Monogenic Syndromes Research Articles

Bronchiectasis in a patient with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy: a case report

BackgroundThe rare monogenic syndrome Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) leads to multisystemic autoimmunity with possible lung involvement. Autoimmune pneumonitis is a rare manifestation, with bronchiectasis being the most frequent radiologic pattern, and may lead to fatal outcome. The Sardinian population in Italy has a high incidence of APECED, although no case of lung manifestation has been reported yet in this cohort. This is the case of a Sardinian APECED patient referred to a bronchiectasis clinic. Our aim is to raise awareness and screen these patients earlier for pulmonary involvement and to initiate multidisciplinary treatment for better outcome.Case presentationA 49-year-old female native of Sardinia from consanguineous parents was diagnosed with APECED in childhood and was referred to our bronchiectasis clinic in March 2023. In addition to typical APECED features, she reported recurrent respiratory infections since childhood, chronic purulent sputum and a hospitalization for pneumonia. She came to our attention with a recent isolation of P. aeruginosa on sputum culture and diffuse cylindrical and varicoid bronchiectasis on her first CT scan. She underwent aetiologic screening for bronchiectasis with no evidence of another cause of disease. Lung treatment was optimized according to bronchiectasis guidelines, and during follow-up the patient developed methicillin-resistant Staphylococcus aureus (MRSA) infection and M. intracellulare pulmonary disease. The patient was offered P. aeruginosa eradication treatment with intravenous antibiotics and initiation of antimycobacterial therapy.ConclusionThis is the first documented lung involvement case of APECED in a Sardinian patient, and the first patient reported to enter a bronchiectasis program. The patient was prescribed lung imaging late in time when bronchiectasis complications were already present. Our case report highlights the need for early pulmonary screening and multidisciplinary management in patients with APECED.

Invasive genetic testing for isolated increased nuchal translucency of 3.0-3.4 mm: Results from cohort analysis with 604 fetuses.

SynopsisIsolated increased nuchal translucency of 3.0–3.4 mm was associated with increased risk of chromosomal anomalies and monogenic syndromes.

A New Frontier in Cystic Fibrosis Pathophysiology: How and When Clock Genes Can Affect the Inflammatory/Immune Response in a Genetic Disease Model.

Cystic fibrosis (CF) is a monogenic syndrome caused by variants in the CF Transmembrane Conductance Regulator (CFTR) gene, affecting various organ and systems, in particular the lung, pancreas, sweat glands, liver, gastrointestinal tract, vas deferens, and vascular system. While for some organs, e.g., the pancreas, a strict genotype-phenotype occurs, others, such as the lung, display a different pathophysiologic outcome in the presence of the same mutational asset, arguing for genetic and environmental modifiers influencing severity and clinical trajectory. CFTR variants trigger a pathophysiological cascade of events responsible for chronic inflammatory responses, many aspects of which, especially related to immunity, are not ascertained yet. Although clock genes expression and function are known modulators of the innate and adaptive immunity, their involvement in CF has been only observed in relation to sleep abnormalities. The aim of this review is to present current evidence on the clock genes role in immune-inflammatory responses at the lung level. While information on this topic is known in other chronic airway diseases (chronic obstructive pulmonary disease and asthma), CF lung disease (CFLD) is lacking in this knowledge. We will present the bidirectional effect between clock genes and inflammatory factors that could possibly be implicated in the CFLD. It must be stressed that besides sleep disturbance and its mechanisms, there are not studies directly addressing the exact nature of clock genes' involvement in inflammation and immunity in CF, pointing out the directions of new and deepened studies in this monogenic affection. Importantly, clock genes have been found to be druggable by means of genetic tools or pharmacological agents, and this could have therapeutic implications in CFLD.

Evidence on Hidradenitis Suppurativa as an Autoinflammatory Skin Disease.

Hidradenitis suppurativa (HS) is a chronic and debilitating inflammatory skin disease that often exhibits heterogeneity in its clinical presentation, especially in the context of its rare syndromic forms. The pathogenesis of HS results from a complex interplay of genetic predisposition, innate and adaptive immunity dysregulation, smoking, obesity and environmental factors. In the early phase of the disease, the innate immune system is hyperactivated, contributing to tissue damage and triggering the activation and amplification of the adaptive immune response, which plays a pivotal role in the chronic stages of the disease. Recent studies focused on elucidating the importance of innate immunity impairment and autoinflammation in HS and increasing evidence has emerged on the occurrence of the disease in the context of well-known monogenic and polygenic autoinflammatory syndromes (AIDs). This review provides a comprehensive examination of the current scientific background supporting the contribution of autoinflammation to HS etiology, including genetic data, molecular studies and clinical evidence, as well as the association between HS and AIDs. However, further research is needed to shed light on the pathogenic mechanism of this challenging condition and to identify potential perspectives for future therapeutic approaches.

Comment on Maghsoudlou et al. Titled “Uveitis Associated with Monogenic Autoinflammatory Syndromes in Children”

ABSTRACT The work by Maghsoudlou et al. provides a comprehensive examination of monogenic autoinflammatory syndromes (MAIS) in children, with a specific focus on uveitis as a significant clinical manifestation. It meticulously details the genetic underpinnings, clinical features, diagnostic criteria, and current therapeutic strategies, including the use of biologics. This critique highlights the strengths of the review and suggests further exploration in areas such as long-term treatment outcomes, genotype-phenotype correlations, and the impact of MAIS on quality of life. Future research could benefit from longitudinal studies and enhanced predictive models to improve management and treatment personalization.

Hereditary Syndromes Associated with Pancreatic and Lung Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PanNETs) and lung NETs (LNETs) represent a rare but clinically significant subgroup of neoplasms. While the majority is sporadic, approximately 17% of PanNETs and a subset of LNETs develop in the context of monogenic familial tumor syndromes, especially multiple endocrine neoplasia type 1 (MEN1) syndrome. Other inherited syndromes associated with PanNETs include MEN4, von Hippel-Lindau (VHL) syndrome, neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC). These syndromes are highly penetrant and their clinical manifestations may vary even among members of the same family. They are attributed to genetic mutations involving key molecular pathways regulating cell growth, differentiation, and angiogenesis. Pancreatic NETs in hereditary syndromes are often multiple, develop at a younger age compared to sporadic tumors, and are associated with endocrine and nonendocrine tumors derived from multiple organs. Lung NETs are not as common as PanNETs and are mostly encountered in MEN1 syndrome and include typical and atypical lung carcinoids. Early detection of PanNETs and LNETs related to inherited syndromes is crucial, and specific follow-up protocols need to be employed to optimize diagnosis and management. Genetic screening is recommended in childhood, and diagnostic screening starts often in adolescence, even in asymptomatic mutation carriers. Optimal management and therapeutic decisions should be made in the context of a multidisciplinary team in specialized centers, whereas specific biomarkers aiming to identify patients denoted to follow a more aggressive course need to be developed.

Complimentary vertebrate Wac models exhibit phenotypes relevant to DeSanto-Shinawi Syndrome.

Monogenic syndromes are associated with neurodevelopmental changes that result in cognitive impairments, neurobehavioral phenotypes including autism and attention deficit hyperactivity disorder (ADHD), and seizures. Limited studies and resources are available to make meaningful headway into the underlying molecular mechanisms that result in these symptoms. One such example is DeSanto-Shinawi Syndrome (DESSH), a rare disorder caused by pathogenic variants in the WAC gene. Individuals with DESSH syndrome exhibit a recognizable craniofacial gestalt, developmental delay/intellectual disability, neurobehavioral symptoms that include autism, ADHD, behavioral difficulties and seizures. However, no thorough studies from a vertebrate model exist to understand how these changes occur. To overcome this, we developed both murine and zebrafish Wac/wac deletion mutants and studied whether their phenotypes recapitulate those described in individuals with DESSH syndrome. We show that the two Wac models exhibit craniofacial and behavioral changes, reminiscent of abnormalities found in DESSH syndrome. In addition, each model revealed impacts to GABAergic neurons and further studies showed that the mouse mutants are susceptible to seizures, changes in brain volumes that are different between sexes and relevant behaviors. Finally, we uncovered transcriptional impacts of Wac loss of function that will pave the way for future molecular studies into DESSH. These studies begin to uncover some biological underpinnings of DESSH syndrome and elucidate the biology of Wac, with advantages in each model.

#1118 Direct delivery of novel gene therapy to podocytes enables pathway to clinical translation for the treatment of glomerular diseases

Abstract Background and Aims Adeno associated vector (AAV) gene therapy has the potential to treat a wide range of kidney diseases via the targeted delivery of genes to kidney cells to repair cellular and renal function. Despite the potential to impact many kidney conditions, kidney AAV gene therapy has proven challenging due to technical and physiological hurdles limiting the ability of AAV to be effectively delivered to podocytes. We have developed a novel AAV gene therapy, PS-001, and local method of administration, to effectively and safely deliver the podocin gene NPHS2 to podocytes. Biallelic NPHS2 mutations are the most common cause of monogenic childhood nephrotic syndrome. Curative efficacy and resolution of disease phenotype was demonstrated in transgenic murine models following PS-001 gene therapy treatment. The potential for translation of this approach to NPHS2 nephropathy patients in the clinic was also demonstrated in pre-clinical studies in Gottingen Minipigs. Method Transgenic murine models representative of NPHS2-driven nephropathy were treated with an AAV gene therapy encoding NPHS2, including a knock in mouse model (Nphs2R140Q/−) which introduces a R140Q mutation in the podocin gene. Mice were assessed for improvement in disease phenotype via analysis of proteinuria, serum albumin, renal histopathology and survival. Mice were treated with an analogue of PS-001, as the PS-001 capsid is not permissive in rodents. Gottingen minipigs were treated with PS-001 and followed for 4 weeks. Clinically relevant doses and a procedure for local administration specifically to the kidney were established. In-life safety assessments from blood and urine were monitored and at study end pig tissues were assessed for podocin biodistribution using multiple assays (qPCR, RT-qPCR, ELISA, RNAScope and IF) and for toxicological effects via histopathological analysis. Results Using our AAV gene therapy platform, which includes a capsid that is highly effective at transducing human podocytes and promoter that drives gene expression specifically in the podocyte, the gene therapy product PS-001 encoding NPHS2 was generated. Using a murine analogue of PS-001, in vivo proof of concept studies in a translationally relevant murine disease model (Nphs2R140Q/−) showed NPHS2 delivery and podocin expression in glomeruli and efficacy in terms of renal function rescue. This was demonstrated by resolution of severe proteinuria (mean ACR ug/mg 6049 ± 2803 vs 192 ± 51 in PS-001 treated animals, n = 11), improved serum albumin (g/L 27.50 ± 3.33 g/L vs 30.75 ± 2.46 in PS-001 treated animals, P = .021) and reduction in glomerulosclerosis (mean sclerosed glomeruli 81% ± 19 vs 18.75% ± 12 in PS-001 treated animals, P < .0001). The methods to translate the approach to the clinical setting using a local administration were established in pigs. Administration of PS-001 resulted in transgene mRNA expression across 89% ± 11% of kidney glomeruli as assessed by RNAScope (n = 3 pigs), and transgene derived podocin could be specifically detected in podocytes as assessed by IF analysis. Using qPCR, RT-PCR and ELISA it was shown that using local administration, podocin gene expression was restricted exclusively to the kidney glomerulus, with gene expression undetectable in off-target organs including the liver. Additional toxicological assessments of renal and other organ function from urine and blood, and post-study histopathological assessments revealed no pre-clinical treatment-related safety concerns. Conclusion We present data showing development of an AAV gene therapy and method of administration for the delivery of transgenes specifically to podocytes. We have shown transgenes can be efficiently targeted to podocytes to replace defective genes or to use the podocyte as a protein factory to modulate glomerular biology. This technology therefore provides an important novel modality for potentially treating a broad range of glomerular disease. PS-001 is being developed as a novel approach to treat steroid resistant nephrotic syndrome caused by mutated NPHS2, and may become the first podocyte targeted gene therapy to enter clinical development.

Updated European guidelines for clinical management of familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), gastric adenocarcinoma, proximal polyposis of the stomach (GAPPS) and other rare adenomatous polyposis syndromes: a joint EHTG-ESCP revision.

Hereditary adenomatous polyposis syndromes, including familial adenomatous polyposis and other rare adenomatous polyposis syndromes, increase the lifetime risk of colorectal and other cancers. A team of 38 experts convened to update the 2008 European recommendations for the clinical management of patients with adenomatous polyposis syndromes. Additionally, other rare monogenic adenomatous polyposis syndromes were reviewed and added. Eighty-nine clinically relevant questions were answered after a systematic review of the existing literature with grading of the evidence according to Grading of Recommendations, Assessment, Development, and Evaluation methodology. Two levels of consensus were identified: consensus threshold (≥67% of voting guideline committee members voting either 'Strongly agree' or 'Agree' during the Delphi rounds) and high threshold (consensus ≥ 80%). One hundred and forty statements reached a high level of consensus concerning the management of hereditary adenomatous polyposis syndromes. These updated guidelines provide current, comprehensive, and evidence-based practical recommendations for the management of surveillance and treatment of familial adenomatous polyposis patients, encompassing additionally MUTYH-associated polyposis, gastric adenocarcinoma and proximal polyposis of the stomach and other recently identified polyposis syndromes based on pathogenic variants in other genes than APC or MUTYH. Due to the rarity of these diseases, patients should be managed at specialized centres.

Canakinumab treatment real world evidence in 3 monogenic periodic fever syndromes in 2009–2022: an interim analysis using the French JIR cohort database

BackgroundOur study aimed to provide real-world evidence on the treatment patterns, effectiveness and safety of canakinumab in France in Familial Mediterranean Fever (FMF), Mevalonate Kinase Deficiency (MKD), and Tumor necrosis factor Receptor Associated Periodic Syndrome (TRAPS).MethodsThis study used the JIR cohort, a multicentre international registry created in 2013 to collect data on patients with juvenile inflammatory rheumatic diseases. French patients diagnosed with FMF, MKD or TRAPS and treated with canakinumab were included in this study.Results31 FMF, 26 MKD and 7 TRAPS patients received canakinumab during the study period. Most of them initiated canakinumab at the recommended dose of 2 mg/kg or 150 mg, but less than half of FMF and MKD patients initiated it at the recommended frequency (every 4 weeks). Two years after initiation, the rate of patients still on treatment was 78.1% in FMF, 73.7% in MKD, and 85.7% in TRAPS patients. While the dose per injection remained globally the same over the course of the treatment, some adjustments of the dose intervals were observed. Six patients had a severe adverse event reported. Of those, three were possibly related to canakinumab.ConclusionThis interim analysis showed a good maintenance of canakinumab treatment 2 years after initiation and confirmed its safety profile in real-life practice in France in patients diagnosed with FMF, MKD and TRAPS. The high variety of dose and interval combinations observed in canakinumab treated patients let suppose that physicians adapt the posology to individual situations rather than a fixed treatment plan.

De novo variants in GABRA4 are associated with a neurological phenotype including developmental delay, behavioral abnormalities and epilepsy

Nine out of 19 genes encoding GABAA receptor subunits have been linked to monogenic syndromes characterized by seizures and developmental disorders. Previously, we reported the de novo variant p.(Thr300Ile) in GABRA4 in a patient with epilepsy and neurodevelopmental abnormalities. However, no new cases have been reported since then. Through an international collaboration, we collected molecular and phenotype data of individuals carrying de novo variants in GABRA4. Patients and their parents were investigated either by exome or genome sequencing, followed by targeted Sanger sequencing in some cases. All variants within the transmembrane domain, including the previously reported p.(Thr300Ile) variant, were characterized in silico and analyzed by molecular dynamics (MD) simulation studies. We identified three novel de novo missense variants in GABRA4 (NM_000809.4): c.797 C > T, p.(Pro266Leu), c.899 C > A, p.(Thr300Asn), and c.634 G > A, p.(Val212Ile). The p.(Thr300Asn) variant impacts the same codon as the previously reported variant p.(Thr300Ile) and likely arose post-zygotically as evidenced by sequencing oral mucosal cells. Overlapping phenotypes among affected individuals included developmental delay (4/4), epileptiform EEG abnormalities (3/4), attention deficits (3/4), seizures (2/4), autistic features (2/4) and structural brain abnormalities (2/4). MD simulations of the three variants within the transmembrane domain of the receptor indicate that sub-microsecond scale dynamics differ between wild-type and mutated subunits. Taken together, our findings further corroborate an association between GABRA4 and a neurological phenotype including variable neurodevelopmental, behavioral and epileptic abnormalities.

Genome Sequencing of Idiopathic Speech Delay

Genetic investigations of people with speech and language disorders can provide windows into key aspects of human biology. Most genomic research into impaired speech development has so far focused on childhood apraxia of speech (CAS), a rare neurodevelopmental disorder characterized by difficulties with coordinating rapid fine motor sequences that underlie proficient speech. In 2001, pathogenic variants of FOXP2 provided the first molecular genetic accounts of CAS aetiology. Since then, disruptions in several other genes have been implicated in CAS, with a substantial proportion of cases being explained by high-penetrance variants. However, the genetic architecture underlying other speech-related disorders remains less well understood. Thus, in the present study, we used systematic DNA sequencing methods to investigate idiopathic speech delay, as characterized by delayed speech development in the absence of a motor speech diagnosis (such as CAS), a language/reading disorder, or intellectual disability. We performed genome sequencing in a cohort of 23 children with a rigorous diagnosis of idiopathic speech delay. For roughly half of the sample (ten probands), sufficient DNA was also available for genome sequencing in both parents, allowing discovery of de novo variants. In the thirteen singleton probands, we focused on identifying loss-of-function and likely damaging missense variants in genes intolerant to such mutations. We found that one speech delay proband carried a pathogenic frameshift deletion in SETD1A, a gene previously implicated in a broader variable monogenic syndrome characterized by global developmental problems including delayed speech and/or language development, mild intellectual disability, facial dysmorphisms, and behavioural and psychiatric symptoms. Of note, pathogenic SETD1A variants have been independently reported in children with CAS in two separate studies. In other probands in our speech delay cohort, likely pathogenic missense variants were identified affecting highly conserved amino acids in key functional domains of SPTBN1 and ARF3. Overall, this study expands the phenotype spectrum associated with pathogenic SETD1A variants, to also include idiopathic speech delay without CAS or intellectual disability, and suggests additional novel potential candidate genes that may harbour high-penetrance variants that can disrupt speech development.

НАСЛЕДСТВЕННЫЕ ЗАБОЛЕВАНИЯ, ПРОТЕКАЮЩИЕ С ПОРАЖЕНИЕМ ПЕЧЕНИ (ЛЕКЦИЯ)

Background. Hereditary liver diseases are a serious problem in all age groups. Diagnosis of the hereditary liver disor-ders in many cases turns out to be difficult, and before final diagnosis, the patient can change more than one doctor and lose time, which can lead to a worsening of the disease. Therefore, the issue of timely diagnosis of hereditary liver diseases remains relevant. The lecture discusses the issues of diagnosing hereditary diseases occurring with liver damage. Both monogenic syndromes and multifactorial diseases are reviewed. Urea cycle disorders, aminoacidopathias and organic acidurias, lysosomal storage diseases, mitochondrial and peroxisomal diseases, disorders of fatty acids β-oxidation, carbohy-drate, lipid and cholesterol metabolism disorders and other diseases are described. The article describes the syndromes of liver disorders that occur in hereditary diseases; presents the combinations of individual syndromes having diagnostic significance. The pathogenetic aspects of the development of hepatic manifestations of hereditary diseases are considered. Conclusion. Symptoms of liver damage are often in the practice of any physician. Most of them are the manifesta-tions of somatic pathology. However, certain combinations of symptoms of liver damage (syndromes) indicate heredi-tary pathology. Therefore, it is extremely important to know the main liver syndromes in specific hereditary diseases, to understand the etiopathogenesis of such disorders and to carry out proper differential diagnosis.

Acquired hypothalamic obesity: A clinical overview and update.

Hypothalamic obesity (HO) is a rare and complex disorder that confers substantial morbidity and excess mortality. HO is a unique subtype of obesity characterized by impairment in the key brain pathways that regulate energy intake and expenditure, autonomic nervous system function, and peripheral hormonal signalling. HO often occurs in the context of hypothalamic syndrome, a constellation of symptoms that follow from disruption of hypothalamic functions, for example, temperature regulation, sleep-wake circadian control, and energy balance. Genetic forms of HO, including the monogenic obesity syndromes, often impact central leptin-melanocortin pathways. Acquired forms of HO occur as a result of tumours impacting the hypothalamus, such as craniopharyngioma, surgery or radiation to treat those tumours, or other forms of hypothalamic damage, such as brain injury impacting the region. Risk for severe obesity following hypothalamic injury is increased with larger extent of hypothalamic damage or lesions that contain the medial and posterior hypothalamic nuclei that support melanocortin signalling pathways. Structural damage in these hypothalamic nuclei often leads to hyperphagia, central insulin and leptin resistance, decreased sympathetic activity, low energy expenditure, and increased energy storage in adipose tissue, the collective effect of which is rapid weight gain. Individuals with hyperphagia are perpetually hungry. They do not experience fullness at the end of a meal, nor do they feel satiated after meals, leading them to consume larger and more frequent meals. To date, most efforts to treat HO have been disappointing and met with limited, if any, long-term success. However, new treatments based on the distinct pathophysiology of disturbed energy homeostasis in acquired HO may hold promise for the future.

Low renin forms of monogenic hypertension: review of the evidence

<b>Background:</b> Monogenic hypertension syndromes result from a single genetic mutation and present with severe, refractory hypertension, distinct laboratory abnormalities, and a positive family history. These syndromes are often unrecognized or misdiagnosed as essential hypertension, thus preventing proper treatment. The rise of molecular genetics has brought these conditions to the limelight, and physicians must be kept abreast of the latest in this field. This paper aims to educate doctors to recognize and institute appropriate management early to prevent end-organ damage.<br /> <b>Discussion: </b>These syndromes all affect sodium transport in the distal nephron of the kidneys. However, they are divided based on the location of the primary disorder, i.e., the adrenal glands or the distal nephron and discussed in that manner. Tables provide an overview of the different syndromes and provide essential information in a snapshot.<br /> <b>Conclusion:</b> The widespread availability of genetic testing facilities will aid in the earlier diagnosis of these conditions to prevent morbidity.

A224 CHARACTERIZATION OF VERY-EARLY-ONSET INFLAMMATORY BOWEL DISEASE IN CHILDREN ampersand:003C6 YEARS OF AGE: A SINGLE CENTER EXPERIENCE

Abstract Background Very-early-onset inflammatory bowel disease (VEO-IBD), diagnosed before the age of six years old, presents a distinct subtype of pediatric inflammatory bowel disease (IBD). This chronic inflammatory condition is believed to result from an abnormal immune response triggered by environmental factors including the gut microbiota, in genetically susceptible individuals. Aims This study aims to analyze the clinical characteristics and management of VEO-IBD patients in a tertiary medical center, evaluating disease presentation, localization and treatment strategies. Methods A retrospective descriptive study was conducted of 28 VEO-IBD patients diagnosed between January 2001 and January 2019 at our institution. Data was abstracted including patient demographics, clinical features, laboratory and histological parameters, treatment, and disease classification based on the revised Porto Criteria. Results Among the 28 patients, Crohn’s disease (CD) was the predominant diagnosis (89%) with predominantly colonic involvement. Thiry-two percent of patients had isolated colitis whereas the upper gastrointestinal (UGI) tract was involved in 57% of the cohort, approximately one third had involvement of the small bowel. The most common presenting symptoms were rectal bleeding and diarrhea, both occurred in 65% of the patients. Patients were followed for a mean duration of 115 months. Despite prior assumptions of its severity, VEO-IBD patients in this cohort responded well to conventional treatments in which 64% were induced with steroid therapy, 25% received biologics and 35% received immunomodulators. Surgical interventions were relatively infrequent. Only 2 patients out the 28 VEO-IBD patients underwent surgery for refractory colitis, one of them in the 1st 2 years of life. There were limited genetic testing results which made it difficult to know our incidence of monogenic IBD. However, only 5 of our patients had full genetic workup done in other centers for research purposes with 1 patient being diagnosed with monogenic IBD consistent IPEX syndrome. Conclusions This study highlights the unique clinical profile of VEO-IBD, with CD being the prevalent diagnosis in this age group in our population. Our cohort did not have a more severe phenotype, emphasizing that there is significant variation within this group Understanding the predictors of response is needed in individual patients with VEO-IBD is vital for tailored management and improved outcomes in this young population. Funding Agencies None

OP08 Multi-ancestry genome-wide association study of inflammatory bowel disease identifies 125 novel loci and directly implicates new genes in disease susceptibility

Abstract Background Genome-wide association studies (GWASs) have identified 320 loci associated with inflammatory bowel disease (IBD). About 15% of these loci include genes that lie in pathways targeted by drugs currently approved to treat IBD. Thus, identifying new loci can not only provide further insights into causal biology but also reveal novel therapeutic targets. Methods We performed a multi-ancestry GWAS meta-analysis of 67 cohorts, from European, East Asian and South Asian populations. The final dataset included 125,992 IBD patients (59,734 with CD; 57,565 with UC) and more than 1.2 million population controls (Fig 1). Genotype imputation was undertaken using the TOPMed diverse population panel and association tests were performed using REGENIE. The results were meta-analysed using a fixed effects meta-analysis via Metal. To prioritise effector genes and generate therapeutic hypotheses, we integrated our results with bulk and single cell transcriptome data from relevant tissues and cell types. Through colocalization analyses we identified those signals driving the expression of nearby genes (cis-eQTL), suggesting that aberrant expression of these genes underpins the association. Results We identified 290 new independent disease susceptibility association signals. Out of these, 125 new signals are located >1Mb from any previously reported loci. Six new loci contain genes implicated in monogenic syndromes that include colitis GUCY2C, G6PC3, NFKBIA, PIK3CD, PIK3R1, ZBTB24. Up to 40% of all disease susceptibility association signals colocalize with a cis-eQTL. For instance, a new variant associated with increased risk of UC (P=8x10-14) decreases the expression of the transmembrane mitochondrial protein TSPO in T cells, B cells, macrophages, and transverse colon. Pro-inflammatory macrophages show consistent TSPO downregulation. Loss of TSPO in mice causes exacerbated DSS-induced colitis. Ongoing clinical trials are evaluating whether targeting this gene could ameliorate the immune response in multiple sclerosis patients. We also identified a new CD susceptibility variant (P=3x10-16) associated with increased expression of WNK1 in monocytes and macrophages. Whereas loss of WNK1 in mice show increased expression of IL-1B in response to NLRP3 inflammasome activation; it also stimulates autophagy through the upregulation of the PI3KC3 complex. Impaired autophagy has shown to be key in promoting CD susceptibility. Conclusion Integrating molecular data from multiple cell types and conditions not only expands our ability to determine novel candidate causal genes, it also provides additional evidence of the utility of genetics as an instrument to guide the development of new therapeutic drugs or the repurposing of existing molecules.

The genetic etiologies of bilateral renal agenesis.

The goal of this study was to review and analyze the medical literature for cases of prenatal and/or postnatally diagnosed bilateral renal agenesis (BRA) and create a comprehensive summary of the genetic etiologies known to be associated with this condition. A literature search was conducted as a scoping review employing Online Mendeliain Inheritance in Man, PubMed, and Cochrane to identify cases of BRA with known underlying genetic (chromosomal vs. single gene) etiologies and those described in syndromes without any known genetic etiology. The cases were further categorized as isolated versus non-isolated, describing additional findings reported prenatally, postnatally, and postmortem. Inheritance pattern was also documented when appropriate in addition to the reported timing of diagnosis and sex. We identified six cytogenetic abnormalities and 21 genes responsible for 20 single gene disorders associated with BRA. Five genes have been reported to associate with BRA without other renal anomalies; sixteen others associate with both BRA as well as unilateral renal agenesis. Six clinically recognized syndromes/associations were identified with an unknown underlying genetic etiology. Genetic etiologies of BRA are often phenotypically expressed as other urogenital anomalies as well as complex multi-system syndromes. Multiple genetic etiologies of BRA have been described, including cytogenetic abnormalities and monogenic syndromes. The current era of the utilization of exome and genome-wide sequencing is likely to significantly expand our understanding of the underlying genetic architecture of BRA.

Genetics of Primary Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) constitutes a rare, potentially life-threatening hyperinflammatory immune dysregulation syndrome that can present with a variety of clinical signs and symptoms, including fever, hepatosplenomegaly, and abnormal laboratory and immunological findings such as cytopenias, hyperferritinemia, hypofibrinogenemia, hypertriglyceridemia, elevated blood levels of soluble CD25 (interleukin (IL)-2 receptor α-chain), or diminished natural killer (NK)-cell cytotoxicity (reviewed in detail in Chapter 11 of this book). While HLH can be triggered by an inciting event (e.g., infections), certain monogenic causes have been associated with a significantly elevated risk of development of HLH, or recurrence of HLH in patients who have recovered from their disease episode. These monogenic predisposition syndromes are variably referred to as "familial" (FHL)or "primary" HLH (henceforth referred to as "pHLH") and are the focus of this chapter. Conversely, secondary HLH (sHLH) often occurs in the absence of monogenic etiologies that are commonly associated with pHLH and can be triggered by infections, malignancies, or rheumatological diseases; these triggers and the genetics associated with sHLH are discussed in more detail in other chapters in this book.

RASopathies are the most common set of monogenic syndromes identified by exome sequencing for nonimmune hydrops fetalis: A systematic review and meta-analysis.

RASopathies are a group of malformation syndromes known to lead to nonimmune hydrops fetalis (NIHF) in severe presentations. Pathogenic variants can be de novo or parentally inherited. Despite being a known frequent presentation, the fraction of monogenic NIHF cases due to RASopathies is limited in the literature. Also, the specific parental contribution of RASopathies to NIHF is not well described. Our objective was to review pooled exome sequencing (ES) diagnostic yield of RASopathies for NIHF and to determine the parental contribution of RASopathy to NIHF. We performed a systematic review of prenatal ES studies from January 1, 2000 to August 1, 2022. Thirty-six studies met inclusion criteria. Cases with RASopathy gene variants were reviewed. NIHF cases were further classified as isolated or non-isolated. Thirty-six ES studies including 46 pregnancies with NIHF and a diagnosed RASopathy were reviewed. Forty-four diagnostic variants and 2 variants of uncertain significance in 12 RASopathy genes were identified. Expanding on what was previously published, a total of 506 NIHF cases were extracted with 191 cases yielding a positive diagnosis by ES. The overall rate of RASopathy diagnosis in clinically diagnosed NIHF cases was 9% (44/506). The rate of RASopathy diagnosis among NIHF cases with positive genetic diagnosis by ES was 23% (44/191). Of the 46 cases identified, 13 (28%) variants were parentally inherited; specifically, 5/13 (38%) maternal, 3/13 (23%) paternal, 2/13 (15%) biparental, and 3/13 (23%) unspecified. Majority of NIHF cases 29/46 (63%) were isolated. Among NIHF cases with positive ES diagnoses, RASopathy diagnostic yield by ES was 23%. NIHF secondary to RASopathies was parentally inherited in 28% of cases. Most cases of NIHF due to RASopathy were isolated, with no prenatal detection of associated anomalies.