Clinical Genetics最新文献

{"title":"Elucidating the Genetic Underpinnings of Human Musculoskeletal System Aging Through Genomic Structural Equation Modeling.","authors":"Hao Xiong, Pan Shen, Qinghua Luo, Leichang Zhang, Bo Li, Zhaohui Ding, Lihua Wang","doi":"10.1111/cge.14766","DOIUrl":"https://doi.org/10.1111/cge.14766","url":null,"abstract":"<p><p>The genetic architecture underlying traits related to Human Musculoskeletal System Aging (MSA) remains largely unexplored. In this study, we conducted a large-scale multivariate genome-wide association study (GWAS) of MSA utilizing Genomic Structural Equation Modeling (Genomic SEM). We estimated causal single nucleotide polymorphisms (SNPs) associated with independent variation and identified 14 genome-wide significant loci (mean.PP > 0.95). We employed multiple transcriptome-wide association methods to analyze tissue, cellular levels, and genomic elements, identifying loci with high relevance to MSA susceptibility, along with associated element information. Our research represents the first comprehensive delineation of the genetic architecture of Musculoskeletal System Aging through a GWAS of unmeasured phenotype.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a De Novo Heterozygous Frameshift Variant in FMR1 in a Female With Fragile X Syndrome","authors":"Alejandro Parra,&nbsp;Juan A. Jimenez-Estrada,&nbsp;Valeria Vásquez-Amell,&nbsp;Mario Cazalla,&nbsp;Manuel Rodríguez-Canó,&nbsp;Natalia Gallego-Zazo,&nbsp;Lucia Miranda,&nbsp;Mónica Mora-Gómez,&nbsp;Elena Vallespín,&nbsp;Rocío Mena,&nbsp;Luis Fernández,&nbsp;Cristina Silván,&nbsp;Pedro Arias,&nbsp;Marta Dominguez-Jiménez,&nbsp;Encarna Guillén-Navarro,&nbsp;Julián Nevado,&nbsp;Jair Tenorio-Castano,&nbsp;Víctor L. Ruiz-Pérez,&nbsp;Pablo Lapunzina","doi":"10.1111/cge.14761","DOIUrl":"10.1111/cge.14761","url":null,"abstract":"<div>\u0000 \u0000 <p>We present a 28-year-old Spanish female with a <i>de novo</i> heterozygous variant in <i>FMR1</i> (NM_002024.6:c.1061_1062delAA), p.(Lys354Thrfs*15) detected by whole-exome sequencing and confirmed by Sanger sequencing from cDNA. She was born full-term with neonatal jaundice requiring phototherapy. At age 11, she exhibited weight and head circumference &gt; 97th percentile, global developmental delay, mild ID (IQ: 71), and hyperactivity. <i>FMR1</i> CGG analysis was normal. NGS panel of over 200 OGS-related genes found no pathogenic variants. By age 28, she presented with macrocephaly, coarse facial features, mild joint hypermobility, left talo-valgus, a port-wine stain, a café-au-lait spot, and a piezogenic papule. Herein, we describe a clinical and molecular report of the second FXS female patient due to a heterozygous point variant. This study was approved by the ethical committee of Hospital Universitario La Paz (CEIm PI-446), and informed consent was obtained from the patient and her parents.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"108 2","pages":"224-226"},"PeriodicalIF":2.9,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Shared Genetic Loci Associated With Inflammatory Bowel Disease, Ischemic Heart Disease, and Atrial Fibrillation and Flutter","authors":"Guojian Chen,&nbsp;Qinghua Luo,&nbsp;Chengcheng Wu,&nbsp;Mingjun Xie","doi":"10.1111/cge.14749","DOIUrl":"10.1111/cge.14749","url":null,"abstract":"<div>\u0000 \u0000 <p>The occurrence of ischemic heart disease (IHD), atrial fibrillation, and flutter demonstrates certain associations with inflammatory bowel disease (IBD), warranting further exploration at the genetic architecture level. This study focused on genome-wide association study (GWAS) data of IHD, atrial fibrillation and flutter, and IBD, analyzing from two dimensions: genetic correlation and shared locus identification. Initially, linkage disequilibrium score regression and genetic covariance analyzer were utilized to assess the overall genetic correlations. Subsequently, the association patterns of local genomic regions were determined using Local Ancestry Variance Association (LAVA) analysis. Mendelian randomization (MR) was employed to assess causal effects. The genetic overlap among different traits was analyzed based on the statistical framework of conditional/conjunctional false discovery rate (cond/conjFDR). Finally, shared loci across these traits were identified by integrating conjFDR analysis with GWAS multi-trait analysis (MTAG). At the genomic level, significant overall correlations were observed among IHD, atrial fibrillation and flutter, and IBD and Crohn's disease (CD), while associations with ulcerative colitis appeared less pronounced. At the local level, IHD and IBD (including subtypes) showed significant associations in multiple regions. However, atrial fibrillation and flutter exhibited local associations only in the context of CD. Through conjFDR analysis, the genetic overlap across these diseases was validated. Additionally, several shared genetic loci were identified by integrating conjFDR and MTAG analyses, with genes confirmed in both IHD and IBD (including subtypes), such as <i>SMAD3</i>, <i>PLCG2</i>, <i>ZNF831</i>, <i>PTPN22</i>, <i>RP11-136O12.2</i>, and <i>RP11-449I17.5</i>. Moreover, six common genes were identified in the analysis between atrial fibrillation and flutter and IBD (including subtypes), such as <i>ZMIZ1</i>, <i>MTHFS</i>, <i>ERAP2</i>, <i>GNA12</i>, and <i>RP1-15D23.2</i>. This study offers empirical evidence of the genetic association between IHD, atrial fibrillation and flutter, and IBD comorbidity, providing new insights for cases where IBD co-occurs with IHD or atrial fibrillation and flutter.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"108 3","pages":"302-312"},"PeriodicalIF":2.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Intronic Variant in the KH3 Domain of HNRNPK Leads to a Mild Form of Au-Kline Syndrome.","authors":"Maura Mingoia, Alessandra Meloni, Silvia Sedda, Sanaa Choufani, Isadora Asunis, Giorgia Gemma, Antonio Ammendola, Arteen Torabi-Marashi, Eleonora di Venere, Gabriella Maria Squeo, Vincenzo Rallo, Maria Giuseppina Marini, Paolo Moi, Salvatore Savasta, Rosanna Weksberg, Giuseppe Merla, Andrea Angius","doi":"10.1111/cge.14763","DOIUrl":"https://doi.org/10.1111/cge.14763","url":null,"abstract":"<p><p>Despite the massive adoption of sequencing technologies, disease-specific diagnosis remains challenging, particularly for genes with highly homologous pseudogenes like HNRNPK. Pathogenic HNRNPK variants cause Au-Kline syndrome (AKS), a neurodevelopmental disorder with malformations and distinctive facial features. We validated a novel de novo HNRNPK intronic variant (c.1192-3 C>A, p.Leu398ValfsTer21) in a patient previously misdiagnosed with Kabuki Syndrome (KS). By combining sequencing, in vitro splicing assays, molecular modelling, and protein function analysis, we characterised the molecular defect. A unique DNA methylation (DNAm) signature was recently identified in AKS, with missense variants showing an intermediate DNAm pattern, suggesting an epi-genotype-phenotype correlation linked to milder clinical features. The DNAm signature is a valuable tool for variant interpretation, especially in unclear AKS cases. We demonstrate that two independent approaches-functional characterisation and DNAm evaluation-confirmed a partial loss of HNRNPK function and validated an AKS diagnosis with a mild phenotype. Our findings highlight that a multidisciplinary approach integrating genomic and epigenomic analyses with functional studies and clinical assessment significantly improves rare disease diagnosis.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spectrum of Inherited Childhood-Onset Dystonia: Case Series of 19 Families With Genotype and Phenotype Characterization Highlighting the Treatable Causes","authors":"Naik Adarsha,&nbsp;Arya Shambhavi,&nbsp;Haseena Sait,&nbsp;Amita Moirangthem,&nbsp;Deepti Saxena,&nbsp;Shubha R. Phadke","doi":"10.1111/cge.14762","DOIUrl":"10.1111/cge.14762","url":null,"abstract":"<div>\u0000 \u0000 <p>Childhood-onset dystonia, a clinically and genetically diverse group of disorders, can be challenging to diagnose. Information on the genotype and phenotype spectrum in the Indian population is limited. This study reports the clinical and molecular findings of monogenic childhood-onset dystonia in 22 individuals from 19 Indian families. Complex dystonia was the most frequent type, followed by combined and isolated forms. A total of 23 variants across 17 genes were identified, including nine novel ones. These disorders include four autosomal dominant, one X-linked recessive, one mitochondrial, and the remaining 11 autosomal recessive conditions. Five potentially treatable disorders were identified, and treatment was initiated in three families, showing satisfactory responses, particularly in dopa-responsive dystonias. Our study contributes four additional genes—<i>CYP27A1</i>, <i>NDUFAF3</i>, <i>FUCA1</i>, and <i>FIG4</i>—to the list of genes associated with complex dystonia. Exome sequencing proved crucial in diagnosing the etiology of dystonia, identifying treatable forms, and aiding genetic counseling. This study emphasizes the significance of using NGS for early genetic diagnosis to enable timely targeted therapies, offer precise genetic counseling to families, and prevent recurrence in the family.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"108 4","pages":"422-432"},"PeriodicalIF":2.3,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of Copy Number Variants Is an Important Consideration in Exome Sequencing","authors":"Asmaa K. Amin,&nbsp;Sara H. El-Dessouky,&nbsp;Marwa Abd Elmaksoud,&nbsp;Amira Nabil,&nbsp;Mona M. Aboulghar,&nbsp;Sameh M. Senousy,&nbsp;Nagham M. Elbagoury,&nbsp;Asmaa F. Abdel-Aleem,&nbsp;Mona L. Essawi,&nbsp;Heba A. El-Awady,&nbsp;Engy A. Ashaat,&nbsp;Mahmoud Y. Issa,&nbsp;Khoushoua Alaadin,&nbsp;Lova S. Matsa,&nbsp;Noha M. Issa,&nbsp;Maha S. Zaki,&nbsp;Maha Mohamed Eid,&nbsp;Wessam E. Sharaf-Eldin,&nbsp;Ebtesam Abdalla","doi":"10.1111/cge.14764","DOIUrl":"10.1111/cge.14764","url":null,"abstract":"<div>\u0000 \u0000 <p>Copy number variants (CNVs) contribute significantly to the pathogenicity of rare genetic diseases and tend to have a more severe effect on phenotype compared to single nucleotide variants (SNVs). In the past decades, exome sequencing (ES) has proven valuable input in the characterization of underlying genetic defects. Our aim was to investigate the impact of integrating CNV analysis tools into standard ES analysis on its diagnostic yield. We worked on ES data from an original cohort of 840 patients, in whom the first analysis was able to detect causative SNVs and indels in 383 (45.6%). Using the ExomeDepth algorithm, clinically relevant CNVs were identified in 55 patients out of the 457 unsolved cases, thus enhancing the diagnostic yield to 52.1%. Among the enrolled subjects, neurodevelopmental delay was the most prevalent phenotype. The detected CNVs comprised 43 deletions (74.1%) and 15 duplications (25.9%), ranging in size from 94 bp to 94.3 Mb, and were classified as 56 pathogenic/likely pathogenic and 2 uncertain with high interest. The study presents further evidence that incorporating CNV analysis tools into ES pipelines improves the diagnostic yield and emphasizes the involvement of CNVs in the etiology of genetic disorders.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"108 4","pages":"433-449"},"PeriodicalIF":2.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep Phenotyping of Pathology-Confirmed Benign Lesions in PTEN Hamartoma Tumor Syndrome Patients","authors":"Ane J. Schei-Andersen,&nbsp;Janneke H. M. Schuurs-Hoeijmakers,&nbsp;Rachel van der Post,&nbsp;Arjen R. Mensenkamp,&nbsp;Jolanda Schieving,&nbsp;PTEN Study Group,&nbsp;Janet R. Vos,&nbsp;Nicoline Hoogerbrugge","doi":"10.1111/cge.14759","DOIUrl":"10.1111/cge.14759","url":null,"abstract":"<p>PTEN Hamartoma Tumor Syndrome (PHTS) is a rare hereditary syndrome. PHTS has a variable phenotype characterized by benign lesions and increased cancer risks. Clarifying the extent of the benign phenotype could facilitate early recognition of PHTS patients before cancer development. Therefore, we assessed the spectrum, frequency, and age of excerpt of pathology-confirmed benign lesions in PHTS patients. Pathology reports were collected for 379 patients with a pathogenic <i>PTEN</i> variant from the Dutch nationwide pathology databank (Palga). Benign lesions were classified as PHTS-related based on current clinical diagnostic guidelines and non-PHTS-related lesions by ICD-10 codes. Age of last follow-up was year of pathology request minus birth year. Analyses were stratified by sex and index status. Patients presented mainly with gastrointestinal (54%), skin (47%), thyroid (31%) and vascular lesions (26%). Males developed lipomas at an early age (9 years (5–34)). Females developed endometrial hyperplasia (16%) at an earlier age (41 years (35–49)) and uterine polyps (13%) more often than the general population. No significant differences were observed between sexes or index and non-index patients. The results are reflective of current diagnostic guidelines. Early-onset lipomas may be useful for early detection of PHTS patients. Additionally, uterine polyps should be considered for inclusion as a PHTS-related lesion.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"108 4","pages":"400-411"},"PeriodicalIF":2.3,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.14759","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Etiology of Epilepsy: A Retrospective Study From a Single-Center Cohort","authors":"Yinchao Li,&nbsp;Xiaowei Xu,&nbsp;Yingfang She,&nbsp;Zhengwei Su,&nbsp;Xianyue Liu,&nbsp;Ying Chen,&nbsp;Chenghui Ye,&nbsp;Yuanchao Zhang,&nbsp;Hang Yu,&nbsp;Chun Chen,&nbsp;Shuda Chen,&nbsp;Liemin Zhou","doi":"10.1111/cge.14757","DOIUrl":"10.1111/cge.14757","url":null,"abstract":"<div>\u0000 \u0000 <p>Next generation sequencing (NGS) technology has made significant progress in the genetic diagnosis and treatment of epilepsy. However, genetic studies on epilepsy with different etiologies remain relatively limited. In this study, whole-genome or whole-exome sequencing was performed on 158 unrelated patients with epilepsy of various etiologies, and the identified variants were analyzed for their association with 1356 seizure-related genes in the database. Additionally, the pathogenicity or likely pathogenicity of those variants associated with known epilepsy genes was evaluated. The results showed that pathogenic or likely pathogenic variants were detected in 31.65% (50/158) of the patients in our cohort study. Further analysis revealed significant differences in the diagnostic rates among different epilepsy categories: 29.60% (37/125) for idiopathic epilepsy and 39.39% (13/33) for symptomatic epilepsy. Moreover, the genes <i>PRRT2</i>, <i>KMT2C</i>, <i>PRKRA</i>, <i>NOTCH3</i>, <i>NAGLU</i>, and <i>SCN1A</i> were identified as potentially important for epilepsy, suggesting they could become key targets for clinical diagnosis and treatment. In conclusion, NGS technology demonstrates high diagnostic efficiency for epilepsy of different etiologies and highlights significant differences among various types. This provides novel genetic insights for the diagnosis and treatment of epilepsy.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"108 4","pages":"393-399"},"PeriodicalIF":2.3,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding the Clinical Spectrum of BCARD Syndrome Caused by Novel Biallelic Variants in the PLOD3 Gene","authors":"Evgeniya Melnik,&nbsp;Tatiana Markova,&nbsp;Yana Fedotova,&nbsp;Eugene Tatarskiy,&nbsp;Viktoria Zabnenkova,&nbsp;Vitaly Kadyshev,&nbsp;Vladimir Kenis,&nbsp;Galina Buyanova,&nbsp;Mikhail Skoblov,&nbsp;Elena Dadali","doi":"10.1111/cge.14756","DOIUrl":"10.1111/cge.14756","url":null,"abstract":"<div>\u0000 \u0000 <p>BCARD syndrome is a rare autosomal recessive connective tissue disorder characterized by bone abnormalities, cataract, risk of arterial rupture due to vascular aneurisms or dissections, and sensorineural deafness. BCARD, linked to biallelic pathogenic variants in the <i>PLOD3</i> gene, was characterized in 10 cases across six reports. Here we present an 11-year-old female patient whose phenotype, alongside the clinical features specific to BCARD syndrome, also exhibited vesico-ureteral reflux, intestinal anomaly, minor cardiac anomalies, focal epilepsy, and brain abnormalities, including polymicrogyria and heterotopia. Whole-exome sequencing revealed two novel nucleotide variants (c.335A&gt;G and c.2158G&gt;T) in the <i>PLOD3</i> gene. The first variant functions as a cryptic splice site variant, and RNA analysis confirmed that it causes a 4 bp truncation of exon 3. This truncation induces a frameshift, resulting in the formation of a premature termination codon (p.(Asp112AlafsTer4)). The second variant, a nonsense mutation located in the final exon, leads to the truncation of a functionally critical protein domain. This case expands our understanding of BCARD syndrome variability, aiding in earlier detection of skeletal pathology, brain, ocular, vascular complications, and intestinal, ureteral, cardiac abnormalities.</p>\u0000 </div>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"108 4","pages":"474-478"},"PeriodicalIF":2.3,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Never Late: Cerebrotendinous Xanthomatosis and Improvements in Neurocognitive Functions in an Adult Patient on Chenodeoxycholic Acid Treatment","authors":"Randa Sultan,&nbsp;Marta Villa-Lopez,&nbsp;Clara Hung,&nbsp;Morganne McCabe,&nbsp;Oksana Suchowersky,&nbsp;Jordan Urlacher,&nbsp;Saadet Mercimek-Andrews","doi":"10.1111/cge.14751","DOIUrl":"10.1111/cge.14751","url":null,"abstract":"<p>Cerebrotendinous xanthomatosis (CTX) is an inherited metabolic disease due to biallelic pathogenic variants in <i>CYP27A1</i>. We report a newly diagnosed patient and the outcome of the chenodeoxycholic acid (CDCA) treatment. This is a 36-year-old male with progressive lower limb spasticity, learning difficulties, and early cataracts. He was diagnosed by targeted next generation sequencing panel for hereditary spastic paraparesis (c.379C&gt;T; p.Arg127Trp and c.1072C&gt;T; p.Gln358* in <i>CYP27A1</i>) with CTX at the age of 33 years. Brain and spine magnetic resonance imaging (MRI) revealed increased T2 signal intensity in the dentate nuclei and bilateral posterolateral spinal cord. Baseline plasma 7a-hydroxy-4-cholesten-3-one (&gt; 5; ref. range &lt; 0.300 nmol/mL) and 7a,12a dihydroxycholest-4-en-3-one (&gt; 5; ref. range &lt; 0.100 nmol/mL) were markedly elevated. Baseline full-scale IQ was 69. The CDCA treatment (750 mg/day) was started at the age of 34 years. Plasma 7a-hydroxy-4-cholesten-3-one level was normalized; plasma 7a,12a dihydroxycholest-4-en-3-one level was markedly improved (0.755 nmol/mL; ref. range &lt; 0.1) and full-scale IQ improved to 83 at two years of the CDCA treatment. This patient highlights improvements in neurocognitive functions despite late diagnosis and late initiation of treatment and exemplifies the importance of diagnosing a treatable disease at any age to improve neurocognitive outcomes.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"108 3","pages":"363-368"},"PeriodicalIF":2.3,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.14751","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}