Genes最新文献

{"title":"Mosaic Trisomy 14 with Severe Short Stature: A Case Report.","authors":"Chunyan Yin, Juan Ye, Ling Hou, Xiaoping Luo","doi":"10.3390/genes17091123","DOIUrl":"10.3390/genes17091123","url":null,"abstract":"<p><p>Mosaic trisomy 14 is a rare chromosomal anomaly with a broad phenotypic spectrum. We report a 10-year-3-month-old girl with severe short stature, developmental delay, and repaired patent ductus arteriosus. An incompletely documented combined insulin-clonidine stimulation test yielded a peak GH concentration of 6.85 ng/mL and was not considered sufficient to establish growth hormone deficiency. Karyotyping of 100 peripheral-blood metaphases showed 47,XX,+14[6]/46,XX[94]. Initial copy-number sequencing detected a 34.37 Mb mosaic 14q gain; repeat SNP-based chromosomal microarray analysis demonstrated an approximately 86.83 Mb 14q11.2-q32.33 mosaic gain at an array-estimated fraction of approximately 50%, compatible with the cytogenetic diagnosis. Targeted 14q32.2 analysis showed increased total and methylated-allele dosage, with methylated fractions of 48.6-62.3%, interpreted as dosage imbalance within the broader 14q gain rather than an independent epimutation. Four STR loci showed biparental inheritance. Quantitative peak-height and peak-area analysis at three informative, bias-correctable STR loci demonstrated excess paternal-allele dosage, providing independent support for, but not definitive proof of, paternal origin of the additional chromosome 14. rhGH was prescribed for SGA with persistent short stature at 0.22 mg/kg/week. At three months, height was 124.7 cm (+1.9 cm); no adverse events were reported. These observations do not establish treatment efficacy or safety.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13606590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population-Specific Carrier Frequencies in an Underrepresented Genetically Heterogeneous Population: Implications for Expanded Carrier Screening.","authors":"Predrag Noveski, Natalija Jovanovska, Ivana Maleva Kostovska, Gjorgji Bozhinovski, Sanja Kiprijanovska, Marija Terzikj, Marija Vujovikj, Emilija Shukarova Stefanovska, Aleksandar Dimovski, Dijana Plaseska-Karanfilska","doi":"10.3390/genes17091118","DOIUrl":"10.3390/genes17091118","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Expanded carrier screening (ECS) panels often rely on pan-ethnic databases, such as the ACMG Tier 3 panel, but their ability to capture population-specific reproductive risk is uncertain. We characterized pathogenic/likely pathogenic (P/LP) variants and at-risk-couple (ARC) probabilities in an underrepresented population from North Macedonia to inform ECS gene prioritization. <b>Methods</b>: NGS data from 1438 subjects of Macedonian, Albanian, and other local ancestry, referred for rare-disease diagnostics, were analyzed across 1795 candidate autosomal recessive/X-linked genes. P/LP variants were compared with gnomAD exomes v2.1.1 non-Finnish European frequencies (Fisher's exact test). Gene-specific ARC probabilities ranked genes and generated cumulative ARC curves per subgroup. <b>Results</b>: We identified 2007 P/LP variants across 1096 genes. One hundred variants in 89 genes reached an allele frequency ≥ 1/200 in the Macedonian or Albanian subgroups; over one-third were absent from candidate ECS panels, mostly linked to severe or variable phenotypes. ARC saturated rapidly: genes with carrier counts ≥ 1/100 (ACMG Tier 2) accounted for over 85% of total ARC, and with ≥1/200 (ACMG Tier 3) for more than 93%. Total ARC among autosomal recessive panel genes (X-linked genes analyzed separately) was 3.42%, rising to 5.02% in the Albanian subgroup. Excluding top hypomorphic variants reduced ARC by 34-37%, highlighting variant-specific penetrance. The highest-ARC genes diverged between subgroups, with limited overlap with pan-ethnic panels. <b>Conclusions</b>: Population-specific carrier frequencies influence gene prioritization and estimated reproductive-risk probabilities for ECS. Population-tailored ECS panels that incorporate local carrier-frequency data, including embryonic/fetal-lethal genes, and account for hypomorphic alleles to avoid overestimating reproductive risk probabilities could improve the identification of couples at increased reproductive risk, particularly in underrepresented populations.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13606519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Variants Involved in Metformin Pharmacokinetics in the Chilean Population.","authors":"José P Miranda, Gigliola Alberti, Ana Pereira, Juan Cristóbal Gana, José L Santos","doi":"10.3390/genes17091114","DOIUrl":"10.3390/genes17091114","url":null,"abstract":"<p><strong>Objective: </strong>To estimate the frequency and potential impact of genetic variants involved in metformin pharmacokinetics, including gastrointestinal absorption, renal elimination, and hepatic transport in the Chilean population.</p><p><strong>Subjects and methods: </strong>The frequency of metformin-related gene variants was estimated using data from a genome-wide, exome-focused genotyping array in 918 participants of the Chilean Growth and Obesity Cohort Study (GOCS). Allele frequencies in Chileans were compared with those published worldwide, and the degree of Amerindian/European ancestry was assessed. A predictive bioinformatic analysis was performed on relevant genetic variants using PolyPhen-2.</p><p><strong>Results and discussion: </strong>The genetic polymorphism (p.Leu125Phe; p.L125F; rs77474263; C>T) in the SLC47A1 gene (MATE1 transporter) showed a much higher frequency of the 125Phe (T-allele) in the Chilean population (15.3%) than in non-American populations, being virtually absent in Africa, Europe, or Asia. The 125Phe variant was associated with a higher percentage of Amerindian ancestry in the Chilean population. This result is consistent with a previous report indicating that this variant is enriched in Native American populations, given its high frequency among Mestizo and Indigenous populations in Mexico. The functional variant p.125Phe has been previously suggested to promote plasma metformin accumulation, mitochondrial dysfunction, and increased plasma lactate concentrations by altering renal metformin elimination.</p><p><strong>Conclusions: </strong>The missense variant p.Leu125Phe (rs77474263) in SLC47A1 is frequent in Chile and Mexico, and apparently absent in non-American populations. In homozygosis, the p.125Phe variant has been previously associated with impaired renal drug elimination, metformin systemic accumulation, and hyperlactatemia.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13606663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Database-Derived Phthalate Ester-Ankylosing Spondylitis Signature Identifies an AP-1/CXCL8 Inflammatory Classical-Monocyte Program.","authors":"Xiqing Luo, Xuqi Zheng, Wenyu Xu, Dan Guo, Xinlei Jia, Jieruo Gu, Xiaoyi Zhao, Yutong Jiang","doi":"10.3390/genes17091113","DOIUrl":"10.3390/genes17091113","url":null,"abstract":"<p><p><b>Objectives:</b> We tested whether a database-derived phthalate ester (PAE)-ankylosing spondylitis (AS) candidate panel identifies an inflammatory transcriptional program and characterized its transcription-factor (TF) architecture. <b>Methods:</b> Machine learning prioritization and repeated nested cross-validation were followed by locked-model transfer from GSE73754 to GSE25101. Donor-level single-cell analyses included 96,746 peripheral blood mononuclear cells from 10 AS and 29 healthy-control donors (GSE194315), with corroboration assessed in 25 additional baseline AS patients (GSE277117). <b>Results:</b> Within classical monocytes, the continuous signature covaried with panel-excluded TNF-α/NF-κB signaling (ρ = 0.571; q = 0.000729), inflammatory response (ρ = 0.447; q = 0.0108), and eight of 10 AP-1-related TF activities. Target-excluded TF activities covaried with CXCL8 (8/10) and IL1B (10/10). AP-1-gene/CXCL8 co-expression received partial corroboration in the additional AS cohort (JUN-CXCL8: ρ = 0.92). Among 16 genes prioritized from 473 shared candidates, CXCL8, IL2RB, STAT5B and TNF were stable. The locked 14-gene model achieved an area under the receiver-operating-characteristic curve of 0.770 (DeLong 95% confidence interval, 0.596-0.943), supporting partial rank transportability. Secondary analyses showed a lower CD56bright fraction among natural killer (NK) cells in AS (-2.699 percentage points; 95% confidence interval, -4.575 to -0.611; q = 0.0498) and reduced NK-cell JUN expression (log₂ fold change = -0.995; adjusted <i>p</i> = 0.0497). <b>Conclusions:</b> The PAE-AS signature identifies an AP-1/CXCL8-associated classical-monocyte inflammatory program, with partial cross-cohort corroboration and secondary NK alterations, providing candidates for exposure-informed mechanistic studies.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13606070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149059815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SCN4A Channelopathies: From Disease Mechanisms to Variant Interpretation.","authors":"Paola D'Ambrosio, Lorenzo Cipriano, Alessia Pugliese, Roberta Petillo, Dario Ricciardi, Francesco Habetswallner, Carmelo Rodolico, Manuela Priolo","doi":"10.3390/genes17091116","DOIUrl":"10.3390/genes17091116","url":null,"abstract":"<p><p>SCN4A encodes the skeletal-muscle voltage-gated sodium channel NaV1.4. Pathogenic variation in this gene produces fundamentally different disease mechanisms, including dominant alpha-pore gain of function, dominant S4 gating-pore currents, and reduced channel availability, with severe biallelic loss of function causing congenital myopathy and fetal hypokinesia. This heterogeneity makes variant interpretation difficult because formal variant classification, the direction of channel dysfunction, and patient-level disease attribution are closely related but distinguishable conclusions. In this review, we synthesize the clinical, genetic, electrophysiological, structural, and functional evidence relevant to SCN4A variant interpretation, with particular attention to missense variants of uncertain significance. We examine how inheritance, channel topology, phenotype, population data, segregation, RNA evidence, regional and residue-level context, and mechanism-matched functional assays can be integrated within the ACMG/AMP framework. Published pathogenic-enriched regions, gnomAD regional missense constraint, and same-residue observations may contribute to variant interpretation when the requirements of an applicable ACMG/AMP criterion are met; when they have not been specifically validated or calibrated for SCN4A, they are best used as contextual information to prioritize additional evidence generation. Based on this literature, we organize these evidence domains into a practical phenotype-first, mechanism-informed workflow for SCN4A variant interpretation. This workflow is not intended as an alternative to or extension of ACMG/AMP but as an SCN4A-specific application of established variant-interpretation principles in a gene associated with multiple inheritance patterns and directionally distinct disease mechanisms. After technical confirmation of a candidate variant, as well as phenotype and inheritance context guide selection of the relevant disease model, appropriately validated functional evidence may contribute directly to ACMG/AMP classification, while functional mechanism and patient-level disease attribution are documented as related but distinguishable interpretative outputs. The same approach applies when a variant is identified through genotype-first sequencing: interpretation should return to deliberate phenotyping, inheritance assessment, electrophysiological characterization, and consideration of the differential diagnosis before disease causality is inferred.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13606911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Strategic Implementation Framework for Integrating Pharmacogenomics (PGx) into Personalized Healthcare in Saudi Arabia.","authors":"Kholud R Alrubaie, Raghad A Alzaylaee, Latifah A Alayyaf, Farjah H Algahtani, Shaker A Alomary, Abdullah M Assiri, Mariam M AlEissa","doi":"10.3390/genes17091115","DOIUrl":"10.3390/genes17091115","url":null,"abstract":"<p><p>Pharmacogenomics has the potential to improve the safety and efficacy of medicines in Saudi Arabia, and has a strong basis for implementation through population-specific genomic evidence, growing laboratory capacity and national digital health investment. We undertook a structured policy analysis and evidence synthesis of Saudi, regional, and international evidence; compared selected implementation capabilities across established models; and assessed national readiness descriptively across key health system domains. Using published evidence and structured expert judgement, we propose gene-drug priority tiers according to their clinical impact, population relevance and feasibility. Saudi Arabia's strengths are in genomic evidence and digital health infrastructure, but large gaps exist in governance, laboratory standardization, electronic health record interoperability, clinical decision support, workforce readiness, reimbursement, and outcome evaluation. Five pathways are proposed for initial implementation: <i>CYP2C19</i>-clopidogrel, <i>DPYD</i>-fluoropyrimidines, <i>TPMT</i>/<i>NUDT15</i>-thiopurines, HLA-guided anticonvulsant prescribing and <i>HLA-B*57:01</i>-abacavir. We propose a framework that could be supported by the Population Health Observatory and a six-phase roadmap, moving from governance and technical design to multicenter pilots, national scale-up and continuous evaluation.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13606155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotypic Heterogeneity Among Carriers of the Same Pathogenic Variant in Hereditary Hemorrhagic Telangiectasia.","authors":"Elena Urízar, Pablo Solis, Nuria Puente, Ana Fontalba, Roberto Zarrabeitia, José A Riancho","doi":"10.3390/genes17091112","DOIUrl":"10.3390/genes17091112","url":null,"abstract":"<p><p><b>Background</b>: Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant vascular disorder primarily caused by pathogenic variants in the <i>ENG</i> and <i>ACVRL1</i> genes. Although genotype-phenotype correlations are well established at the population level, the degree of phenotypic similarity among relatives sharing the same variant is poorly characterized. <b>Objective</b>: to explore differences in expressivity and quantify the degree of phenotypic variability among individuals with HHT carrying the same pathogenic variant. <b>Methods</b>: We evaluated 60 patients from a reference center with recurrent <i>ENG</i> and <i>ACVRL1</i> variants, to quantify intra-familial phenotypic heterogeneity using Shannon entropy indices, Jaccard distances, and a latent variable liability-threshold approach. <b>Results</b>: There was substantial phenotypic variability among individuals and families, with cutaneous telangiectasia being the most frequent manifestation. Shannon entropy and Jaccard analyses indicated broadly high variability. The shared variant accounted for only 3.3% of total variance. Age was significantly associated with disease manifestations (β = 0.027, <i>p</i> = 0.002; OR = 1.028, 95% CI 1.010-1.045), with each additional year increasing the odds of severe symptoms by 2.7%, particularly bleeding severity and skin telangiectasias. <b>Conclusions</b>: These findings suggest that the variable expressivity in HHT is predominantly driven by individual-level factors other than the specific pathogenic variant carried by each patient.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13606601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative Assessment of Evidence for Anagenetic Speciation in Ulleungdo Endemic Plants: Plastid, Nuclear, and Morphological Perspectives.","authors":"Sajid Ali, Adnan Amin","doi":"10.3390/genes17091109","DOIUrl":"10.3390/genes17091109","url":null,"abstract":"<p><p>Ulleungdo Island harbors several endemic plant lineages commonly interpreted as products of anagenetic speciation following long-distance colonization. Yet plastome phylogenies represent a single organellar genealogy and may conflict with nuclear genomic structure, morphology, or taxonomic boundaries. This critical mini-review evaluates whether plastid-based hypotheses for the origin and diversification of Ulleungdo endemics are supported by independent molecular and phenotypic evidence. We synthesize findings from comparative plastomics, chloroplast haplotype and network analyses, nuclear microsatellites, nrDNA sequencing, genome-wide multiplexed inter-simple sequence repeat genotyping by sequencing (MIG-seq) single-nucleotide polymorphisms (SNP), cytogenetics, morphology, and multicompartment phylogenomics. The evidence reveals heterogeneous evolutionary outcomes. <i>Prunus takesimensis</i> and <i>Phedimus takesimensis</i> are broadly consistent with probable single-origin scenarios, although confidence is constrained by progenitor sampling and marker resolution. <i>Rubus takesimensis</i> exhibits chloroplast non-monophyly and elevated haplotype diversity consistent with multiple maternal origins, whereas <i>Acer takesimense</i> shows signatures of historical drift and loss of rare nuclear alleles. Morphological, chromosomal, plastid, and nuclear-ribosomal evidence strongly support <i>Allium ulleungense</i>, while the delimitation of <i>Viola ulleungdoensis</i> remains unresolved. Plastid-nuclear incongruence in <i>Hepatica maxima</i> and <i>Fagus multinervis</i> further indicates that introgression, hybridization, incomplete lineage sorting, and restricted taxon sampling can complicate evolutionary inference. This comparative framework distinguishes species histories from provisional interpretations based on limited accessions or uniparentally inherited markers. The novelty of this review lies in its cross-taxon assessment of plastome-nuclear-morphological congruence rather than a descriptive plastome inventory. Ulleungdo lineages interpreted as products of anagenetic speciation do not exhibit a uniform genomic signature and that robust taxonomic, evolutionary, and conservation inference requires population-level integration of independently inherited genomic compartments with standardized morphological and reproductive data.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13606731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rapidly Progressive Infantile Dilated Cardiomyopathy in Long-Olsen-Distelmaier Syndrome Associated with <i>RRAGC</i> NM_022157.4:c.343T>C, p.(Trp115Arg): A Case Report.","authors":"Mohammed Shahab Uddin, Fayez AlShammari, Amr Esmail, Khaled Shafeen, Fahad Alnajim, Danah AlMohaimeed, Nujud Alessa, Wojod Alothman, Fay Aldenaini, Karthiga Gurumurthy, Maryam AlQannas","doi":"10.3390/genes17091106","DOIUrl":"10.3390/genes17091106","url":null,"abstract":"<p><p><b>Background:</b> Infantile dilated cardiomyopathy (DCM) is uncommon but carries substantial mortality, particularly when accompanied by neurological, ocular, or metabolic abnormalities. Long-Olsen-Distelmaier syndrome is a rare mTORopathy caused by heterozygous gain-of-function variants in <i>RRAGC</i> and may include cortical malformations, congenital cataracts, mineral disturbances, and early-onset DCM. <b>Case Summary</b>: We describe a term male infant born to consanguineous parents with hypocalcemia and hyperphosphatemia, bilateral frontoparietal polymicrogyria, bilateral congenital lamellar cataracts, small patent ductus arteriosus and ventricular septal defect, and initially preserved biventricular function. At 53 days of age, he developed cardiogenic shock, severe lactic acidosis, and hyperkalemia during a rhinovirus/enterovirus-positive respiratory illness. Echocardiography showed severe DCM with marked left ventricular dilatation and an ejection fraction of 27%. Despite multi-agent inotropic support, ventricular function did not recover, and he died at approximately two months. Accordingly, the contemporaneous clinical WES record documented a heterozygous <i>RRAGC</i> c.343T>C, p.(Trp115Arg) variant, reported by the diagnostic laboratory as likely pathogenic. The variant was subsequently standardized in this manuscript as NM_022157.4:c.343T>C, and an independent manuscript-level ACMG/AMP reassessment was concordant. <b>Conclusions:</b> Because p.(Trp115Arg) was previously reported, the principal contribution is detailed documentation of rapid progression from preserved neonatal ventricular function to fatal infantile DCM, while extending the clinical and geographic spectrum of <i>RRAGC</i>-related Long-Olsen-Distelmaier syndrome. Respiratory viral detection should be interpreted cautiously because myocarditis was not established; early exome-based testing should be considered in infants with cardiomyopathy and multisystem abnormalities.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13606137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of <i>CD320</i>-Associated Cobalamin Transport Deficiency Through Newborn Screening Caused by Novel Homozygous Candidate Variants.","authors":"Faisal Almalki, Amal Saleh Alsofyany, Abdulaziz K Almalki, Ashraf Oudah Abu Shuaylan, Haya Alruqi, Jwaher Mesleh Althobiti","doi":"10.3390/genes17091108","DOIUrl":"10.3390/genes17091108","url":null,"abstract":"<p><strong>Background: </strong>The transcobalamin receptor, encoded by the <i>CD320</i> gene, mediates the cellular uptake of the transcobalamin-cobalamin complex (vitamin B₁₂). Pathogenic variants in <i>CD320</i> impair the intracellular transport, resulting in methylmalonic acid (MMA) and propionylcarnitine (C3) level, despite normal circulating vitamin B₁₂ levels, with variable clinical phenotypes.</p><p><strong>Methods: </strong>Whole-exome sequencing (WES) was carried out for a newborn screening positive proband. Further plasma metabolic investigation and blood gas analysis were carried out for the proband. Sanger sequencing was carried out to confirm the candidate variant and identify the familial segregation.</p><p><strong>Results: </strong>The proband presented with elevated C3 and MMA levels and exhibited an expanded clinical phenotype that included severe microcephaly, metabolic acidosis, low bicarbonate and pancytopenia. WES identified a homozygous missense candidate variant in the last amino acid of exon 1 in the <i>CD320</i> gene (NM_016579.3: c.142G>C, p.Gly48Arg). Another adjacent synonymous homozygous candidate variant was identified (NM_016579.3: c.141A>C, p.Ala47=). Both variants were identified in a male proband from a consanguineous family. Both variants were confirmed by Sanger and segregated within the family members. During one year of follow-up, the patient showed persistent microcephaly while receiving a specialized metabolic formula and levocarnitine supplementation.</p><p><strong>Conclusions: </strong>This study identified a novel recessive missense candidate variant and an adjacent synonymous candidate variant in <i>CD320</i>, supported with biochemical and clinical features of <i>CD320</i>-associated cobalamin transport deficiency. This suggests microcephaly may be a previously unrecognized phenotype with possible association of impaired intracellular cobalamin transport, while elevated C3 detected through routine newborn screening may be the earliest biochemical indicator of <i>CD320</i>-associated cobalamin transport deficiency.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13606811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}