Human molecular genetics最新文献

{"title":"Neurodevelopmental alterations are key drivers of SPG56.","authors":"Daniele Galatolo, Devid Damiani, Valentina Naef, Matteo Baggiani, Carla Cona, Giuseppe Neri, Claudia Dell'Amico, Ugo Borello, Marco Onorati, Maria Marchese, Filippo M Santorelli","doi":"10.1093/hmg/ddag071","DOIUrl":"10.1093/hmg/ddag071","url":null,"abstract":"<p><p>Biallelic pathological variants in CYP2U1 are associated with SPG56, a complex ultra-rare form of hereditary spastic paraplegia. CYP2U1 encodes a member of the cytochrome P450 family 2, which is highly expressed in the brain and involved in arachidonic acid metabolism and lipid hydroxylation. Little is known about the early stages of neurodevelopment in SPG56. To gain insight into the molecular mechanisms of the disease, we generated and characterized both a zebrafish knock-out model (cyp2u1-/-) and cortical neurons derived from induced pluripotent stem cells (iPSCs) of two patients affected by SPG56. cyp2u1-/- zebrafish showed increased mortality and locomotor impairment, and transcriptome analysis revealed defects in the cell cycle, neural development, and oxidative phosphorylation pathways, consistent with observed decreased cell proliferation, increased apoptosis, and bioenergetic impairment. To assess whether these molecular alterations impact network function, we performed local field potential recordings and whole-brain calcium imaging in mutant larvae. Local field potential analyses revealed prolonged high-frequency events despite reduced overall power, and calcium imaging showed increased skewness of neuronal activity distributions, findings indicating altered brain network dynamics in mutants. Transcriptional profiling of cortical cultures performed at neural progenitor, early-born, and mature neuron stages pointed to altered neural network development as one of the main pathogenic mechanisms of the disease and highlighted several similarities with the zebrafish model. Multiple features of the cyp2u1-/- zebrafish recall the human SPG56 phenotype, and combined transcriptomics profiling in cyp2u1-/- zebrafish and SPG56 patient iPSC-derived cortical neurons supports impaired neural network development as a key disease mechanism.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 16","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148602218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 patient-derived mouse model reproduces molecular, neurological, and sleep symptoms of SHINE syndrome.","authors":"Sharon Tamir, Jiffin Paulose, Anh Nguyen, Darshak Gadara, Rochelle M Witt, Bhagwat Prasad, John B Hogenesch","doi":"10.1093/hmg/ddag065","DOIUrl":"10.1093/hmg/ddag065","url":null,"abstract":"<p><p>SHINE syndrome is a rare neurodevelopmental disorder caused by mutations in DLG4, which encodes the postsynaptic scaffolding protein PSD-95. Key symptoms include sleep problems, hypotonia, intellectual disability, neurological disorders, and epilepsy, hence the name 'SHINE.' Here, we developed and characterized a mouse model of SHINE syndrome carrying the patient-derived DLG4V692Wfs*12/+ variant associated with a severe form of the disorder. The mutant transcript escapes nonsense-mediated decay but results in reduced PSD-95 protein expression, faithfully reproducing the molecular phenotype observed in the patient. Behavioral analyses revealed that Dlg4V692Wfs*12/+ mice recapitulate several hallmark features of SHINE syndrome, often in a sex-specific manner. Male mutants showed deficits in learning and cognitive flexibility. Dlg4V692Wfs*12/+ mice also demonstrate trends toward altered sensory processing and socialization. Male mutants exhibited an increased proportion of short sleep bouts and compensatory longer average sleep bout length, suggesting sporadic sleep reminiscent of the patient. While spontaneous seizures were not observed, future studies will test susceptibility to provoked seizures. Together, these findings establish Dlg4V692Wfs*12/+ mice as a robust and translationally relevant model that reproduces key molecular and behavioral features of SHINE syndrome. This model provides a valuable resource for elucidating the mechanisms underlying synaptic neurodevelopmental disorders and for identifying potential therapeutic strategies.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 16","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148684492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical genome sequencing in neurodegenerative diseases-outcome in the first 500 patients.","authors":"Emma Ehn, Håkan Thonberg, Inger Nennesmo, Anna Lindstrand, Malin Kvarnung, Caroline Graff","doi":"10.1093/hmg/ddag072","DOIUrl":"10.1093/hmg/ddag072","url":null,"abstract":"<p><p>Neurodegenerative diseases (NDDs) are clinically and genetically heterogeneous, requiring neuropathology or molecular testing for a definitive diagnosis. Clinical whole genome sequencing (WGS) enables comprehensive variant calling across flexible gene lists that can be tailored to the clinical presentation. By allowing simultaneous detection of single-nucleotide variants, copy-number variants, structural variants, and repeat expansions, WGS has the potential to improve diagnostic yield, facilitate genetic counseling and support clinical trial inclusion. This study assesses the diagnostic performance of WGS in individuals with NDD. WGS in 500 individuals representing a wide spectrum of NDDs identified a disease-causing variant in 61 cases, resulting in a diagnostic yield of 12%. These variants were found in 16 different genes, with C9orf72 being the most prevalent. Repeat expansions represented the largest variant class, accounting for 35 of 61 LP/P cases (57%); most of which were C9orf72 expansions (31/35). In the largest phenotype groups, frontotemporal dementia (FTD) had the highest diagnostic yield (19%) followed by amyotrophic lateral sclerosis (ALS, 13%), whereas an underlying monogenic cause was expectedly low in Alzheimer disease (AD, 4%). A positive family history was present in the majority (74%) of FTD, ALS, combined ALS-FTD and AD cases with an LP/P finding. Clinical WGS provides a clear diagnostic advantage in NDDs marked by substantial clinical and genetic overlap. WGS enables comprehensive variant detection and mapping of genotype-phenotype relationships across the disease continuum. In FTD and ALS, these results support universal access to genetic testing independent of age at onset or family history.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 16","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13648039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148684480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NRAS mutation in a central conducting lymphatic anomaly and PPFIBP1::ROS1 fusion in a Gorham-stout disease patient.","authors":"Guangxian Yang, Haoran Ren, Jinghua Wang, Weijian Chen, Xiaoming Li, Si Chen, Huafei Chen, Lina Zhao, Wenwen Fan, Sheng Xiao","doi":"10.1093/hmg/ddag070","DOIUrl":"10.1093/hmg/ddag070","url":null,"abstract":"<p><p>Lymphatic malformations (LMs) can lead to severe clinical complications, including disfigurement and even death. While genomic alterations have been identified in LMs, the genomic landscape of complex LMs remains poorly defined due to their rarity. In this study, we report two novel findings: an NRAS p.Q61R mutation in central conducting lymphatic anomaly (CCLA) and a PPFIBP1::ROS1 fusion in Gorham-Stout disease (GSD), both described for the first time in their respective LM subtypes. The discovery of the PPFIBP1::ROS1 fusion provided a unique opportunity to localize the somatic event to a specific cell type. Using serial tissue sections from the same specimen, we observed that the fusion signal was spatially associated with lymphatic endothelial cells, based on serial section analysis with D2-40 staining. Given that both NRAS mutations and PPFIBP1::ROS1 fusions have also been identified in other LM subtypes, our findings support the hypothesis that LMs may share common molecular mechanisms. We propose that phenotypic diversity among LM subtypes may arise from differences in developmental timing, anatomic location, and microenvironmental context at the time the somatic mutation occurs.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 16","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148663794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell transcriptomic integrated with machine learning reveals human retinal cell-specific biomarkers in diabetic retinopathy.","authors":"Sen Lin, Luning Yang, Yiwen Tao, Qi Pan, Tengda Cai, Yunyan Ye, Jianhui Liu, Yang Zhou, Yongqing Shao, Quanyong Yi, Zen H Lu, Lie Chen, Gareth McKay, Richard Rankin, Fan Li, Weihua Meng","doi":"10.1093/hmg/ddag069","DOIUrl":"https://doi.org/10.1093/hmg/ddag069","url":null,"abstract":"<p><strong>Background: </strong>Diabetic retinopathy (DR) is a leading cause of vision impairment worldwide, yet the cell-type-specific molecular alterations associated with disease progression remain incompletely understood. This study aimed to characterize transcriptional changes across retinal cell types in diabetes and DR and identify candidate disease-associated biomarkers using single-cell transcriptomics and machine-learning approaches.</p><p><strong>Methods: </strong>We generated a single-cell RNA sequencing (scRNA-seq) atlas comprising 297 121 high-quality retinal cells from 20 eyes of 13 Chinese donors, including non-diabetic controls (NON), diabetes without retinopathy (DM), and DR samples. Following quality control, batch correction, clustering, and cell-type annotation, differential expression analyses were performed across disease states within each retinal cell type. Candidate biomarkers were further prioritized using a machine-learning framework incorporating L1-regularized logistic regression, recursive feature elimination with cross-validation, and stability selection.</p><p><strong>Results: </strong>We identified 10 major retinal cell populations and characterized extensive cell-type-specific transcriptional alterations associated with diabetes and DR. Pathway enrichment analyses consistently highlighted immune activation, oxidative stress, neurodegeneration, and synaptic dysfunction across multiple retinal cell types. A total of 707 cell-type-specific candidate marker genes were identified, providing a comprehensive resource for investigating disease-associated molecular mechanisms and potential therapeutic targets.</p><p><strong>Conclusions: </strong>This study establishes a single-cell transcriptomic atlas of the Chinese diabetic retina and reveals cell-type-specific molecular signatures associated with DR progression. These findings provide biological insights into retinal disease mechanisms and nominate candidate biomarkers for future functional and translational studies.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 16","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148630286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A de novo TRPV4 variant c.2479C>G (p.Pro827Ala) in Spondylometaphyseal dysplasia Kozlowski type: identification and functional analysis.","authors":"Congcong Teng, Ming He, Chao Zhang, Juhua Yang, Tao Jiang, Yuecheng Yang, Xiaoyan Zhou, Na Feng, Xilun Cai, Junxue Ni, Hong Shi, Jie Zhang","doi":"10.1093/hmg/ddag064","DOIUrl":"10.1093/hmg/ddag064","url":null,"abstract":"<p><p>Spondylometaphyseal dysplasia, Kozlowski type (SMDK), is an autosomal dominant skeletal disorder characterized by abnormalities of the spine, metaphyses and epiphyses. It is associated with variants in TRPV4, although the underlying molecular mechanisms remain unclear. A de novo heterozygous TRPV4 variant (c.2479C>G, p.Pro827Ala) was detected in a patient with SMDK by whole-exome sequencing, and transcriptome sequencing was performed in available family members. Expression analyses showed reduced TRPV4 transcript and protein levels associated with the p.Pro827Ala variant. Cellular functional assays further showed decreased intracellular Ca2+ concentrations without detectable changes in plasma membrane localization. In addition, ATP2B1 and PRKCQ were downregulated. To further investigate the pathogenic mechanism, a heterozygous knock-in Trpv4P827A/+ mouse model was generated using CRISPR/Cas9. Trpv4P827A/P827A homozygous mice exhibited significant skeletal developmental delay, and transcriptome profiling revealed dysregulated expression of homeobox, zf_C2H2, and forkhead transcription factor families during early development. Collectively, these findings expand the spectrum of pathogenic TRPV4 variants and provide mechanistic insights into the pathogenic effect of TRPV4 p.Pro827Ala in SMDK, supporting improved clinical diagnosis and future functional studies.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 15","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148455636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SPEN deficiency contributes to the development of orofacial clefts in humans and mice.","authors":"Bum Jun Kim, Andrés Hernández-García, David L Curtis, Olivia Thompson, Neena Champaigne, Manuela Priolo, Francesca Clementina Radio, Marco Tartaglia, Muge Gucsavas-Calikoglu, Yael Shiloh-Malawsky, Yezmin Perilla-Young, Sarah Josephi-Taylor, Adam M Bournazos, Sandra T Cooper, Koen van Gassen, Marie-José van den Boogaard, Yunus H Ozekin, Emily Anne Bates, Natee Kongchan, Chih-Wei Hsu, Daryl A Scott","doi":"10.1093/hmg/ddag063","DOIUrl":"10.1093/hmg/ddag063","url":null,"abstract":"<p><p>Haploinsufficiency of SKI, PRDM16, RERE, PAX7, and GRHL3 have been implicated in the development of orofacial clefting (OFC) associated with chromosome 1p36 deletions based on human and/or mouse data. Haploinsufficiency of SPEN, a 1p36 gene that encodes a transcriptional repressor, causes Radio-Tartaglia syndrome, a neurodevelopmental syndrome in which high/narrow palates are common, and OFC is occasionally observed. We show that Spen-null embryos have abnormal palatal shelf elevation and extension leading to the development of cleft palate. Mesenchymal cell proliferation in the medial halves of the palatal shelves of Spen-null embryos at E13.5 is significantly reduced. This contributes to the delay of palatal shelf elevation. Tissue specific ablation of Spen in the cranial neural crest cells results in delayed palatal development. This pattern of abnormal palatal development mimics the pattern described in RERE-deficient mice. We show that Rere and Spen are expressed in same cell types, that Rere and Spen interact genetically in the development of the palate, that Spen expression is reduced in the palates of RERE-deficient embryos at E14.5, and that the rate of OFC in individuals with 1p36 deletions involving both RERE and SPEN is higher than those of individuals with RERE or SPEN haploinsufficiency. Our results suggest that SPEN is required for normal mammalian palatal development, that RERE and SPEN interact in a common pathway during palatal development, and that haploinsufficiency of RERE and SPEN are likely to contribute to the development of OFC in individuals with 1p36 deletions.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 15","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13372097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148455700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional constraint, not evolutionary domain expansion, is a stronger correlate of pathogenic variant burden in human RNA-binding proteins.","authors":"Kyota Yasuda","doi":"10.1093/hmg/ddag067","DOIUrl":"https://doi.org/10.1093/hmg/ddag067","url":null,"abstract":"<p><p>Whether evolutionary innovation predisposes genes to pathogenic variation is a fundamental question in evolutionary medicine. RBP domain family diversity correlates with neural complexity across metazoans via vertebrate-specific domain expansions. Here, we tested whether such expanded RBP domains harbor elevated pathogenic variant burden relative to evolutionarily conserved domains. We classified 2961 human RBP-encoding genes into expanded (n = 25 genes, 8 Pfam domains; vertebrate/invertebrate gene count ratio ≥ 3.0) and non-expanded control (n = 231 genes, 89 Pfam domains) groups, and integrated ClinVar pathogenic variants with gnomAD v4.1 constraint metrics. Contrary to our hypothesis, expanded domains showed lower median pathogenic variant density than non-expanded domains (P = .140, rank-biserial r = 0.180, 95% CI [-0.089, 0.444]), consistent across sensitivity analyses and count-based models. In multivariable analysis, functional constraint (pLI) was a stronger predictor of variant density than evolutionary expansion status. At the family level, no expanded domain showed significantly elevated burden; instead, the most prominent outliers were conserved non-expanded domains associated with established neurodegenerative diseases (SMN, Nop). The RNaseA family, despite 26-fold vertebrate expansion, harbored ClinVar pathogenic variants in only 1 of 15 members-fewer than expected by chance (binomial P = 0.030). The sole exception, ANG (Angiogenin), concentrates all seven ALS9-associated variants at its catalytic triad and nuclear localization signal, reflecting functional specialization rather than expansion per se. These findings indicate that evolutionary domain expansion does not confer generalized disease vulnerability in RBPs, and that pathogenic variant burden is more closely linked to functional constraint and lineage-specific subfunctionalization than to evolutionary novelty.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 15","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148584206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DDX3X syndrome mutations lock DDX3X-RNA conformational states to drive persistent pathological condensation and neuronal death.","authors":"Poulami Ghosh, Shivani Krishna Kapuganti, Sabhyata Gopal, Vhasnsciani A R, Swati Lamba, Purusharth I Rajyaguru, Sannula Kesavardhana","doi":"10.1093/hmg/ddag066","DOIUrl":"https://doi.org/10.1093/hmg/ddag066","url":null,"abstract":"<p><p>DDX3X is a highly conserved RNA helicase associated with RNA metabolism, translation initiation, and deciding cell fate choices. Spontaneous mutations in DDX3X cause a rare genetic human disorder called DDX3X syndrome, showing a spectrum of neurodevelopmental and intellectual abnormalities. How missense mutations in DDX3X lead to aberrant cellular functions and pathological consequences is unclear. Here, we demonstrate that specific DDX3X syndrome missense mutations induce the formation of persistent, solid-like DDX3X stress granules by structurally altering the conformation of the DDX3X-RNA complex. Structural interrogation of DDX3X syndrome missense mutations revealed critical mutations that perturb the DDX3X-RNA complex, exhibit high clinical pathogenicity scores, and are associated with cancers. N and C-terminal mutations adjacent to the helicase domain of the DDX3X (F182V, I190S, T198P, L556S, and L559H) showed augmented stress granule (SG) assembly, and formation of persistent DDX3X-SGs in neuronal and non-neuronal cells. Intriguingly, these mutations altered the liquid-like properties of DDX3X-SGs, forming solid-like SGs. Mechanistically, these mutations drive the persistent DDX3X-SGs by either locking DDX3X in an open, RNA-bound conformation or by increasing the rigidity of the DDX3X-RNA complex (I190S; T198P), thereby conferring a loss of liquid-like properties. The persistent solid-like DDX3X-SGs preferentially promoted neuronal lytic cell death and did not affect translation. Also, the C-terminal L556S and L559H mutations, which form persistent granules, promoted the DDX3X-driven β-amyloid aggregation. Our observations indicate that DDX3X syndrome mutations near the N- and C-termini promote the formation of solid-like DDX3X condensates, neuropathological aggregation, and neuronal cell death, which might underlie the disease pathogenesis in humans.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 15","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148584171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated multi-platform genetic profiling reveals dual molecular pathology in 46, XY disorders of sex development through NR5A1 Haploinsufficiency and maternal chromosome 15 UPD.","authors":"Rui Dong, Chen Liu, Min Gao, Kunkun Yu, Lei Zhang, Xiaochen Wang, Kaisheng Li, Hongying Li, Kaihui Zhang, Guohua Liu","doi":"10.1093/hmg/ddag055","DOIUrl":"10.1093/hmg/ddag055","url":null,"abstract":"<p><strong>Background: </strong>Dual molecular diagnoses involving concurrent monogenic variants and imprinting disorders are increasingly recognized in complex phenotypes, yet systematic approaches to elucidate such convergence remain limited.</p><p><strong>Methods: </strong>We report a 46,XY proband with disorders of sex development (DSD), global developmental delay, and clinical features suggestive of Prader-Willi syndrome (PWS). We performed whole-exome sequencing (WES) to identify sequence-level variants. Upon detection of copy-neutral loss of heterozygosity (CN-LOH), we used methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) to assess imprinting status and performed single-nucleotide polymorphism (SNP) microarray to characterize the extent and allelic architecture.</p><p><strong>Results: </strong>WES identified a maternally inherited heterozygous deletion spanning exons 2-7 of NR5A1, classified as likely pathogenic based on its predicted loss-of-function impact on this dosage-sensitive transcription factor. WES also detected a 13.95 Mb CN-LOH at 15q21.1q21.3. MS-MLPA revealed a methylation profile consistent with maternal uniparental disomy of chromosome 15 (UPD(15)), confirming PWS. SNP microarray detected a larger 32.7 Mb CN-LOH across 15q14-q21.3. The combined data support maternal UPD(15) involving mixed heterodisomy and isodisomy, likely arising from meiotic nondisjunction followed by trisomy rescue.</p><p><strong>Conclusions: </strong>An integrated genomic strategy resolved dual etiologies-NR5A1 haploinsufficiency and maternal UPD(15)-underlying complex neurodevelopmental and reproductive features. Demonstrating how integrated analysis of sequence variation, epigenetic regulation, and genome-wide allelic architecture can uncover coexisting monogenic and imprinting mechanisms, this case highlights a diagnostic strategy warranting further evaluation in broader cohorts.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 14","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148411566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}