Compound heterozygous NFKB1 missense variants in cis associated with immunodeficiency.

Memory clinic patients are interested in genetic testing for monogenic causes of dementia, but it remains unknown how they experience receiving the results. We explored the psychosocial and behavioral impact of DNA diagnostics on patients and their families. In this mixed-methods study, 37 patients visiting Alzheimer Center Amsterdam, meeting eligibility criteria, were offered genetic testing for monogenic causes as part of their diagnostic work-up. Patients were 41% female and aged 61±7 years (MMSE=22±5, 1 Subjective Cognitive Decline, 1 MCI, 30 dementia [20 AD, 4 PPA, 6 other], 5 other/undetermined). Six declined testing, 25 tested negative and six positive. Per potential proband, we included patients (n=4), one or two relatives (n=4), or both (n=29). Relatives (n=34) were 59% female, and aged 54±13. Participants completed questionnaires assessing psychosocial and behavioral factors (including anxiety, depression and distress) at first visit, one week after counseling, one week and three months after disclosure. We used linear mixed models to calculate effects of group (un-tested, negative, or positive), time, and interactions on outcome variables, with patients and relatives analyzed separately. In addition, 9 patients and 11 relatives participated in 14 semi-structured interviews. Verbatim transcripts were analyzed inductively. Average anxiety, depression and distress levels remained below clinical threshold and did not change between groups or over time, in patients nor relatives (see figures). Three months after disclosure, patients tested positive showed an increase in perceived risk of carrying a monogenic cause (β=48.55, 95%CI[9.17,87.93], p<0.05). In addition, patients tested positive expressed greater willingness to participate in research than those un-tested (scale:1-5, 4.6vs2.6, p<0.05). Decision-regret was low and independent of group (scale:1-100, 13.6, p>0.05). Interviews revealed patients tested negative were relieved, reassured their offspring were not at genetic risk, but sometimes unsatisfied for not knowing the cause of their disease. Those tested positive appreciated having clarity, yet experienced emotional distress about potential implications for their children. Genetic testing for monogenic causes of dementia did not cause short-term psychosocial harm. Patients understood the gist of the results, deemed them actionable and reported no regret. Further research in larger populations should confirm and expand upon these findings.

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in children. At least 10 monogenic causes and 28 syndromes have been reported to be associated with CHI. The aim of this study was to evaluate epidemiologic data and genetic background of persistent nonsyndromic CHI in Slovakia. Based on data from the nationwide DIABGENE database of children with persistent hyperinsulinemic hypoglycaemia, 28 children were diagnosed with nonsyndromic CHI during the years 2005 - 2024. DNA analysis of the most common CHI genes was performed. Epidemiology of CHI was calculated using Slovak demographic data. The overall incidence of nonsyndromic CHI in Slovakia over the last 20 years was 1:39,804 live births. In 2024, the prevalence was 1:161,802 children younger than 19 years. A genetic cause was identified in 9 children (32%), the most common was CHI due to mutation in ABCC8 gene (n=4), followed by the KCNJ11 (n=2), HNF4A (n=2) and HK1 (n=1) genes. In diazoxide-unresponsive CHI (n=6), 5 children had a mutation in the ABCC8 or KCNJ11 genes and one in the HK1 gene. Four children had the focal form based on the paternally inherited recessive mutation and underwent pancreatic surgery. Nonsyndromic CHI is a rare disease with nation-wide incidence in Slovakia of 1:39,804. Diazoxide-unresponsive CHI accounts for 21% of all the cases. A genetic cause was identified in 32% (100% in diazoxide-unresponsive) of children; mutations in the ABCC8 gene were the most prevalent. The type of mutation determines the most appropriate management strategy, including pancreatic surgery.

Background Interferon regulatory factor-2–binding protein-2 (IRF2BP2) is a nuclear transcriptional co-regulator originally characterised as a co-repressor of IRF2 but now recognised to exert broader functions as both a co-repressor and co-activator of additional transcription factors, including NFAT1, KLF2, and others. IRF2BP2 plays a pivotal role across innate and adaptive immune systems: it constrains CD4+ T cell activation by repressing IL-2–induced JAK-STAT5 signalling and activation markers (CD25 and CD69), promotes B cell maturation and immunoglobulin class switching, and attenuates NF-κB–mediated pro-inflammatory cytokine production. Beyond immunity, IRF2BP2 contributes to cholesterol homeostasis by facilitating cholesterol efflux in macrophages. Pathogenic variants in the IRF2BP2 gene have recently been identified as a monogenic cause of inborn errors of immunity, typically presenting with hypogammaglobulinaemia, poor vaccine responses, and pronounced immune dysregulation. Mouse models further implicate IRF2BP2 deficiency as a cause of accelerated cholesterol accumulation in macrophages, leading to macrophage-driven inflammation and early atherosclerosis. While case series have begun to define its phenotypic spectrum, single case reports remain valuable for highlighting clinical heterogeneity and expanding genotype–phenotype correlations. Case Presentation We report a 23-year-old male who presented with recurrent pyogenic skin and deep-seated abscesses, sinopulmonary infections, seronegative symmetric inflammatory polyarthritis affecting large joints (knees, wrists, ankles), radiologically confirmed bronchiectasis, and significant dyslipidaemia. Immunological evaluation demonstrated pan-hypogammaglobulinaemia, markedly reduced switched memory B cells, and impaired responses to both protein and polysaccharide vaccines, fulfilling criteria for common variable immunodeficiency (CVID). Genetic testing identified a heterozygous nonsense variant, c.1665C&amp;gt;A (p.Cys555*), in exon 2 of the IRF2BP2 gene, resulting in a premature stop codon and predicted truncation of the protein. The patient is the proband with no family history of immunodeficiency or autoimmunity. Although functional validation was not performed, the variant’s predicted loss-of-function effect and the congruent clinical phenotype strongly support pathogenicity. Conclusion This case adds to the expanding body of evidence implicating IRF2BP2 deficiency as an inborn error of immunity presenting with humoral immunodeficiency, autoinflammatory manifestations, and metabolic derangement. Recognition of this emerging genotype–phenotype association has important implications for diagnosis, genetic counselling, and the future development of targeted immunomodulatory therapies.

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent monogenic cause of kidney failure, marked by fluid-filled cysts, aberrant cell proliferation, metabolic reprogramming, and extensive genetic and epigenetic alterations. The mechanisms by which loss-of-function mutations in PKD1 and PKD2 drive disease progression remain poorly understood. Here, we demonstrate that ER-mitochondria contacts are disrupted in Pkd -mutant mice prior to cyst formation. This disconnection induces mitochondrial dysfunction and epigenetic remodeling, which in turn promote metabolic reprogramming and cystogenesis. Restoration of PKD function in the ER or pharmacological enhancement of ER-mitochondria coupling mitigates these pathological changes. Our findings uncover a critical role for ER-mitochondria crosstalk in suppressing cystogenesis and identify a promising therapeutic target for ADPKD.

Using the stages of change model to develop an understanding of caregiver intent for family behavior change following pediatric testing for genetic obesity: A qualitative analysis

Nephrolithiasis (NL) and nephrocalcinosis (NC) are common, recurrent conditions globally. While monogenic causes are increasingly recognized, data on their prevalence and spectrum remain limited in Saudi pediatric populations. This retrospective cross-sectional study was conducted in our tertiary care center from January 2008 to April 2023. Pediatric patients (0-18years) with radiologically confirmed NL/NC who underwent genetic testing were included. Clinical, biochemical, radiological, and genetic data were analyzed. Genetic variants were classified using ACMG criteria, and segregation analysis was performed when available. Of 186 pediatric patients diagnosed with NL/NC, 54 (29.03%) underwent genetic testing. Median age at diagnosis was 3months [IQR: 3-60], with median follow-up 56months [IQR: 24-108]. Genetic mutations related to NL/NC were identified in 35/54 patients (64.81%), most commonly in CLDN16 (28.57%), SLC2A2 (17.14%), AGXT (11.43%), and SLC12A1 (8.57%). Thirteen novel variants were identified, with eleven linked to NL/NC phenotypes. Eight patients (14.81%) developed kidney failure requiring kidney replacement therapy; CLDN16 was significantly associated with kidney failure and transplant (P = 0.003), and AGXT with liver transplant (P < 0.001). Notably, the MOCS1 gene was found in a patient with early-onset neurological symptoms, hypouricemia, and later confirmed NL/NC. Monogenic causes were identified in 35 of 54 (64.81%) Saudi pediatric patients with NL/NC who underwent genetic testing, a prevalence higher than reported internationally, likely due to the high consanguinity rate. Our findings underscore the importance of genetic testing in early-onset NL/NC. We recommend adding MOCS1 to the list of genes associated with monogenic NL/NC.

BackgroundKidney transplantation is the preferred treatment for end-stage renal disease (ESRD), yet challenges persist in long-term graft survival and post-transplant complications. Genomic profiling, especially whole-exome sequencing (WES), offers new opportunities to personalize donor-recipient matching and predict transplant outcomes. This study aimed to explore the genetic landscape of both transplant recipients and donors using WES.MethodsThis prospective cohort study included 64 kidney transplant recipients (51 adults, 13 pediatric) and 61 donors in Kazakhstan. WES was performed to identify monogenic causes of ESRD, evaluate rejection-associated immune polymorphisms (31 SNPs), and screen for post-transplant risk using a 355-gene Transplant Morbidity Panel. Variants were classified following ACMG/AMP guidelines, and allele frequencies were compared to global reference datasets.ResultsAmong recipients, pathogenic/likely pathogenic variants were found in 15.4% of pediatric and 9.1% of adult cases, with additional variants of uncertain significance detected in 23.1% and 23.6%, respectively. WES identified monogenic nephropathies including Alport syndrome, cystinuria, and polycystic kidney disease. In donors, 13.1% carried variants associated with latent renal or systemic conditions despite no clinical manifestation at donation. The APOE p.Cys130Arg variant, linked to lipid dysregulation, was observed more frequently in recipients (allele frequency 0.17) than donors (0.09), though not statistically significant. Among the 31 SNPs evaluated, significant associations with acute rejection were observed for IL1B rs1143634 and TP53 rs1625895 under dominant models. IL1B carriers showed increased rejection risk (OR = 4.62, p = 0.039), whereas TP53 carriers appeared protected (OR = 0.058, p = 0.027). Given the limited number of rejection cases, these findings should be considered exploratory and require validation in larger cohorts. Additionally, 44.3% of recipients carried at least one pathogenic or likely pathogenic variant in the Transplant Morbidity Panel, particularly in genes related to malignancy, cardiomyopathy, and monogenic diabetes.ConclusionsThis study provides one of the first applications of WES in a Central Asian kidney transplant population. Findings highlight the prevalence of monogenic and comorbid risk variants in both recipients and donors and support the use of genomic screening for improving pre- and post-transplant care. The identification of immune-related SNPs and extra-renal findings further underscores the utility of WES for personalized transplant management. Integration of genomics into transplant workflows may help address the ongoing gap between clinical need and transplant outcomes, particularly in low-resource settings.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12882-025-04553-x.

Introduction: Monogenic causes of dilated cardiomyopathy (DCM) are commonly identified in children. While DCM frequently presents with symptomatic heart failure (HF), whether an identified genetic cause of DCM implies disease severity or eventual outcome in children is unclear. Goals/Aims: To assess whether clinical or phenotypic disease severity is different in children with an identifiable pathogenic or likely pathogenic (P/LP) variant in a cardiomyopathy gene, using a multi-institutional cohort of children with DCM, and to determine the association of these variants with disease outcomes. Methods: Children (0-18 yrs) from 14 pediatric centers in North America with an echo diagnosis of non-syndromal DCM were studied: phenotypic features included ancestry, family history, presentation age, severity of LV dilation, ejection fraction (EF), and clinical HF. A panel of 37 known cardiomyopathy-associated genes was interrogated by exome sequencing with targeted analysis for P/LP variants. Outcomes of death, cardiac transplant, and continuing LV dysfunction vs echo normalization were assessed prospectively. Results: Between 2012-2016, 279 DCM probands (47% male) were enrolled with a median (IQR) age at diagnosis of 1.6 (0.4-10.4) yrs. Median follow-up time was 1.1 (0.2-4.0) yrs, Gene variants designated as P/LP were identified in 18 of the 37 genes evaluated, with TTN (17%), TNNT2 (15%), MYH7 (15%), RBM20 (9%), and LMNA (8%) being the most frequently implicated genes. Only 19% of the overall cohort yielded an identifiable genetic cause, without any difference between ancestries. Children &gt;12 yrs old had the highest genetic yield at 34% (p&lt;0.05). Symptoms of HF occurred in 62% of pts at or within 12 months of presentation who carried P/LP genetic variant, but presentation HF symptoms, LVEF, or LV dilation were not associated with an identifiable genetic cause. The rate of death or cardiac transplant did not differ with P/LP variant presence or absence and exceeded 60% at 10 yrs after diagnosis. On competing risks analysis (Figures 1 and 2), a trend (p=0.09) towards greater echo normalization, reaching 25% vs 10%, was noted in P/LP variant-negative pts by 10 yrs after diagnosis. Conclusions: A genetic etiology was not associated with the phenotypic severity of DCM at diagnosis. Echo normalization of LV function over time was noted more frequently in patients who did not have an identified P/LP variant.

Introduction: Ascending aortic aneurysm is a complex multicellular disease with high mortality associated with both monogenic causes and sporadic disease. Known causative genes include FBN1 in Marfan syndrome or TGFB pathway variants in Loeys-Dietz Syndrome (LDS). However, sporadic ascending aortic aneurysms can also occur in patients without variants in known causative genes, especially with increasing age. Yet, it is not clear whether these sporadic cases share common mechanisms with monogenic subtypes. Research Goal: Mapping the genetic regulatory network disrupted in monogenic and sporadic aortic aneurysm to identify shared and genotype-specific dysregulation and predict candidate therapeutic targets. Methods: We leveraged single-cell RNA sequencing data from aortic tissue in sporadic and monogenic aortic aneurysm patients to map disease-dependent gene networks and predict candidate therapeutic targets. First, we inferred the gene network dysregulated in TGFBR1/2 +/- smooth muscle cells (SMCs) and fibroblasts using CellOracle, mapping the rewiring in the most severe form of LDS aortic aneurysm. We next fine-tuned Geneformer – a foundational artificial intelligence (AI) model enabling context-specific predictions in network biology – to distinguish disease-dependent dysregulation in sporadic and monogenic cases stratified by genotype (heterozygous TGFBR1/2, SMAD3, FBN1, or ACTA2 ). Then, we performed in silico deletion to predict cell type-specific candidate therapeutic targets for monogenic and sporadic aortic aneurysms. Results: We identified 10 network communities in the control vs TGFBR1/2 +/- SMCs, each enriched for genes associated with distinct pathways such as contractility and immune activation. In TGFBR1/2 +/- SMCs, KLF4 and KLF2 were central regulators of the network and key nodes within the contractility network community. Upon in silico deletion for monogenic and sporadic cases, targets whose repression was predicted to be beneficial in aneurysmal SMCs included NFATC2, which is reported to promote macrophage infiltration in vascular disease, IL-1, which promotes immune activation, and LMO7, a regulator of TGFB signaling. Conclusions: We mapped the gene network disrupted in aortic aneurysm, revealing primary regulators in the disease-dependent network. Ongoing work is experimentally validating shared and genotype-specific AI-predicted therapeutic targets for their impact on in vitro SMC function and in vivo aortic aneurysm progression.

ABSTRACT Background Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease characterized by sterile bone inflammation. While monogenic causes are rare and typically present with early-onset, distinct skin or lytic bone lesions, the contribution of COX-pathway genes remains underexplored. TBXAS1 gene variants are classically associated with Ghosal hematodiaphyseal dysplasia (GHDD), which causes osteosclerosis and hematologic abnormalities. Research design and methods In this single-center, cross-sectional study, whole-exome sequencing first revealed the TBXAS1 variants in the index case, a 6-year-old boy with multifocal CNO and good clinical response to NSAIDs. Afterward, we performed next-generation sequencing (NGS) of the TBXAS1 gene in a single-center CNO cohort. Results Among 16 patients within the CNO cohort, NGS revealed two siblings with the same variants who were also presented with CNO, but without signs of osteosclerosis or hematologic involvement. Conclusions These findings suggest a potential link between TBXAS1 deficiency and a distinct, milder CNO phenotype potentially mediated by the COX pathway. However, it remains uncertain whether TBXAS1 mutations define a new CNO subtype or represent an attenuated form of GHDD. Further functional and genetic studies targeting COX-pathway-related genes are needed to clarify the role of TBXAS1 in the pathogenesis of CNO and to identify novel disease mechanisms.

Abstract Introduction We present the cases of two siblings both of whom were born in Goa to non-consanguineous parents with juvenile onset systemic lupus erythematosus (jSLE) with differing clinical and laboratory features. Case description Patient 1: Presented acutely in 2022 at the age of 16 with fevers, rash and inflammatory arthritis with a 4 year history of Raynaud’s since arriving in the UK. She had strongly positive dsDNA, RNP and Sm antibodies with low C3 and C4 and a borderline lupus anticoagulant (IgG or IgM?). ESR was &amp;gt;100 mm/h, Hb 84 g/l and urine PCR 42 with normal renal function. She was treated initially with prednisolone and mycophenolate before switching to methotrexate due to intolerance. Over 3 years she has had frequent relapses with fevers, severe Raynaud’s and arthritis despite remaining on steroids and having 3 pulses of rituximab in addition to methotrexate and hydroxychloroquine. She has not developed significant renal or cerebral involvement. She is developing into a scleroderma phenotype with some early sclerodactyly and digital ulceration. Patient 2: Presented in January 2024 with a history of recurrent high-grade fevers, weight loss, fatigue, and constitutional symptoms, initially managed as viral illness, but symptoms persisted despite antibiotic therapy. During travel to India, he developed lymphadenopathy, joint pain, and constipation. On return to the UK, he continued to deteriorate with systemic inflammation, testicular pain (with normal imaging and exploratory surgery), and progressive fatigue. Investigations revealed malar rash, lymphadenopathy, mild hepatosplenomegaly, anaemia, thrombocytopenia, positive Coombs test, and persistent low-grade proteinuria. Immunology showed strongly positive ANA and dsDNA, hypocomplementaemia, and negative ENA and antiphospholipid antibodies, meeting 6 SLICC and 18 ACR/EULAR criteria for jSLE. Initial treatment included two rounds of IV methylprednisolone and high-dose oral prednisolone, with partial response. He was started on mycophenolate and hydroxychloroquine with gradual clinical improvement on immunosuppressive therapy, with ongoing monitoring for renal and systemic involvement. However, the level of complement and ds-DNA remain abnormal. Discussion There are around 100 loci for polygenic SLE and 30 genes associated with monogenic SLE. Patients with jSLE are more likely to carry either the polygenic or monogenic genes than those patients presenting as adults. There is considerable discordance between the clinical phenotypes and immunobiochemistry of patients with the same genetic mutation. There is a concordance rate for SLE of 24% in monozygotic twins compared with 2% in dizygotic twins. The differing presentations of jSLE in these non-consanguineous siblings highlight the complex interplay of genetic and environmental factors. Genetic testing is currently awaited and may help identify monogenic causes, clarify disease mechanisms, and guide personalised management and family counselling. Looking after two family members with an autoimmune condition carries both benefits and issues. There is much to be gained from the peer support and shared understanding of family members having the same condition. It is however important for both family members and clinicians to remember that each person is an individual, with differing symptoms, social context and therefore clinical need. Key learning points jSLE is a multisystem, heterogeneous disease with variable clinical expression. Genetic factors are especially relevant in early-onset or familial cases. Siblings may show different disease patterns despite shared genetics, suggesting environmental influence. Management should be individualised, considering both medical and psychosocial needs. Genetic testing can aid diagnosis and inform treatment in familial or severe jSLE.

Novel pathogenic variants in CTLA4 and LRBA immune dysregulation: Reduced CTLA-4 expression with normal expression of co-stimulatory surface molecules.

Idiopathic cholestasis in adults: Genetics as another lens for liver pathologists.

Autosomal Dominant Tubulointerstitial Kidney Disease: A Review.

Protective or Pathogenic? Kinase activity and the neurodevelopmental origins of G2019S LRRK2-Associated Parkinson's disease.

Non-genetic factors and their impact on severity of inherited cardiomyopathies: Tipping the balance.

IntroductionIdiopathic scoliosis (IS) is a complex spinal deformity affecting ~3% of the population, with a multifactorial and genetically heterogeneous origin. This study aimed to investigate the genetic origins of severe IS by examining both constitutional and post-zygotic alterations.MethodsWe analyzed 70 unrelated IS-affected individuals using whole exome sequencing (WES) and SNP array approaches on intraoperatively collected articular processes and blood samples.ResultsTwo pathogenic constitutional copy number variants (CNVs) were identified – a 43.6 Mb duplication on chromosome 8p and trisomy X – along with eight regions of homozygosity (ROH) located on chromosomes 1, 2, 8, 12, 14, and 16, absent in ethnically matched controls. Additionally, a heterozygous DMD deletion (exons 17–36) was found in one female, and rare recurrent pathogenic single-nucleotide variants (SNVs) were detected in ENAM and FLNB genes. Notably, 13% (95% CI, 6.1–23%) of individuals harbored pathogenic variants, spanning CNVs, ROH, and SNVs, suggesting a genetic contribution to IS.DiscussionOur findings demonstrate that one in seven cases classified as idiopathic may have an underlying monogenic cause. This study underscores the polygenic and heterogeneous nature of IS and highlights the need for genetic testing by integrating WES and SNP array analyses into its diagnostic workflow. Our findings suggest that incorporating genetic testing into the diagnostic evaluation of severe IS patients may enable personalized genetic counseling and, consequently, improve clinical management.

Disclosure: L.G. Nasr: None. R. Senguttuvan: None. N. Mitre: None. F.J. Al Muhaisen: None.Background: MODY type 1, driven by pathogenic HNF4A mutations, represents a rare and intriguing form of monogenic diabetes. It is marked by early-onset hyperglycemia, a strong familial inheritance, and a remarkable response to sulfonylureas. Clinical Case: We present the case of a 15-month-old girl born at 37 weeks of gestation to a mother with uncontrolled gestational diabetes managed with long- and short-acting insulin. The pregnancy was complicated by polyhydramnios and circumvallate placenta. Delivered via cesarean section due to her large for gestational age (LGA) status, the patient required NICU admission for respiratory distress and persistent hypoglycemia. Initial stabilization included stimulation, oxygen, gastric suctioning, and a face mask via CPAP. On day one of life, the patient developed low BG down to 11 mg/dlL(n: 60-110mg/dL). Critical blood sampling revealed a serum glucose level of 46 mg/dL (n: 60-110mg/dL), a markedly elevated insulin level of 95 µIU/mL (n: 2-23 µIU/mL), a cortisol level of 1 µg/dL (n: 3-17 µg/dL), and beta-hydroxybutyrate of 0.07 mmol/L (n: 0.02-0.27 mmol/L).The infant was started on IV fluids. Due to persistent hypoglycemia, Fluids and dextrose were advanced. Her GIR was increased to 16.93 mg/kg/min. Enteral feeds were started, and volumes were advanced. Feeds were fortified up to 24 cal/oz to keep glucose above 70 mg/dL.A fasting challenge was done at one month of age and her blood glucose droped below 50 mg/dL by the fourth hour, with critical results showing an insulin level of 16 µIU/mL, cortisol of 13 µg/dL, and beta-hydroxybutyrate of 0.07 mmol/L. Treatment with diazoxide at 5mg/kg/day and chlorothiazide at 5mg/kg/day stabilized blood glucose levels between 70-80 mg/dL. The patient passed a safety fasting challenge before discharge. The patient was seen for follow-up, and at 12 months of age, she continued to need diazoxide treatment. Given the persistent need for diazoxide to maintain stable glucose levels, a hyperinsulinism genetic panel was conducted, identifying a heterozygous pathogenic variant in the HNF4A genec.932G>A(p.Arg311His). This finding confirmed the diagnosis of autosomal dominant HNF4A-related disease, a condition associated with MODY type 1 and neonatal hyperinsulinism, transitioning over time to early-onset diabetes. Conclusion: The identified mutation highlights the unique biphasic clinical course of HNF4A-related disease, where neonatal hyperinsulinism often resolves at 12-18 months of age but predisposes affected individuals to metabolic challenges later in life. This case underscores the critical role of genetic testing in persistent neonatal hypoglycemia to identify monogenic causes, enabling early diagnosis and personalized treatment strategies. Additionally, it emphasizes the importance of long-term follow-up and tailored management to address the evolving clinical manifestations of the disease.Presentation: Monday, July 14, 2025

Disclosure: G.J. Kim: None. E.V. de Albuquerque Albuquerque: None. R.C. Rezende: None. L.D. Cellin: None. L.S. de Santana: None. A.M. Lerario: None. V. de Souza: None. R.D. Scalco: None. A.A. Jorge: Novo Nordisk.Background: Monogenic causes of syndromic tall stature result in a recognizable pattern of clinical characteristics that include dysmorphisms, malformations, and/or neurodevelopmental disorders. Thus far, few articles have been published regarding the diagnosis of syndromic tall stature by genetic testing. The purpose of this study was to use whole exome sequencing (WES) to evaluate a cohort of patients with syndromic tall stature, with the aim of describing genetic causes of and new candidate genes for tall stature. Methods: We included 37 patients referred to a single, tertiary academic center specialized in growth disorders for the evaluation of tall stature from January 2017 to February 2024. Patients included both novel cases and cases being reanalyzed. Trio analysis was performed for four patients, and WES was performed for only the index cases for the remaining patients. Variants were prioritized based on minor allele frequency, prediction to be loss-of-function, inheritance pattern compatibility, and prior reports. Copy number variations (CNVs) were further prioritized based on involved protein-coding genes displaying haploinsufficiency. If diagnosis of a known tall stature disorder could not be achieved, analysis for candidate genes was performed, taking into account the above criteria as well as GWAS catalog associations with height and weight phenotypes, DECIPHER catalog listings of overlapping CNVs, medical literature on our candidate genes, recurrence of rare variants with similar phenotypes, and animal models consistent with the proposed phenotype. Results: Of the 37 patients included in this study, genetic diagnosis was achieved in 11 patients, for a diagnostic yield of 29.7%. Pathogenic or likely pathogenic variants were identified in FBN1 (3x), PTEN, NSD1, SUZ12, CDH8, and DEPDC5, with some of these results having been previously described in other papers. One patient carried significant variants in two genes, FBN2 and COL5A1. Furthermore, we identified two patients with pathogenic deletions confirmed by chromosomal microarray analysis. Through analysis of the gene content compromised by these deletions, description of other cases with overlapping CNVs, biological plausibility, and data from the literature, two candidate genes for tall stature were identified: PTCH1 and SST. Additionally, three genes (KDM4A, RAP1GAP2 and GRB10) were identified via WES based on gene constraints, recurrence in our cohort (KDM4A), biological plausibility, and additional cases in literature (GRB10). Conclusions: These findings indicate a diagnostic yield of syndromic tall stature by WES that is comparable to those found in studies of other syndromic growth disorders. We also present five new candidate genes for tall stature. Further work is required to continue characterizing the impact of these genes on adult height, as well as to describe novel candidate genes for height.Presentation: Saturday, July 12, 2025