","authors":"Zhiping Zhang, Jiayao Chen, Lei Zhang, Ruiyang Wei, Zhen Liu, Dunmei Zhao, Xingyu Bi, Lixia Liang, Xueluo Zhang, Dan Su, Xueqing Wu","doi":"10.1002/mgg3.70050","DOIUrl":"10.1002/mgg3.70050","url":null,"abstract":"<p><strong>Introduction: </strong>This study investigated the impact of the carrier on transferable blastocyst rate and live birth outcomes in couples with structural chromosomal abnormalities.</p><p><strong>Methods: </strong>Couples were grouped into reciprocal translocation, Robertsonian translocation, or inversions groups, and clinical data were retrospectively analyzed. Preimplantation genetic testing for chromosomal structural rearrangements (PGT-SR) was conducted, and pregnancy outcomes were compared.</p><p><strong>Results: </strong>Embryo euploidy rates between male and female carriers differed nonsignificantly in the reciprocal translocation and inversion groups but significantly among the three groups. In the Robertsonian translocation group, male carriers had a higher embryo euploidy rate than that of female carriers. Sperm density of male carriers with reciprocal and Robertsonian translocation was significantly lower than that of the female carrier in the same group, whereas the difference was non-significant in the inversion group. The clinical outcomes of embryo transfer post-PGT were similar regardless of the sex of carriers with structural chromosomal abnormalities. Female carriers with Robertsonian translocations displayed a higher risk of producing embryos with chromosomal abnormalities than male carriers. Pregnancy, live birth, and cumulative live birth rates following a PGT-SR cycle were similar, irrespective of chromosomal structural rearrangement type, and carrier sex.</p><p><strong>Conclusion: </strong>Our findings offer valuable information for genetic counseling.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 1","pages":"e70050"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11672741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896196","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":"Interpreting Variants of Uncertain Significance in PCD: Abnormal Splicing Caused by a Missense Variant of DNAAF3.","authors":"Haixia Zheng, Chongsheng Cheng, Miao He, Wangji Zhou, Yixuan Li, Jinrong Dai, Ting Zhang, Kai-Feng Xu, Xue Zhang, Xinlun Tian, Yaping Liu","doi":"10.1002/mgg3.70036","DOIUrl":"https://doi.org/10.1002/mgg3.70036","url":null,"abstract":"<p><strong>Background: </strong>Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterized by dysfunction of motile cilia. While approximately 50 genes have been identified, around 25% of PCD patients remain genetically unexplained; elucidating the pathogenicity of specific variants remains a challenge.</p><p><strong>Methods: </strong>Whole exome sequencing (WES) and Sanger sequencing were conducted to identify potential pathogenic variants of PCD. Minigene assays were performed to evaluate the pathogenicity of variants. Transmission electron microscopy (TEM) and high-speed video analysis (HSVA) were conducted to analyze the function of cilia in respiratory epithelial cells.</p><p><strong>Results: </strong>We identified two variants of DNAAF3: c.557G>A, p.G186E in exon 5, and c.1364G>A, p.G455D at the terminal nucleotide of exon 10 in a 16-year-old male patient. Through a minigene assay, we demonstrated that the c.1364G>A variant led to a four-nucleotide skipping. The cilia in epithelial ciliary cells of the proband were almost immotile. The absence of outer dynein arms and inner dynein arms was also observed.</p><p><strong>Conclusions: </strong>Our study identified two compound heterozygous variants of DNAAF3, a pathogenic gene for PCD, and proved that a novel missense variant c.1364G>A affects splicing. Our findings not only expanded the spectrum of mutations in the DNAAF3 gene but also highlighted the importance of investigating variants of uncertain significance (VUS) for comprehensive genetic diagnoses.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 1","pages":"e70036"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951743","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":"Phenylbutyric Acid Modulates Apoptosis and ER Stress-Related Gene Expression in Glycogen Storage Disease Type Ib In Vitro Model.","authors":"Marina Parezanovic, Nina Stevanovic, Marina Andjelkovic, Milena Ugrin, Sonja Pavlovic, Maja Stojiljkovic, Anita Skakic","doi":"10.1002/mgg3.70054","DOIUrl":"10.1002/mgg3.70054","url":null,"abstract":"<p><strong>Introduction: </strong>Chronic endoplasmic reticulum (ER) stress and increased apoptosis are involved in the pathogenesis of glycogen storage disease Ib (GSD Ib), whereas small molecule phenylbutyrate (4-PBA) showed the capability of reducing ER stress-induced apoptosis. The objective was to generate an in vitro system in which capability of small molecules (SMs) to influence ER stress and apoptosis could be screened at the expression level.</p><p><strong>Methods: </strong>G6PT-deficient FlpInHEK293 cell line was created and validated using the CRISPR/Cas9 knockout method. Molecular markers of unfolded protein response (ATF4, DDIT3, HSPA5, XBP1s), and apoptosis (BCL2/BAX, CASP3, CASP7) in G6PT-deficient cells were analyzed using RT-qPCR method before and upon the treatment with 4-PBA.</p><p><strong>Results: </strong>Treatment with the most effective dose of 1 mM 4-PBA reduced the expression of UPR markers and executioner caspases, while increased BCL2/BAX ratio in G6PT-deficient cells. Our results proved the concept that 4-PBA could alleviate markers of ER stress detected in the GSD Ib in vitro model system and prevent cell death.</p><p><strong>Conclusion: </strong>This cost-effective in vitro model screens the therapeutic potential of SMs affecting ER stress and apoptosis in G6PT-deficient kidney cells, offering a first-line screening assay for promising compounds. 4-PBA's potential repurposing for GSD Ib patients opens new research directions.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 1","pages":"e70054"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971661","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":"Genetics of Primary Adrenal Insufficiency Beyond CAH in Saudi Arabian Population.","authors":"Mohamed H Al-Hamed, Alya Qari, Lamya Alrayes, Mohammed Alotaibi, Zainab Al Masseri, Afaf Alotaibi, Abdullah AlAshwal, Zuhair N AlHassnan, Afaf Alsagheir","doi":"10.1002/mgg3.70052","DOIUrl":"10.1002/mgg3.70052","url":null,"abstract":"<p><strong>Background: </strong>The use of exome sequencing (ES) has helped in detecting many variants and genes that cause primary adrenal insufficiency (PAI). The diagnosis of PAI is difficult and can be life-threatening if not treated urgently. Consanguinity can impact the detection of recessively inherited genes. Here, we report families with PAI in a consanguineous population of Saudi Arabia.</p><p><strong>Materials and methods: </strong>A cohort of 47 PAI patients (41 males and six females) representing 30 families was recruited. The cohort excluded congenital adrenal hyperplasia (CAH) cases and had a known consanguinity of 70%. Using ES, molecular genetic causes of PAI were investigated.</p><p><strong>Results: </strong>In 30 unrelated families with PAI, pathogenic/likely pathogenic variants were detected in 27 families with a diagnostic yield of (90%). Clinically associated variants of uncertain significance (VUS) were identified in a further two PAI families (7%). Hemizygous variants in ABCD1 were the most common cause of PAI in this cohort (16 families) leading to adrenoleukodystrophy. A total of six novel variants were detected, of which four were predicted to be pathogenic (P) / likely pathogenic (LP) and two were VUS. Four pathogenic variants in ABCD1, NR0B1, and MC2R were detected in 10 families suggesting founder mutations.</p><p><strong>Conclusion: </strong>In this cohort, ES detected a diagnostic molecular abnormality in 90% of patients with PAI phenotypes. X-linked inheritance is the most common cause of PAI and founder mutations likely contributed to a high diagnostic yield.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 1","pages":"e70052"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11757666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143033712","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":"Clinicopathological features of Lynch syndrome pedigrees with MSH2 c.351G>A gene variant.","authors":"Shuai Zhang, Guanyu Fu, Gongping Sun, Yuanxin Tang, Jin Meng, Zhigang Wang, Rongjun Su, Wei Liu, Xiaoxia Li","doi":"10.1002/mgg3.2506","DOIUrl":"10.1002/mgg3.2506","url":null,"abstract":"<p><strong>Background: </strong>Lynch syndrome (LS) is an autosomal-dominant disorder that increases the risk of many cancers. To identify novel or rare pathogenic variants of MMR genes associated with LS, especially in Chinese pedigrees.</p><p><strong>Methods: </strong>One four-generation Chinese Han family from northeast China with 29 members was enrolled. Clinical diagnosis of LS was established in this family, according to Amsterdam II. The proband and some relatives of the family were subjected to immunohistochemical analysis of MMR protein, microsatellite instability (MSI) testing, whole-exome sequencing, and Sanger sequencing.</p><p><strong>Results: </strong>Nine patients with 19 primary cancers were found in this family, with a wide spectrum of synchronous and metachronous cancers, including digestive, reproductive, respiratory, urinary, and other systems. In addition, one member of this family is found to have both thyroid and lung cancers, which have been reported only once in LS patients before but have not been considered extracolonic in the LS spectrum. The immunohistochemical analysis of the mother of the proband showed loss of MSH2 and MSH6 protein, and consistently, high microsatellite instability (MSI-H) was confirmed in LS patients. Furthermore, whole-exome sequencing identified a nonsense variant in MSH2, MSH2:NM_000251:c.351G > A(p.W117*), in all three tested LS patients (II-1, III-1, and III-4), but not in healthy relatives IV-1 in this family. This result is further verified by Sanger sequencing.</p><p><strong>Conclusion: </strong>Uncover a rare nonsense variant in MSH2 gene, which contributes to LS of this family. The clinicopathological characteristics of LS in this family include common simultaneous or heterogeneous multiple primary cancers, a broad tumor spectrum, and a younger age with the continuation of genetic algebra.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 1","pages":"e2506"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695460/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142922001","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":"Successful Diagnosis of Sengers Syndrome Using a Comprehensive Genomic Analysis.","authors":"Kohta Nakamura, Yukiko Yatsuka, Sachie Naito, Akira Hasegawa, Takeya Kasukawa, Atsushi Kondo, Yoshihito Kishita, Yohei Sugiyama, Takanori Onuki, Tomohiro Ebihara, Tomoko Tsuruoka, Takuya Fushimi, Akira Ohtake, Kei Murayama, Atsuko Imai-Okazaki, Yasushi Okazaki","doi":"10.1002/mgg3.70048","DOIUrl":"10.1002/mgg3.70048","url":null,"abstract":"<p><strong>Background: </strong>Sengers syndrome is an autosomal recessive mitochondrial DNA depletion syndrome characterized by hypertrophic cardiomyopathy, congenital cataracts, skeletal myopathy, exercise intolerance, and lactic acidosis. Dysfunction of acylglycerol kinase (AGK) is responsible for the disease, and several AGK gene variants have been reported.</p><p><strong>Methods: </strong>We employed a comprehensive genomic analysis approach, including whole-genome sequencing and RNA sequencing, combined with various bioinformatics tools.</p><p><strong>Results: </strong>Our analysis successfully diagnosed Sengers syndrome in a patient by detecting a known pathogenic variant and a previously unreported large deletion involving the AGK gene in a segmental duplication.</p><p><strong>Conclusion: </strong>This study demonstrates the effectiveness of combining multiple genomic analysis approaches for the accurate diagnosis of Sengers syndrome, particularly in cases involving complex genetic variations such as large deletions in segmental duplications.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 1","pages":"e70048"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055957","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":"Analysis of a Series of 26 Cases With Prenatal Skeletal Dysplasia via Multiplatform Genetic Detection.","authors":"Li-Min Cui, Hua-Ying Hu, Xiao-Mei Zhai, Ming-Fei Qi, Yan-Ming Liu, Cong-Ying Han, Jing Zhang, Ming Shen, Yu-Lan Xiang, Wen-Qi Chen, Kai Yang, Dong-Liang Zhang, Huan-Xia Xing","doi":"10.1002/mgg3.70062","DOIUrl":"10.1002/mgg3.70062","url":null,"abstract":"<p><strong>Background: </strong>Skeletal dysplasia (SD) represents a series of highly heterogeneous congenital genetic diseases affecting the human skeletal system. Refined genetic diagnosis is helpful for the accurate diagnosis and prognosis evaluation of SDs.</p><p><strong>Materials and methods: </strong>In this study, we recruited 26 cases of SD and analyzed them with a designed sequential genetic detection. Chromosome karyotyping, microarray analysis (CMA), and whole exome sequencing (WES) techniques are performed as needed. Sanger sequencing and fluorescent quantitative PCR (QF-PCR) were used as validation methods.</p><p><strong>Results: </strong>A total of 16 cases (61.5%, 16/26) received positive results at various levels of testing, including one trisomy 18, four copy number variations (CNVs), and 11 sequence variations. Additionally, four novel SD-related sequence mutations were detected in this study.</p><p><strong>Conclusion: </strong>Our findings provide conclusive evidence for genetic counseling of corresponding families and expand the mutation spectrum of SD. In addition, this study demonstrates that a strategy sequentially including various genetic techniques contributes to the diagnosis of highly heterogeneous genetic disorders such as SD.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 1","pages":"e70062"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008528","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":"Clinical Features and Genetic Characteristics of XLID Patients With KDM5C Gene Mutations: Insights on Phenotype-Genotype Correlations From 175 Previous Cases and Identification of a Novel Variant.","authors":"Mohammad-Reza Ghasemi, Zahra Esmaeilizadeh, Sahand Tehrani Fateh, Hossein Sadeghi, Saman Bagheri, Farzad Hashemi-Gorji, Morteza Sheikhi Nooshabadi, Rasoul Madannezhad, Toktam Sadat Tavabe Ghavami, Reza Mirfakhraie, Mohammad Miryounesi","doi":"10.1002/mgg3.70057","DOIUrl":"10.1002/mgg3.70057","url":null,"abstract":"<p><strong>Background: </strong>X-linked intellectual disability (XLID) is a genetically heterogeneous disorder that results in cognitive impairment and developmental delays. Mutations in the KDM5C gene have been identified as a causative factor in XLID. This study aimed to identify novel variants associated with XLID and to investigate the clinical and genetic characteristics of XLID patients with mutations in the KDM5C gene. This study also conducted a narrative review of the literature to identify key clinical and genetic characteristics of XLID caused by mutations in the KDM5C gene.</p><p><strong>Study design: </strong>Whole-exome sequencing was performed on the proband's DNA, and Sanger sequencing was used to confirm and analyze the identified variant in a 20-month-old male patient with motor and speech delays. Moreover, a comprehensive literature review was conducted to gather previously reported cases, providing insights into the molecular findings and clinical characteristics of this disorder.</p><p><strong>Results: </strong>The study identified a novel variant, c.2704C>T:p.Gln902X, located in exon 19 of the KDM5C gene (NM_004187.5) using Whole exome sequencing (WES), highlighting the utility of this approach in identifying rare genetic disorders. The analysis also revealed the variable clinical features associated with KDM5C-related disorders and identified missense variants as the most prevalent among the reported variants.</p><p><strong>Conclusions: </strong>This study provides insights into the clinical and genetic characteristics of XLID associated with KDM5C gene mutations, highlighting the higher manifestation of seizures in males and also addressing the heterogeneity of phenotypes in females. It also identifies a novel pathogenic variant and emphasizes the importance of considering gender-specific factors and further research to understand the underlying molecular mechanisms.</p><p><strong>Clinvar accession number: </strong>SCV004034082.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"13 1","pages":"e70057"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008540","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}