HGG Advances最新文献

{"title":"Deciphering the genetic underlying causes of sex differences in multiple myeloma incidence and mortality.","authors":"Ajibola Opakunle, Yuting Shan, Yingbo Huang, Christina Printzis, Catherine Therese Stanhope, Barbara E Stranger, Rong Stephanie Huang","doi":"10.1016/j.xhgg.2026.100596","DOIUrl":"10.1016/j.xhgg.2026.100596","url":null,"abstract":"<p><p>Multiple myeloma (MM) is a genetically complex cancer that has a higher incidence and mortality in males when compared to females. These sex differences are well documented epidemiologically, yet their biological mechanisms remain uncharacterized. We hypothesized that sex-specific genetic regulation by somatic mutations affects MM cell gene expression differently in each sex and subsequently leads to differential functional genetic dependencies between the two sexes. To test this, we first identified genes with sex-biased expression in MM, then identified sex-specific somatic regulators of these genes, evaluated their association with overall survival outcomes, and finally assessed their functional importance using CRISPR-Cas9 dependency screens in MM cell lines. Our findings provide systematic evidence that sex-differentiated somatic regulation underlies tumor-intrinsic mechanisms in MM, establishing the importance of incorporating sex-aware molecular analyses for improved biomarker discovery and precision medicine. Collectively, these results establish sex as a fundamental biological variable in MM with significant implications for disease outcomes.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100596"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13122808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147533199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome sequencing for the diagnosis of rare disorders: The Brazilian Rare Genomes Project.","authors":"","doi":"10.1016/j.xhgg.2026.100624","DOIUrl":"10.1016/j.xhgg.2026.100624","url":null,"abstract":"<p><p>Genome sequencing (GS) has emerged as a transformative tool in the diagnosis of rare diseases with complex phenotypes. This technology uncovers structural, intronic, non-coding, and mitochondrial variants that traditional methods might miss, thereby facilitating the understanding of the underlying genomic basis of human disorders. We enrolled 10,305 patients with suspected rare diseases or hereditary cancer risk syndromes from 21 centers throughout Brazil. Their genomes were sequenced with short, paired-end reads, and diagnostic reports were provided for 9,448 of these patients. The overall diagnostic yield was 35.6%, and 4.6% of all positive reports had GS-exclusive findings (e.g., short copy-number variants overlapping fewer than three exons, deep intronic variants, short tandem repeat expansions, and mitochondrial structural variants-usually not detected by other diagnostic tests such as exome sequencing). Preliminary analysis of transcriptome sequencing (TS) or long-read GS combined with GS interpretation provided a small but welcome improvement in diagnostic yield (0.1% and 1.0% of positive reports, respectively). Almost 3,200 variant/phenotype interpretations were submitted to ClinVar. GS is proving to be an invaluable resource for shortening the diagnostic odyssey of patients with rare diseases, providing crucial genomic diagnostics, and enriching genetic databases with variant interpretations from underrepresented populations. Therefore, GS has the potential to significantly enhance the precision of healthcare in genetically diverse populations.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100624"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13285375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of von Hippel Lindau gene variants in an African American cohort.","authors":"Yusra F Shao, Diana Duque, Abdul-Rahman Alloghbi, Bayan Al Share, Seongho Kim, Courtney Kokenakes, Elisabeth Heath","doi":"10.1016/j.xhgg.2026.100617","DOIUrl":"10.1016/j.xhgg.2026.100617","url":null,"abstract":"<p><p>Autosomal-dominant (AD) pathogenic/likely pathogenic (P/LP) variants in von Hippel-Lindau (VHL) gene cause VHL disease. We characterize VHL variants and disease phenotypes in Black/African American (AA) patients, a demographic that has not been thoroughly studied. Black/AA patients undergoing germline genetic testing at a CLIA-certified commercial laboratory from November 2014 to March 2022 and carrying a P/LP AD VHL gene variant were identified. Personal and family histories were obtained from test requisition forms, and patients were categorized into VHL disease subtypes: type 1, type 2A, type 2B, and type 2C. Patients with a personal or family history of cancer but no lesions typical of VHL disease were categorized as \"unclassified.\" Patients with an incomplete personal or family history available were noted as \"unknown.\" Final analysis included 38 patients. Among the cohort's personal cancer history, hemangioblastoma and pheochromocytoma were most prevalent (16%). Among the cohort's family cancer history, renal cell carcinoma was most prevalent (8%). Type 1 was the most common VHL disease class recorded (34%). Substitution variants were most common (76%); p.Arg167Trp (c.499C>T) was the most common substitution (8%). Unique variants in Black/AA patients include p.Pro81Leu (c.242C>T), p.Leu129Pro (c.386T>C), p.Asp121Val (c.362A>T), p.His110Profs∗49 (c.329del), and p.Arg82His (c.245G>A). This dataset informs future research on VHL disease and treatment in Black/AA populations.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100617"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13207352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147783481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Burden of heterozygote carriers for autosomal recessive conditions in the Middle East: A study of 14,392 genomes.","authors":"Esther Nkrumah, Hajer Al-Mulla, Aryan Bashar, Vishal Soman, Chadi Saad, John Wang, Helia Darabi, Svetlana A Yatsenko, Aleksandar Rajkovic, Uma Chandran, Hamdi Mbarek, Mahmoud Aarabi","doi":"10.1016/j.xhgg.2026.100625","DOIUrl":"10.1016/j.xhgg.2026.100625","url":null,"abstract":"<p><p>The American College of Medical Genetics and Genomics (ACMG) recommends Tier-3 reproductive carrier screening for 97 genes associated with autosomal recessive (AR) conditions (AR genes). Gene selection for screening is based on a gene carrier frequency (GCF) of ≥1/200 in the Genome Aggregation Database (gnomAD)v2 populations and disease severity. The utility of ACMG Tier 3 in the Middle Eastern population is unclear as this ancestral group was not represented in the gnomADv2. We utilized genome data from 14,392 individuals in the Qatar Genome Project to estimate the carrier frequency of AR conditions in the Middle Eastern population. The frequency of 136,624 pathogenic/likely pathogenic variants in 2,987 AR genes from ClinVar was analyzed to estimate the GCF in the Qatari cohort. Genes with GCF ≥ 1/200 were curated by an expert panel for the severity of corresponding conditions. We identified 69 genes with GCF ≥ 1/200 associated with moderate to profound clinical presentations, 53 of which were unique to the Middle Eastern population. Common variants were observed with high frequency for individual genes such as IL2RA that suggested the presence of founder effects not described previously. Simulation studies predicted that inclusion of the ancestry-specific genes increased the chance of detecting at-risk couples from 3.85% to 8.15% in the Middle Eastern population. This study highlights the limitations of relying on global datasets to accurately identify the candidate genes for carrier screening in different populations. Our findings provide a framework for targeted, population-specific carrier-screening programs in regions not represented in the large genome datasets.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100625"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13254388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147943102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Layers in the sand: The genetic imprint of migration, culture, and Indus craft in the Thar Desert.","authors":"Rishabh Jain, Sachin M Rathod, Pankaj Jha, Deepika Jangir, Mohammed Faruq, Ganga Nath Jha, Mitali Mukerji","doi":"10.1016/j.xhgg.2026.100623","DOIUrl":"10.1016/j.xhgg.2026.100623","url":null,"abstract":"<p><p>The Thar Desert of northwestern India, despite its harsh ecology, has sustained settlement of ancient crafts and pastoral communities. Their persistence provides a unique opportunity to study how migration, ecology, and culture have shaped genetic diversity. We analyzed genome-wide SNP data from 176 individuals across eight occupational communities along with global Indian populations and diverse ancient genomes. Population history, ancestral migration, population structure, demography, admixture, and founder effects were elucidated using diverse population genetic statistical methods. The Thar groups occupy an intermediate position on the Indian north-south cline. Pastoralists and artisans (woodcarvers and Persian gold embossers) align with West Eurasian lineages, while potters and performers align with southern clines. Uniparental data confirmed heterogeneous Indian lineages. Gene-culture co-evolution was evident from the lactase-persistence allele being higher in pastoralists but lower in gold embossers despite shared ancestry. Noteworthy, despite the desert environment, the populations retain a high frequency of the SLC24A5 allele associated with lighter skin pigmentation in Europeans. Demographic analyses indicate an admixture of 60-80 generations before present and strong founder effects in certain groups, particularly tie and dye and Persian migrant artisans ∼500-600 years ago. Ancient DNA (aDNA) comparisons confirmed continuity with the Indus Periphery and historical South Asian populations. The genetic landscape of the Thar is a palimpsest shaped by successive layers of settlement, migration, and cultural continuity. By establishing the genomic baseline of Thar's craft and pastoral communities, this study shows how ecology and endogamy, along with population history, shape distinct genetic landscapes. These findings provide essential context for studying genetic risk, adaptation, and human resilience in extreme environments.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100623"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13213775/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An efficient LASSO framework for admixture-aware polygenic scores.","authors":"Franklin Ockerman, Brian D Chen, Quan Sun, Elena V Kharitonova, Chang Chen, Laura Y Zhou, Ruth J F Loos, Charles Kooperberg, Ulrike Peters, Jeffrey Haessler, Alexander P Reiner, Su Yon Jung, JoAnn E Manson, Rami Nassir, Kari E North, Steven Buyske, Christopher A Haiman, David V Conti, Lynne R Wilkens, Ethan M Lange, Nancy J Cox, Hongyuan Cao, Laura M Raffield, Yun Li, Ran Tao","doi":"10.1016/j.xhgg.2026.100628","DOIUrl":"10.1016/j.xhgg.2026.100628","url":null,"abstract":"<p><p>Polygenic scores (PGSs) have promising clinical applications for risk stratification, disease screening, and personalized medicine. However, most PGSs are trained on predominantly European ancestry cohorts and have limited portability to external populations. While cross-population PGSs have demonstrated greater generalizability than single-ancestry PGSs, they fail to properly account for individuals with recent admixture between continental ancestry groups. GAUDI, a recently proposed PGS method, overcomes this gap by leveraging local ancestry to estimate ancestry-specific effects, penalizing but allowing ancestry-differential effects. However, the modified fused LASSO approach used by GAUDI is computationally expensive and does not readily accommodate more than two-way admixture. To address these limitations, we introduce HAUDI, an efficient LASSO framework for admixed PGS construction. HAUDI reparameterizes the GAUDI model as a standard LASSO problem, allowing for extension to multiway admixture settings and far superior computational speed than GAUDI. In extensive simulations, HAUDI compares favorably to GAUDI while dramatically reducing computation time. In real data applications, HAUDI uniformly outperforms GAUDI across 18 clinical phenotypes, including total triglycerides, C-reactive protein, and mean corpuscular hemoglobin concentration, and shows substantial benefits over ancestry-agnostic PGSs for white blood cell count and chronic kidney disease. It is also substantially faster and more accurate than the recently proposed SDPR_admix method.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100628"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13233548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147975936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide investigation of prosody perception: Shared genetic influences between speech rhythm, musical rhythm, and reading traits.","authors":"Alyssa C Scartozzi, Youjia Wang, Peyton L Coleman, Ximena León Du'Mottuchi, Tara L Henechowicz, Daniel E Gustavson, Lauren E Petty, Heather M Highland, Nicole Creanza, Cyrille L Magne, Rosa S Gísladóttir, Nancy J Cox, Jennifer E Below, Srishti Nayak, Reyna L Gordon","doi":"10.1016/j.xhgg.2026.100581","DOIUrl":"10.1016/j.xhgg.2026.100581","url":null,"abstract":"<p><p>Prosody perception is an often overlooked aspect of human language despite its importance in facilitating spoken language comprehension. Sensitivity to prosodic cues varies between individuals, and prosody perception skills are shown to be associated with various language- and reading-related outcomes. Despite the importance of prosody perception in human communication, its underlying biology is poorly understood. This study investigates the genetic architecture of prosody (speech rhythm) perception and explores its evolutionary roots. We conducted a GWAS of prosody (n = 1,501) as measured by scores on the Test of Prosody via Syllable Emphasis (\"TOPsy\"). GWAS results yielded 14 suggestive significant signals (p < 5.00 × 10^-6). Gene set enrichment analysis identified shared genetic architecture between human prosody perception and key vocal learning brain regions in songbirds, suggesting that human prosody perception may have evolutionary convergence in communication mechanisms in animal vocal learning. Additionally, cross-trait polygenic score analyses suggest shared genetic influences between prosody perception and both word reading and musical beat synchronization, emphasizing how genetics influence prosody perception and its associations with communication-, education-, and music-related traits. These initial efforts could inform advances in communication sciences and disorders as well as educational contexts.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100581"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13091348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146228919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss-of-function variants in MARK2 cause neurodevelopmental disorder.","authors":"Yunseon Yang, Yoon-Kyung Shim, Noriko Miyake, Sanami Takada, Sebastian Silva, Alexander Peters-Foitzick, Abha R Gupta, Emily Neuhaus, Catherine Bradley, Cora Taylor, Bianca Russell, Amanda Shrewsbury, Jacob J Michaelson, Chaya N Murali, Amanda Gerard, Alexa Geltzeiler, Wendy K Chung, Hyung-Lok Chung","doi":"10.1016/j.xhgg.2026.100600","DOIUrl":"10.1016/j.xhgg.2026.100600","url":null,"abstract":"<p><p>Microtubule-affinity regulating kinase 2 (MARK2) is a conserved serine/threonine kinase that plays a critical role in microtubule dynamics and neuronal polarity. Rare MARK2 variants have recently been reported in individuals with autism spectrum disorder (ASD) and neurodevelopmental disorder (NDD), and here we expand the number of affected individuals, including a familial case. Despite these clinical findings, the functional significance and underlying mechanisms of patient-derived variants remain poorly understood. To address this gap, we established a humanized Drosophila model and systematically evaluated eight NDD-linked MARK2 variants using tissue-specific expression assays. Functional assessments in Drosophila indicate that MARK2 variants span a range of functional consequences, primarily exhibiting hypomorphic or loss-of-function effects. Truncating variants consistently showed reduced protein levels and rescued lethality, a loss-of-function mechanism. Most missense variants (e.g., p.Val231Met, p.Gly135Arg, p.Ala80Val, and p.His167Pro) maintained protein expression and induced mild to moderate phenotypes, consistent with partial loss of function. The p.Lys224Glu variant behaved similarly to the wild type in both viability and wing patterning assays and exhibited elevated protein levels but did not display overt pathogenicity in flies. Based on these findings, we propose a functional classification of MARK2 variants into three categories: not pathogenic (p.Lys224Glu), hypomorphic (missense variants), and loss of function (truncating variants). These results highlight the value of Drosophila as a scalable in vivo platform for variant interpretation and provide insight into how reduced MARK2 activity may contribute to neurodevelopmental disorders.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100600"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13127627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147595203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanopore-based haplotype-resolved X chromosome inactivation for severity assessment in X-linked disorders: An AIFM1 study with a mosaic PDHA1 carrier.","authors":"Kohta Nakamura, Atsuko Okazaki, Daisuke Motooka, Naoyuki Matsumoto, Yuiko Hasegawa, Sayaka Fukuda, Manami Yabe, Ayumu Sugiura, Yukiko Yatsuka, Takuya Fushimi, Takanori Onuki, Yuko Aida, Akira Ohtake, Kei Murayama, Yasushi Okazaki","doi":"10.1016/j.xhgg.2026.100632","DOIUrl":"10.1016/j.xhgg.2026.100632","url":null,"abstract":"<p><p>X chromosome inactivation (XCI) modifies disease severity in females with X-linked variants, but clinically applicable high-resolution assessment remains limited. We report a family with an apoptosis-inducing factor, mitochondria-associated 1 (AIFM1) variant that shows marked intrafamilial phenotypic variability and evaluated whether haplotype-resolved nanopore sequencing can inform clinical interpretation. Targeted long-read sequencing was performed in a severely affected hemizygous male, his asymptomatic heterozygous mother, and a severely affected heterozygous sibling. In the hemizygous male, the sample served as a technical control, with all reads mapping to a single haplotype, consistent with a hemizygous X chromosome. Among heterozygous carriers with the identical variant (c.506C>T [p.Pro169Leu]), XCI correlated with severity: the affected sibling showed 84% skew favoring activation of the pathogenic allele, whereas the mother showed preferential inactivation (20%). This family-based study shows that using nanopore sequencing for haplotype-resolved XCI analysis may provide a practical framework for selected X-linked disorders with variable expressivity.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100632"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13347936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148212600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined skeletal dysplasia and vasculopathy phenotypes associated with in-frame intragenic deletion in PRKACA.","authors":"K Nicole Weaver, Jan W Broeckel, Kari Brown, Halley Wasserman, Jian Wu, Ashley Neal, Carlos E Prada, Neil Lennart Kleinschmidt, Erik M F Machal, Daniela Bertinetti, Victor L Ruiz-Perez, Susan S Taylor, Samantha A Brugmann, Friedrich W Herberg","doi":"10.1016/j.xhgg.2026.100626","DOIUrl":"10.1016/j.xhgg.2026.100626","url":null,"abstract":"<p><p>Pathogenic missense variants in PRKACA cause craniofacial, skeletal, and cardiac defects similar to Ellis-van Creveld syndrome. We report an individual with a previously unreported, de novo 3-amino-acid deletion in PRKACA, identified on trio genome sequencing, and phenotypic features including severe neonatal hypotonia, appendicular skeletal abnormalities, osteopenia, aortic dilation, coronary dilation, and vascular tortuosity. To assess this variant's effects, we performed in vitro and in vivo studies, generated an in silico model, and assessed cell ciliation in induced pluripotent stem cells from the patient. Although the protein product of the PRKACA (Protein kinase A [PKA]-Cα) 3-amino-acid-deletion variant is catalytically active, it shows reduced interaction with the regulatory subunits of PKA (particularly type II), resulting in overactivation of the PKA pathway and/or an inability to initiate Hedgehog signaling. The deletion affects a key portion of PKA-C important for substrate tethering. Patient-derived induced pluripotent stem cells (iPSCs) have reduced ciliation compared to controls. Collectively, this supports that the PRKACA variant is pathogenic, and we propose that it is causal for our patient's unique skeletal dysplasia and vasculopathy phenotypes. This expands the phenotypic spectrum of pathogenic variants in PRKACA and suggests that affected individuals may require periodic screening for aortic and coronary dilation as well as osteopenia.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100626"},"PeriodicalIF":3.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13262138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147975925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}