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Results for “genotype-phenotype correlation”

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PubMed2026

Novel splice site variants in GBA1 are associated with Gaucher disease and genotype-phenotype correlations.

BACKGROUND: Variants in GBA1 are associated with neurodegenerative disease. This study aimed to explore pathogenic GBA1 variants. METHODS: Four patients with progressive myoclonic epilepsy (PME) and extremely low β-glucosidase levels were recruited. Whole-exome sequencing and long-range PCR were performed to identify GBA1 variants. Bioinformatic analyses were used to predict the impact of the identified variants. A literature review was performed to explore the genotype-phenotype correlations. GBA1 expression data across different brain regions and developmental stages were analyzed using the BrainSpan database. RT-PCR was performed to verify the splicing effects. RESULTS: Compound heterozygous GBA1 variants were identified in four patients. Five distinct variants were detected, including two novel splice site variants (c.308-2A>G and c.762-2A>C) and three previously reported variants. All identified variants were rare or absent in gnomAD. Splice site variants c.308-2A>G and c.762-2A>C were predicted to cause aberrant splicing. Minigene-based splicing assays coupled with RT-PCR and Sanger sequencing confirmed that both variants cause complete exon skipping (exon 4 and exon 7, respectively). All patients presented with PME onset in childhood/adolescence, intellectual regression, low β-glucosidase, and diffuse brain atrophy and were subsequently diagnosed with Gaucher disease type 3. GBA1 expression in the brain showed two distinct peaks: one in infancy and another after five years of age. The onset age of PME aligned with the second GBA1 expression peak (after five years of age). CONCLUSION: This study identified compound heterozygous GBA1 variants, including two novel candidate pathogenic splice site variants, in Gaucher disease type 3 patients, expanding the known mutational spectrum.

Humans↗

PubMed2026

Phenotypic manifestations and variant reclassification of germline PTEN variants: a nationwide Danish study.

BACKGROUND: Classification of heterozygous germline PTEN variants in patients with, or suspected of having, PTEN hamartoma tumour syndrome (PHTS) remains challenging. Accurate classification is essential as these patients require lifelong cancer surveillance. METHODS: We identified all patients with a PTEN variant previously classified as a variant of uncertain significance (VUS), likely pathogenic (LP) or pathogenic (P), collected clinical data and reclassified all variants using the latest PTEN gene-specific American College of Medical Genetics (ACMG) guidelines. Moreover, genotype-phenotype correlations were assessed. RESULTS: 167 patients from 112 families were enrolled. Eighty-seven unique PTEN variants were identified, including 20 novel variants. After applying the PTEN gene-specific ACMG guidelines, 32 variants (36.8%) were reclassified, resulting in 60 PTEN variants classified as LP/P (69.0%), 18 variants classified as VUS (20.7%), while 9 variants were classified as LB/B (10.3%). Genotype-phenotype correlation was performed among 104 patients with LP/P variants: 51 cancer cases were recorded in 41 patients and a distinct PHTS phenotype was observed in 25% of patients, with macrocephaly being present in 99% of patients with a known head circumference. Twenty-three patients had neurodevelopmental delay and/or autism, and we observed an increased prevalence of missense variants in these patients. CONCLUSION: We identified 87 different PTEN variants, and application of PTEN gene-specific ACMG guidelines led to reclassification of 32 variants (36.8%), underscoring the importance of regular variant reassessment using the most recent gene-specific guidelines, ensuring optimal patient management and surveillance.

Genetic Predisposition to Disease↗

PubMed2026

Phenotypes of Hereditary Diseases Associated With Rauch-Steindl Syndrome.

PURPOSE: Prenatal phenotypic manifestations of genetic disorders associated with NSD2 variants remain poorly characterized. This study presents our institutional experience with the prenatal diagnosis of NSD2-associated genetic disorders, specifically Rauch-Steindl syndrome (RAUST), aiming to improve understanding of both the molecular and clinical features of RAUST. METHODS: We performed a retrospective analysis of six fetuses and one adult diagnosed with RAUST at our institution and thoroughly reviewed the prenatal ultrasound reports of six fetuses. Prenatal and postnatal phenotypes of RAUST cases were summarized alongside findings from previously published literature. Correlations between NSD2 variant locations, variant types, and phenotypes were analyzed. Additionally, protein modeling was used to visualize structural changes in NSD2 protein before and after C-terminal variants. We integrated single-cell transcriptomic and gene expression data from multiple public databases to investigate spatiotemporal expression patterns of NSD2 during human fetal development. RESULTS: Fetal growth restriction (FGR) was the most prevalent prenatal manifestation in RAUST fetuses, followed by microcephaly. Bilateral renal hypoplasia emerged as a novel prenatal ultrasonographic feature. Postnatally, speech and motor developmental delays were the most commonly reported phenotypes, followed by physical developmental delays and intellectual disability. Genotype-phenotype correlation analysis revealed an association between N-terminal truncating variants in NSD2 and impaired fetal growth parameters. Notably, C-terminal truncating variants-predicted not to directly impact NSD2 functional domains-also exerted disease-causing effects. CONCLUSION: This study provides a comprehensive analysis of prenatal phenotypes in RAUST cases, enriching the prenatal phenotypic spectrum of the disease and facilitating early diagnosis and clinical management of RAUST. Furthermore, our genotype-phenotype correlation findings lay a foundational basis for future research into the complex molecular mechanisms underlying NSD2-associated genetic disorders.

Humans↗

PubMed2026

Gastric carcinoma classification in the WHO 6th edition (2026): Updated framework and emerging entities.

The sixth edition of the WHO Classification of Digestive System Tumours (2026) represents an important step in the continuing evolution of gastric carcinoma classification. While preserving morphology as the foundation of diagnosis, it incorporates advances in molecular pathology, genotype-phenotype correlations, tumour evolution, and predictive biomarker assessment. This review summarizes the development of the WHO classification from the third edition (2000) to the sixth edition (2026) and highlights its relationship with other major classification systems, including those of Laurén, Nakamura, and the Japanese Gastric Carcinoma Association (JGCA). Major histological categories remain largely unchanged; however, several important conceptual and diagnostic refinements have been introduced. These include recognition of crawling-type adenocarcinoma as a distinctive variant of tubular adenocarcinoma, subclassification of poorly cohesive carcinoma into signet-ring cell and non-signet-ring cell subtypes, introduction of the concept of pure signet-ring cell carcinoma, and increased emphasis on tumour evolution. The sixth edition also expands and refines the spectrum of uncommon gastric carcinoma subtypes, including gastric carcinoma with lymphoid stroma, AFP-producing carcinoma, micropapillary adenocarcinoma, gastric adenocarcinoma of fundic-gland type, and gastric sarcomatoid carcinoma. Crucially, molecular subgroups originally proposed by The Cancer Genome Atlas (TCGA) and actionable biomarkers-including HER2 (ERBB2), Claudin 18.2, mismatch repair deficiency/microsatellite instability (dMMR/MSI), and programmed death-ligand 1 (PD-L1)-have transitioned from research-based categories into essential tools for precision oncology. Rather than providing exhaustive diagnostic criteria, this review offers a conceptual framework and encourages consultation of the original WHO text for full details. These advances illustrate the transition of gastric carcinoma classification from a predominantly morphology-based system toward an integrated histomolecular framework that more closely links pathological diagnosis with tumour biology, prognostication, and therapeutic stratification.

Crawling-type adenocarcinoma↗

PubMed2026

Homozygous initiation codon-altering complex variant causes rapid-onset chorioretinopathy phenotype in ABCA4 disease.

PURPOSE: To characterize the clinical phenotype associated with a homozygous start codon-altering complex variant in the ABCA4 gene and evaluate its severity and prognosis in the context of Stargardt disease. METHODS: Patient records were retrospectively reviewed for homozygous ABCA4 start codon variants. Patients underwent ophthalmic exam, multimodal imaging, full-field electroretinography (ffERG), and inherited retinal disease panel testing. Structural and functional retinal assessments were reviewed to determine phenotype severity. RESULTS: Three brothers of Ashkenazi Jewish descent presented with profound early-onset vision loss beginning at age 7, with best-corrected visual acuity reduced to counting fingers or hand motion by early adulthood. Imaging revealed widespread macular atrophy, extensive intraretinal pigment migration, and near-complete foveal outer nuclear layer loss. ffERG demonstrated extinguished scotopic and photopic responses. The patients were found to be homozygous for a complex ABCA4 allele containing the start codon variant c.[1A > G;6089G > A]. These features were consistent with the rapid-onset chorioretinopathy phenotype, previously associated with null ABCA4 alleles. CONCLUSIONS: This report characterizes the clinical findings in patients homozygous for the c.[1A > G;6089G > A] variant in ABCA4, confirming its association with a severe, rapid-onset chorioretinopathy phenotype. The data support the pathogenic nature of this complex allele and expands the genotype-phenotype correlational spectrum of ABCA4-related disease, with implications for prognosis and genetic counseling.

Humans↗

PubMed2026

Prader-Willi syndrome as a neurogenetic model for psychosis and obsessive-compulsive disorder: A review of clinical, behavioral, and biological insights.

Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder classically defined by hyperphagia and obesity. However, its profound psychiatric phenotype offers a unique genetic framework for understanding major mental illnesses. This review positions PWS as a potentially informative biological model for psychosis and obsessive-compulsive disorder (OCD), bridging the gap between 15q11-q13 imprinting defects and neural circuit dysfunction. We synthesize evidence demonstrating that psychosis in PWS is not a uniform trait but is disproportionately linked to the maternal uniparental disomy (mUPD) subtype. This genotype-phenotype correlation suggests that overexpression of maternally imprinted genes and loss of paternal expression disrupt cortical excitatory-inhibitory balance, resembling the "schizophrenia-bipolar" genomic architecture. Furthermore, synthesized evidence characterizes the repetitive, ritualistic behaviors in PWS not merely as behavioral challenges, but as a developmentally arrested OCD-spectrum phenotype driven by distinct serotonergic-oxytocinergic imbalances and hypothalamic-limbic dysconnectivity. Mechanistic insights from preclinical models of MAGEL2, SNORD116, and NDN deficiency are integrated with clinical findings to highlight shared neurobiological substrates. Finally, we outline a roadmap for precision psychiatry in PWS, emphasizing the necessity of pharmacogenomics in antipsychotic management and the potential of targeted circuit-based therapeutics. By deconstructing the psychiatric comorbidities of PWS, we provide a framework for translating genomic architecture into mechanistic understanding and targeted treatment for complex neuropsychiatric disorders.

15q11-q13↗

PubMed2026

Missense mutations in the SNCA gene: Molecular mechanisms and clinical implications.

The SNCA gene on chromosome 4 encodes the alpha-synuclein (αSyn) protein, which plays a central role in the pathogenesis of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). While αSyn has established roles in synaptic vesicle dynamics and neuronal signaling, alterations in SNCA regulation and sequence contribute to protein misfolding, aggregation, and loss of function. Alterations in secondary and tertiary structure, as well as protein aggregation, affect biochemical interactions, ultimately leading to pathogenesis. This review outlines the molecular architecture of the SNCA gene, including regulatory regions, alternative splicing, and untranslated regions that influence αSyn expression and isoform diversity. Seven missense mutations of the SNCA gene are discussed in detail from the genomic level, extending to phenotypic presentations. These missense mutations have different effects on the aggregation kinetics and fibril formation. Specific genotype-phenotype correlations are evident, with mutations such as A30P and H50Q commonly resembling idiopathic PD, E46K strongly associated with DLB, and G51D, A53T, and A53E linked to atypical parkinsonism and MSA-like syndromes. Differences in age at onset, disease progression, cognitive involvement, and response to therapy further reflect mutation-specific effects and modifying influences of allelic dosage and epigenetic regulation. Collectively, these findings emphasize the importance of SNCA genetic variation in shaping disease phenotype and progression. Improving the understanding of SNCA genotype-phenotype relationships in future studies may facilitate earlier diagnosis, refine prognostic stratification, and support the development of targeted, disease-modifying therapies for synucleinopathies.

Molecular mechanisms↗

PubMed2026

Expanding the clinical spectrum of ARV1-related disease beyond classical developmental and epileptic encephalopathy.

PURPOSE: Biallelic pathogenic variants in ARV1 are classically associated with developmental and epileptic encephalopathy-38 (DEE38), a severe infantile-onset disorder characterized by drug-resistant epilepsy, profound neurodevelopmental impairment, and early mortality. However, emerging evidence suggests broader phenotypic variability. We aimed to expand the clinical and molecular spectrum of ARV1-related disease through a retrospective case series and structured literature review. METHODS: We retrospectively identified five unrelated Saudi Arabian families with biallelic pathogenic or likely pathogenic ARV1 variants confirmed by whole-exome sequencing. Clinical, neurodevelopmental, neurophysiological, neuroimaging, and multisystem findings were reviewed. A structured literature review was performed to integrate previously reported cases. RESULTS: We identified marked clinical heterogeneity, including a novel ARV1 missense variant (c.214G>T; p.Asp72Tyr), which remains classified as a variant of uncertain significance according to ACMG/AMP criteria despite multiple computational predictions supporting a deleterious effect. Clinical severity ranged from severe developmental and epileptic encephalopathy with drug-resistant epilepsy and early mortality to milder static neurodevelopmental phenotypes with sustained seizure remission and long-term survival into adulthood. Families harboring the same homozygous frameshift variant exhibited markedly different clinical severity, supporting the absence of a strict genotype-phenotype correlation. Multisystem involvement included neurological, cardiac, skeletal, sensory, gastrointestinal, and genitourinary manifestations, and metabolic phenocopies contributed to diagnostic delays. CONCLUSION: Our findings demonstrate that ARV1-related disease represents a broad multisystem clinical spectrum, with classical DEE38 representing its most severe presentation rather than its sole manifestation. Recognition of milder phenotypes, prolonged seizure remission, and marked phenotypic variability has important implications for diagnosis, prognostic counseling, and multidisciplinary long-term surveillance. Early genomic testing should be considered in patients with early-onset epilepsy and multisystem involvement, particularly in consanguineous populations.

ARV1↗

PubMed2026

Population-scale disease-associated tandem repeat analysis reveals locus and ancestry-specific insights.

Tandem repeat (TR) expansions, including short TRs (motifs ≤6 bp) and variable number TRs (motifs >6 bp), underlie many monogenic disorders, with variable length and sequence influencing pathogenicity, penetrance, severity, and onset. Accurate genotype-phenotype correlation and disease prevalence estimation require characterization beyond repeat length. Here we present a population-scale analysis of 66 disease-associated TR loci using long-read assemblies from 2530 diverse haplotypes from 1265 unaffected donors. Integrating repeat length, motif composition, local ancestry, linkage disequilibrium, and phylogenetic analyses, we reveal extensive locus-, population-, and allele-specific variation shaping disease risk. Up to 8.5% of individuals carry expansions above established pathogenic thresholds, many containing interrupting motifs or sequence structures that attenuate pathogenicity. After excluding alleles from loci with uncertain disease association, non-pathogenic interrupted expansions, and carrier states inconsistent with inheritance patterns, ~4% carried expansions predicted to confer disease risk, largely at adult-onset loci with reduced penetrance. Ancestry-resolved analyses uncover population-specific TR architectures contributing to epidemiological disparities in repeat expansion disorders. Phylogenetic analyses identify conserved ancestral alleles and loci with recent instability. We describe variable linkage disequilibrium patterns and recombination signatures around specific disease-associated TR loci. Our findings emphasize integrating sequence, ancestry, and evolutionary context to understand the complex landscape of disease-associated TRs.

Humans↗

PubMed2026

Clinical Variability and Genotype-Driven Outcomes in CHRND-Related Congenital Myasthenic Syndrome.

BACKGROUND: Congenital myasthenic syndromes (CMS) caused by pathogenic variants in CHRND, encoding the δ-subunit of the nicotinic acetylcholine receptor (AChR), are rare, and data on genotype-phenotype correlations and long-term outcomes are limited. METHODS: We performed a retrospective, multicenter study of nine patients with genetically confirmed CHRND-related CMS from specialized neuromuscular centers. Clinical, electrophysiological, genetic, and therapeutic data were systematically collected. All diagnoses were established by exome sequencing during routine clinical work-up. RESULTS: Eight patients were compound heterozygous and one was homozygous for pathogenic CHRND variants, including nonsense, missense, splice-site variants, and one microdeletion. Disease onset ranged from the neonatal period (n = 7) to adolescence (n = 2). Three patients were followed longitudinally for 22-43 years. Ocular involvement, particularly ptosis and ophthalmoparesis, was present in all patients. Generalized fatigable weakness was common, whereas bulbar and respiratory involvement occurred in a subset and reflected overall disease severity. Genotypes including a null allele or a homozygous missense variant tended to be associated with more severe phenotypes, while compound heterozygous missense variants were linked to a broader and generally milder spectrum, sometimes limited to ocular symptoms. Long-term outcomes ranged from minimal symptoms under therapy to severe motor impairment with respiratory insufficiency, highlighting substantial interindividual variability. CONCLUSIONS: This study expands the phenotypic and genotypic spectrum of CHRND-related CMS and underscores the critical role of genotype in determining disease severity. Comprehensive genetic testing, longitudinal phenotyping, and genotype-informed management are essential for optimal diagnosis and care in this rare disorder.

Humans↗

PubMed2026

Epidermolysis Bullosa Classification and Current Approach to Diagnosis.

Epidermolysis bullosa (EB) is a heterogeneous group of rare genodermatoses marked by skin fragility and bullae formation induced by minor trauma. Pathologic variants in at least 21 genes are associated with EB, grouped into four major subtypes based predominantly on the plane of cleavage within the skin. EB simplex is characterized by epidermal bullae formation and is due to gene mutations that affect epidermal proteins, most commonly keratin filaments. Junctional EB is due to gene mutations affecting proteins in the basement membrane zone, causing a split within the lamina lucida of the dermal-epidermal junction. Dystrophic EB is characterized by subepidermal bullae formation and is due to mutations in the gene encoding type VII collagen, which makes up the anchoring fibrils in the papillary dermis. Kindler EB is the rarest subtype and may be associated with cleavage at various levels within the skin due to a mutation in the FERMT1 gene causing defects in kindlin-1, a protein associated with integrins and focal adhesions. Because EB is such a heterogeneous disease, an understanding of genotype-phenotype correlations is necessary to help guide management. Traditionally, the first step in diagnosis was inducing a blister that was biopsied for immunofluorescence mapping. Currently, the gold standard for diagnosis is a blood sample or buccal swab for extraction of genomic DNA via next-generation sequencing, which can identify the exact causative gene. A diagnosis of EB is life altering for patients and families alike. A firm understanding of EB classification and initial diagnostic workup can help dermatologists feel empowered to support and counsel families.

Humans↗

PubMed2026

Solid tumours in RASopathies: insights from a large monocentric cohort and systematic review of the literature.

BACKGROUND: Dysregulation of the RAS-mitogen-activated protein kinase signalling pathway underlies RASopathies, a family of neurodevelopmental disorders associated with variable cancer predisposition. However, the prevalence and spectrum of solid tumours and the contribution of specific variants to tumour susceptibility remain poorly defined. METHODS: We assessed solid tumour prevalence and spectrum in the largest single-centre cohort of individuals with RASopathies (n=138), excluding neurofibromatosis type 1 and integrated these findings with a systematic literature review to evaluate tumour distribution and genotype-phenotype correlations. RESULTS: In our cohort, at least one solid tumour was identified in 10.8% of individuals with Noonan syndrome (NS), 47.8% with Costello syndrome (CS) and 7.3% with cardiofaciocutaneous syndrome (CFCS). Malignant tumours occurred in 5.4%, 30.4% and 2.4%, respectively. CS showed the highest tumour burden, frequently with multiple primary tumours, predominantly of the bladder. In NS, low-grade central nervous system (CNS) tumours were most common, particularly among individuals carrying PTPN11 variants. Tumour onset occurred with a median age of 19, 14 and 13 years in NS, CS and CFCS, respectively. Literature data analysis identified candidate variants in HRAS, PTPN11 and SOS1 genes associated with increased risk for solid tumours, which differed from mutational hotspots reported in childhood leukaemia or sporadic cancers. CONCLUSION: Solid tumour risk in RASopathies is syndrome-dependent and genotype-dependent, with CS showing a high burden of bladder tumours and NS mainly associated with CNS tumours. These findings may support tailored surveillance strategies.

Human Genetics↗

PubMed2026

An Update on Inborn Errors of V(D)J Recombination.

V(D)J recombination is the fundamental process by which developing T and B lymphocytes generate diverse antigen receptors, enabling adaptive immunity. This tightly regulated program operates exclusively in lymphoid precursors during G1 phase and depends on the lymphocyte-specific RAG1-RAG2 recombinase to introduce programmed DNA double-strand breaks at recombination signal sequences, followed by repair through the classical nonhomologous end joining (c-NHEJ) pathway. Disruption of any step in this molecular choreography compromises antigen receptor diversity and underlies a spectrum of inborn errors of immunity (IEIs), ranging from severe combined immunodeficiency (SCID) to immune dysregulation with autoimmunity and granulomatous disease. In this review, we place disorders of V(D)J recombination within the broader framework of T-cell development, detailing the temporal waves of recombinase activity, chromatin accessibility, and DNA damage responses that guide thymocyte differentiation. We discuss pathogenic variants affecting the cleavage phase [RAG1, RAG2, and the recently identified RAG cochaperone NudC domain-containing 3 (NUDCD3)], end processing (ARTEMIS), ligation and repair (LIG4, XLF, XRCC4, PRKDC), and genome surveillance pathways (ATM, MRN complex, RNF168), highlighting genotype-phenotype correlations and mechanisms driving immune deficiency and dysregulation. We briefly review recent diagnostic advances, including newborn screening using T-cell receptor excision circles, repertoire sequencing, and functional assays, alongside current therapeutic strategies. Finally, we outline key unanswered questions and argue that continued integration of clinical observation with molecular discovery is essential to improve outcomes and deepen understanding of adaptive immune development.

Humans↗

PubMed2026

The Role of Genetic Variation in Phenotypic Variability in Loeys-Dietz Syndrome.

BACKGROUND: Loeys-Dietz syndrome (LDS) is a heritable connective tissue disorder caused by pathogenic variants in genes of the transforming growth factor-β (TGF-β) signaling pathway. Although genotype-phenotype correlations have been suggested, comprehensive comparative data across LDS subtypes remain limited. Improved understanding of these correlations is essential to guide individualized surveillance and management strategies. METHODS: We conducted a retrospective cohort study of adults with genetically confirmed LDS evaluated between 2018 and 2024 across Mayo Clinic sites. Patients with pathogenic, likely pathogenic, or suspicious variants in TGFBR1, TGFBR2, or SMAD3 were included. Clinical characteristics, physical examination findings, cardiovascular and noncardiovascular manifestations, surgical interventions, and mortality were compared across genotypes. Categorical variables were analyzed using chi-square tests and continuous variables using parametric or nonparametric methods as appropriate. RESULTS: A total of 93 patients were included (29 TGFBR1, 33 TGFBR2, 31 SMAD3). Demographics and mortality did not differ significantly between groups. Patients with TGFBR1 and TGFBR2 demonstrated trends toward higher rates of ascending aortic aneurysm and aortic dissection compared with SMAD3 patients, though these differences were not statistically significant. Renal artery aneurysms were significantly more common in TGFBR1 patients (13.8%, p = 0.010). SMAD3 patients had significantly higher rates of mitral regurgitation (54.8%, p = 0.04), peripheral neuropathy (29.0%, p = 0.018), and trends toward increased atrial fibrillation and osteoarthritis. A novel association was identified between TGFBR1 variants and migraine, which was significantly more prevalent in this group (62.1%, p = 0.017). The rates of major cardiovascular surgical interventions were high and comparable across all genotypes. CONCLUSION: Distinct genotype-phenotype associations exist among LDS subtypes. TGFBR1 and TGFBR2 variants are associated with a greater burden of aggressive vascular disease, whereas SMAD3 variants are linked to mitral valve disease, peripheral neuropathy, and osteoarthritis. We also identified a novel association between TGFBR1 genotype and migraine. These findings reinforce the importance of comprehensive genetic testing to inform personalized surveillance and management strategies in LDS.

Humans↗

PubMed2026

Familial short stature: genetic architecture, risk stratification, and precision management.

BACKGROUND: Familial short stature (FSS) has traditionally been considered a benign growth pattern characterized by short stature clustering within families and has often been regarded as a normal variant of growth. However, recent advances in genomic technologies have demonstrated that a subset of children presenting with an FSS phenotype harbor identifiable monogenic variants, particularly in genes involved in growth plate development and skeletal growth. These findings challenge the traditional phenotype-based understanding of FSS and support an etiology-oriented diagnostic framework. OBJECTIVE: To summarize current knowledge regarding the genetic architecture of FSS, review existing clinical risk stratification frameworks for genetic evaluation, and evaluate available evidence regarding treatment outcomes across different genetic etiologies. METHODS: A literature search was performed in PubMed, Embase, and Web of Science from inception to May 2026, using keywords including "familial short stature," "familial idiopathic short stature," "genetic testing," "ACAN," "SHOX," and "NPR2". Relevant original studies and review articles addressing genotype-phenotype correlations, diagnostic yield of genetic testing, or responses to recombinant human growth hormone (rhGH) therapy were considered. RESULTS: Emerging evidence indicates that monogenic variants can be identified in a subset of children with an FSS phenotype, especially among those with more severe short stature and autosomal dominant inheritance patterns. Variants affecting growth plate biology represent some of the most frequently reported genetic causes of FSS, with ACAN, SHOX, and NPR2 being the most frequently implicated genes. Existing clinical frameworks based on parental height patterns and inheritance characteristics may help stratify patients with FSS according to the likelihood of monogenic etiology and guide selection of individuals who may benefit from genetic testing. Available evidence suggests that rhGH therapy may improve growth outcomes in several monogenic forms of FSS, although treatment responses vary according to genetic etiology. CONCLUSIONS: FSS should be regarded as a heterogeneous clinical phenotype rather than a single diagnostic entity. Integration of existing clinical risk stratification approaches with molecular diagnosis may enable more precise identification of underlying genetic causes and facilitate individualized therapeutic decision-making. Future advances in FSS management will likely depend on precision medicine approaches linking phenotype, genotype, and treatment response.

Humans↗

PubMed2026

Genetic architecture of endometriosis: risk factors, comorbidities and clinical implications.

BACKGROUND: In 1999, Dr Susan Treloar and colleagues conducted a landmark twin study in Australia and reported their estimate of 51% for the heritability of endometriosis. This important result led several groups to begin mapping genetic factors contributing to increased endometriosis risk. Despite early challenges, advances in genome-wide association studies (GWAS) have identified multiple genetic risk factors and some target genes implicated in follow-up studies on genetic regulation of transcription. Access to large publicly available genetic datasets and analysis with endometriosis GWAS results is also providing new opportunities to answer important questions about comorbid conditions associated with endometriosis and their implications for clinical practice. OBJECTIVE AND RATIONALE: The objective of the review is to summarize the last 25 years of genetic studies in endometriosis, outline contributions to our understanding of the disease, and suggest future directions to accelerate biological insights from genetic studies to improve clinical outcomes. SEARCH METHODS: A comprehensive review of scientific literature on the genetics of endometriosis was conducted through searches in PubMed and Google Scholar up to June 2026. Search terms included "endometriosis AND (genetics OR GWAS OR genetic risk factors)", For studies addressing the functional characterization of genetic risk loci, additional searches employed the terms "endometriosis AND (genotype-phenotype associations OR colocalization OR eQTL OR mQTL OR multi omics methods)". To identify studies examining shared genetic risk between endometriosis and comorbid conditions, the search strategy included "endometriosis AND (genetic correlation OR colocalization OR Mendelian randomisation)". Publications reporting discoveries related to genetic risk factors for endometriosis and studies interpreting their biological and clinical significance were critically evaluated, and 144 publications were discussed in the review. OUTCOMES: Discovery of genetic risk factors started slowly and has accelerated in recent years with developments in technology and international collaborations to combine data and increase statistical power. GWAS have mapped 80 genetic risk factors that implicate gene regulation of hormonal targets, development of the reproductive tract, regulation of cell proliferation, and regulation of epithelial cell differentiation. In common with most other complex diseases, effects of individual common genetic risk factors are small. However, several examples demonstrate that small effect sizes are not a good predictor for the impact of drugs developed against genetically validated targets. Genetic risk factors implicate five genes regulating gonadotrophin release and oestrogen action, the major target pathway of current drugs for treatment of endometriosis demonstrating proof-of-principal for biologically meaningful results. Genetic correlation and Mendelian Randomization studies highlight important causal relationships between endometriosis and comorbid conditions including a possible role for testosterone during development and shared genetic risk factors for gynaecological, gastrointestinal, pain, psychiatric, and inflammatory conditions. Understanding causal relationships between endometriosis and related conditions will aid clinical management and more personalized treatments. WIDER IMPLICATIONS: Genetic studies provide novel insights into endometriosis pathogenesis and associations with related comorbid conditions. Genetic factors modifying gene regulation and disease risk likely act in specific cell types, and access to datasets from genetically informed cell-based models, single-cell and spatial omics data are needed to accelerate progress. Future studies should address critical questions of heterogeneity and disease subtypes, expand the search for genetic risk factors to non-European populations, evaluate the role of rare and structural variants, and better integrate data from functional, genomics, genetics, and clinical studies to reduce diagnostic delay, develop novel treatment strategies, and translate discoveries into personalized management strategies for affected individuals. REGISTRATION NUMBER: N/A.

comorbid conditions↗

PubMed2026

Human Monocytic Models Reveal Genotype-Dependent Inflammatory Programs in VEXAS Syndrome.

OBJECTIVES: VEXAS syndrome is a severe X-linked autoinflammatory disorder caused by somatic mutations in ubiquitin-like modifier activating enzyme 1 (UBA1), with clinical outcomes that vary by UBA1 genotype. We aimed to elucidate genotype-specific inflammatory programs and identify potential therapeutic targets. METHODS: We conducted longitudinal deep phenotyping, including whole-blood RNA sequencing (RNA-seq) and clinical activity assessment. Peripheral blood samples were analyzed by single-cell RNA-seq. Human monocytic cell lines harboring each major UBA1 mutation (p.Met41Val, p.Met41Thr, or p.Met41Leu) were generated and subjected to transcriptomic and functional analyses. RESULTS: Thirteen patients with VEXAS syndrome contributed a total of 79 RNA-seq samples. Among genes upregulated in VEXAS syndrome, RNASE1 showed the strongest correlation with longitudinal disease activity (r = 0.70, FDR < 0.05) and was upregulated in patients' monocytes. In UBA1-mutant monocytic cell lines, genotype-dependent ubiquitination defects were observed in a graded manner (p.Met41Val > p.Met41Thr > p.Met41Leu), even in the absence of exogenous stimuli. These defects were accompanied by unfolded protein response activation, increased pro-inflammatory cytokine production, progressive cell death, and RNASE1 upregulation, all following the same graded pattern, recapitulating patient genotype-phenotype associations. Transcriptomic analyses demonstrated enrichment of pro-inflammatory, interferon, and necroptosis signatures in more severe genotypes. Notably, inhibition of receptor-interacting protein kinase 3 (RIPK3) markedly attenuated all pathological features, including RNASE1 upregulation. CONCLUSIONS: Our UBA1-mutant monocytic cell-line models, representing three distinct genotypes, recapitulate genotype-dependent inflammatory phenotypes that can be modulated by RIPK3 inhibition, providing a translational platform for mechanistic investigation and precision therapy development in VEXAS syndrome.

Journal Article↗

PubMed2026

Single-cell profiling of mitochondrial phenotyping-coupled mtDNA genotyping.

Simultaneously profiling mitochondrial DNA (mtDNA) heteroplasmy and phenotypic variability at the single-cell level remains a challenge due to the absence of integrated methods that map mitochondrial genotypes alongside their functional states. We introduce human single-cell mitochondrial phenotype-coupled mtDNA sequencing (scMPCDS), a platform that quantifies mtDNA mutations and heteroplasmy together with mitochondrial membrane potential and reactive oxygen species within individual cells. Unlike bulk sequencing or separate single-omics techniques, scMPCDS directly correlates mitochondrial genomic instability with functional outcomes. Using this approach, we demonstrate that DdCBE-mediated mtDNA editing induces cell-specific off-target mutations in the mitochondrial genome, which coincide with diverse phenotypic changes. Applying scMPCDS to HeLa cells and clear cell renal cell carcinoma tissues, we identify single-cell subpopulations exhibiting distinct mtDNA mutation burdens and altered bioenergetic profiles, implicating potential mitochondrial heterogeneity-driven tumor evolution. Overall, scMPCDS serves as a versatile tool to unravel mitochondrial genotype-phenotype relationships at the single-cell level in both normal and disease states, thereby advancing precise mitochondrial diagnostics and therapeutics.

Humans↗