Index Case Research Articles

Post-exposure prophylaxis in leprosy (PEOPLE): a cluster randomised trial.

Post-exposure prophylaxis (PEP) using single-dose rifampicin reduces progression from infection with Mycobacterium leprae to leprosy disease. We compared effectiveness of different administration modalities, using a higher (20 mg/kg) dose of rifampicin-single double-dose rifampicin (SDDR)-PEP. We did a cluster randomised study in 16 villages in Madagascar and 48 villages in Comoros. Villages were randomly assigned to four study arms and inhabitants were screened once a year for leprosy, for 4 consecutive years. All permanent residents (no age restriction) were eligible to participate and all identified patients with leprosy were treated with multidrug therapy (SDDR-PEP was provided to asymptomatic contacts aged ≥2 years). Arm 1 was the comparator arm, in which no PEP was provided. In arm 2, SDDR-PEP was provided to household contacts of patients with leprosy, whereas arm 3 extended SDDR-PEP to anyone living within 100 m. In arm 4, SDDR-PEP was offered to household contacts and to anyone living within 100 m and testing positive to anti-phenolic glycolipid-I. The main outcome was the incidence rate ratio (IRR) of leprosy between the comparator arm and each of the intervention arms. We also assessed the individual protective effect of SDDR-PEP and explored spatial associations. This trial is registered with ClinicalTrials.gov, NCT03662022, and is completed. Between Jan 11, 2019, and Jan 16, 2023, we enrolled 109 436 individuals, of whom 95 762 had evaluable follow-up data. Our primary analysis showed a non-significant reduction in leprosy incidence in arm 2 (IRR 0·95), arm 3 (IRR 0·80), and arm 4 (IRR 0·58). After controlling for baseline prevalence, the reduction in arm 3 became stronger and significant (IRR 0·56, p=0·0030). At an individual level SDDR-PEP was also protective with an IRR of 0·55 (p=0·0050). Risk of leprosy was two to four times higher for those living within 75 m of an index patient at baseline. SDDR-PEP appears to protect against leprosy but less than anticipated. Strong spatial associations were observed within 75 m of index patients. Targeted door-to-door screening around index patients complemented by a blanket SDDR-PEP approach will probably have a substantial effect on transmission. European and Developing Countries Clinical Trials Partnership. For the French translation of the abstract see Supplementary Materials section.

Cochlear Implantation in Patients With Osteolytic Labyrinthitis: A Case Series.

To describe the rare process of osteolytic labyrinthitis, previously referred to as labyrinthine sequestrum, which involves progressive obliteration of the bony and membranous labyrinth with eventual supplantation with soft tissue and, in some cases, bony sequestrum. Three patients with diverse presentations of osteolytic labyrinthitis from two tertiary care academic medical centers. Case series report analyzing the relevant clinical, radiologic, pathologic, and surgical data on our patients with osteolytic labyrinthitis and comparing these index cases to the existing literature. We describe the varying image findings seen in osteolytic labyrinthitis on computed tomography and magnetic resonance imaging. Also, we report successful surgical intervention and hearing rehabilitation with cochlear implantation in patients with osteolytic labyrinthitis. Our three patients presented with profound sudden sensorineural hearing loss and vertigo consistent with labyrinthitis. None of the three patients had a history of chronic otitis media. Imaging workup revealed varying degrees of erosion to the otic capsule bone demonstrating the spectrum of disease seen in osteolytic labyrinthitis. Although two cases showed osteolytic changes to the semicircular canals and vestibule, the first case revealed frank bony sequestrum within the obliterated labyrinth. The three cases were taken for surgical debridement and cochlear implantation. We propose the new term, osteolytic labyrinthitis-previously referred to as labyrinthine sequestrum-to describe the rare spectrum of disease characterized by destruction of the osseous and membranous labyrinth and potential supplantation with bony sequestrum. Cochlear implantation is a viable option in selected patients with osteolytic labyrinthitis.

Homophily and social mixing in a small community: Implications for infectious disease transmission.

Community mixing patterns by sociodemographic traits can inform the risk of epidemic spread among groups, and the balance of in- and out-group mixing affects epidemic potential. Understanding mixing patterns can provide insight about potential transmission pathways throughout a community. We used a snowball sampling design to enroll people recently diagnosed with SARS-CoV-2 in an ethnically and racially diverse county and asked them to describe their close contacts and recruit some contacts to enroll in the study. We constructed egocentric networks of the participants and their contacts and assessed age-mixing, ethnic/racial homophily, and gender homophily. The total size of the egocentric networks was 2,544 people (n = 384 index cases + n = 2,160 recruited peers or other contacts). We observed high rates of in-group mixing among ethnic/racial groups compared to the ethnic/racial proportions of the background population. Black or African-American respondents interacted with a wider range of ages than other ethnic/racial groups, largely due to familial relationships. The egocentric networks of non-binary contacts had little age diversity. Black or African-American respondents in particular reported mixing with older or younger family members, which could increase the risk of transmission to vulnerable age groups. Understanding community mixing patterns can inform infectious disease risk, support analyses to predict epidemic size, or be used to design campaigns such as vaccination strategies so that community members who have vulnerable contacts are prioritized.

30years of prophylactic thyroidectomy for hereditary medullary thyroid cancer : Amilestone in translational medicine

Medullary thyroid cancer (MTC) is the most frequent manifestation of multiple endocrine neoplasia type 2 (MEN2) that determines the oncological outcome. Germline mutations in the rearranged during transfection (RET) protooncogene, atumor suppressor gene on chromosome 10q11.2, were identified 30 years ago as the genetic basis of MEN2 and published in 1993 and 1994. These seminal findings gave rise to the concept of prophylactic thyroidectomy for asymptomatic gene mutation carriers based on apositive RET gene test, which has become the standard of care ever since. Clinical genetic investigations showed genotype-phenotype correlations with respect to the individual gene mutation regarding the penetrance and onset of MTC and to alesser extent also with respect to the other components of MEN2, pheochromocytoma and primary hyperparathyroidism. From this a clinically relevant risk stratification could be derived. Initially, the optimal timing of prophylactic thyroidectomy was primarily based on the RET genotype alone, which was not sufficient for a precise age recommendation and subsequently required additional consideration of calcitonin serum levels for fine tuning. Calcitonin levels first show the risk of lymph node metastasis when they exceed the upper normal limit of the assay independent of carrier age and RET mutation. Routine calcitonin screening of patients with nodular thyroid disease, screening of families on identification of MEN2 index patients, and pre-emptive thyroidectomy in carriers of gene mutations with normal calcitonin levels have led to the fact that nowadays, 30years after the first description of the gene mutations causing the disease, the life-threatening hereditary MTC has become curable: ashining example for the success of translational transnational medical research for the benefit of patients.

Scrotal calcinosis cutis an unrelated finding in benign prostatic hyperplasia patient, is treatment sine qua non? A case report

Calcinosis cutis is a reactive and nonmalignant lesion characterized by solitary or multiple cutaneous nodules that can affect different parts of the body including the scrotum among other structures. Treatment is often sought because of cosmesis, itching, or pain. Despite this, it remains unclear or unimaginable why patients will be reluctant to accept treatment in the face of disfigurement. Several reasons have been documented, but the fear of genital mutilation from open surgical intervention is an unfamiliar reason advanced by the index case for declining open surgical intervention. Its diagnosis requires careful clinical evaluation and is confirmed by lesional biopsy for histological confirmation. This is a case of a 50-year-old trader who presented to our facility with a 35-year history of multiple, painless scrotal nodules and difficulty in passing urine for six months’ duration. He was diagnosed with benign prostatic hyperplasia (BPH) with the indication for surgical therapy and idiopathic scrotal calcinosis cutis. He consented and had endoscopic therapy for benign prostatic hyperplasia (BPH) but was reluctant to open surgical intervention for idiopathic scrotal calcinosis cutis despite disfigurement because of the fear of genital mutilation. The current treatment options include follow-up observation, medications, cryotherapy, laser, and surgical excision, depending on the patient’s choice, availability, and surgical expertise. The surgical option is often favored and encouraged due to its associated reduced chances of recurrence. Therefore, it is pertinent to respect the patient’s opinion and should override other considerations in clinical practice. The lesson herein can assist other clinicians in avoiding justifiable medical litigations, hence, the need for this case report and a review of the literature.

Current real-world evidence of genetic testing diagnostic yield in a large cohort of long QT syndrome

Abstract Background Diagnostic yield in long QT syndrome (LQTS) ranges between 30-70%, depending on the studied population. LQTS can lead to an unexpected sudden cardiac death. For this reason and due to its wider current availability, genetic testing in patients with suspicion of LQTS has spread. Purpose The aim of this study is to investigate the genetic testing yield among a large cohort of heterogeneous index cases with LQTS phenotype. Methods Diagnostic yield was restrospectively evaluated in a cohort of index cases referred to our laboratory for genetic study with LQTS phenotype. Genetic study was performed with customized libraries through next generation sequencing (NGS), which included copy number variations (CNVs) analysis. Patients with LQTS phenotype studied both with "long QT panels" and with broader cardiovascular panels were included, but those with additional cardiac phenotype (cardiomyopathies, heart defects or catecholaminergic polymorphic ventricular tachycardia) were excluded. Positive genetic reports were considered when a likely pathogenic (LP) or pathogenic (P) variant could explain patient´s phenotype. Inconclusive reports were described when a variant considered risk factor (RF) or a variant of uncertain significance variant (VUS) or a hot-VUS was identified in a clinically relevant gene. Results 1183 index cases were genotyped for LQTS phenotype. Only 164 index cases (13,8%) were studied with broader panels which included between 77 and 368 genes. The rest (n=1019) were studied with LQTS panels (either with small panels which included KCNQ1, KCNH2, KCNE1, KCNE2, SCN5A, KCNJ2, CACNA1C and with up to 36 genes-QT panels). Around 27% (n=321) of the index cases had a positive result. They carried LP/P variants in the following genes: KCNQ1 (n=166, 52%), KCNH2 (n=112), SCN5A (n=25), RYR2 (n=5), CACNA1C (n=3), HCN4 (n=4), KCNJ2 (n=2), KCNE2 (n=2) and CALM2 (n=1). 53,3% of the reports were negative. However, there were some incidental findings: 2 index cases carried P variants in LDLR, 2 carried P variants in PKP2, 2 carried a P variant in MYBPC3 and 1 index case each carried a P variant in DES, TTN and DSG2. From the 231 inconclusive reports, 37 index cases carried the RF variant in KCNE1 (p.Asp85Asn), 2 carried the RF variant in SCN5A (p.Arg1193Gln) and 50 patients carried hot-VUS in KCNQ1, KCNH2, CACNA1C, SCN5a or RYR2 gene. Conclusions In our large cohort of index cases referred for genetic testing for LQTS, diagnostic yield was around 27% when considering only LP/P variants in LQTS or arrhythmic phenotype related genes. Even by including the inconclusive but potentially relevant genetic results (RF and hot VUS), the diagnostic yield in our cohort reaches 35%. This is lower than expected for LQTS cohort. It should be taken into consideration that our cohort consists of heterogeneous patients referred for LQTS genetic testing, which would probably reflects better the real world patients seen in every day practice.

Contribution of clinically relevant copy number variations in long QT syndrome: a large cohort study

Abstract Background Copy number variations (CNVs) have increasingly been recognized in the cardiovascular setting. Their role in hypertrophic cardiomyopathy or sudden cardiac death has been described, but their involvement in Long QT syndrome (LQTS) has been scarcely studied. Most of these descriptions are confined to case reports or small series. Purpose The aim of this study is to investigate the proportion of clinically relevant CNVs among a large cohort of index cases referred for genetic testing due to LQTS. Methods Retrospective study in which the presence of likely pathogenic (LP) or pathogenic (P) CNVs was evaluated in a cohort of index cases referred for genetic study with LQTS phenotype. Index cases were genotyped with customized libraries through next generation sequencing (NGS). CNVs analysis was conducted by a proprietary method by means of comparative analysis of normalized read depth data. Clinically relevant (LP or P) CNVs were then confirmed by other techniques. Results 1183 index cases were referred for genetic testing to our laboratory with long QT syndrome phenotype. Some of these index cases were referred for suspicion of Jervell-Lange-Nielsen syndrome (JNLS) or for LQTS associated with congenital deafness (n=10) or Anderson-Tawil syndrome (n=1). Around 27% (n=322) of the index cases had a positive result. CNVs analysis was run on 1071 (91%) of the index cases. Most of the CNVs were considered negative (n=994, 93%), 59 could not be analysed (6%) and in 11 patients (1%), a LP/P CNV was identified. All CNVs but three (72.72%), were confirmed by orthogonal molecular techniques (Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA)). In all, but two, the genetic study was considered positive due to the CNV findings. One of these patients carried a pathogenic lost-of-function (LOF) CNV in the LDLR gene (incidental finding) but the report was negative because he was referred for suspicion of JLNS. In another case a CNV in the DSP gene was identified in mosaicism (30-40%). However, in this case, the positive report was attributed to the presence of an additional pathogenic variant in CACNA1C. Regarding the other index cases with LP/P CNVs: 4 carried a deletion in the KCNH2 gene, 3 carried a deletion in KCNQ1 gene (one of them in homozygosis and was studied for suspicion of JLNS) and 1 carried a duplication in the KCQN1 (LOF variant). In addition, one patient carried a deletion of exon 3 in the RYR2 gene. Even if the patient was referred for suspicion of LQTS, the report was considered positive. These clinically relevant CNVs represented around 3% of the positive genetic results. Conclusions In our large cohort of patients referred for genetic testing for LQTS, around 1% of clinically relevant CNVs were identified. As such large genomic rearrangements underlie a non-neglectable portion of cases, we consider that their analysis should be performed as part of the routine genetic testing.Deletion exons 6-14 in KCNH2 gene (CNV)MLPA with deletion exons 6-14 in KCNH2

RESCUED (REgistry for Sudden Cardiac and UnExpected Death): the German registry for families affected by sudden cardiac death in the young

Abstract Background Sudden cardiac death in the young (SCDY) refers to an abrupt and unexpected cardiac arrest at a young age due to an underlying cardiac cause. Previous studies have shown that estimated more than 10% of SCDY victims 1 to 35 years of age suffered from a – previously often undiagnosed – rare genetic cardiac disorder. Due to the inheritability of such sequence variations in disease-causing cardiac genes, blood relatives of the deceased may equally be carriers of the causative genetic variation and therefore have an increased risk for cardiac arrhythmia. Purpose Despite sudden cardiac death (SCD) increasingly gaining global awareness, systematic data collection in form of registries is sparse. The data sets collected in the RESCUED registry allow for the identification of leading causes of SCDY in Germany and offer unique opportunities for further scientific analyses with the aim of revealing unrecognized trends, risk factors and clinical warning signs of SCDY. Methods Our workflows are based on international guidelines for post mortem examination of SCDY victims and clinical assessment of their relatives. Post-mortem assessment of the index patient includes autopsy, histology, toxicology, genetic testing and review of pre-mortem clinical data. Biological relatives within the family of the index patient undergo a cardiogenetic consultation, a set of cardiological examinations and a cascade genetic screening to determine each individual´s cardiac risk profile. Data is recorded in the registry through the web-based interface of the OSSE registry software (Open Source Registry System for Rare Diseases). Results Based on our experience with complex cases of SCD (over 150 SCDY cases and more than 450 relatives) and an in-depth literature research regarding SCD registries, we have developed designated questionnaires for systematic data collection for the deceased index patient and their biological relatives, respectively. We will present insights from the design of this registry, which represents a novel, pedigree-based approach to SCDY as a consequence of a possible underlying genetic cause, and offers a new viewing angle of identifying a possible cause of SCDY. For illustrational purposes, two SCDY cases including clinical data of the family members will be shown. Conclusions RESCUED is Germany´s first registry with a holistic, pedigree-based approach to SCDY. Apart from thoroughly documenting the cardiac deaths of young individuals under the age of 50, the phenotypes of their relatives are equally recorded. Ultimately, insights gained from the RESCUED registry will lead to improved and targeted diagnostic possibilities, risk stratification and, if need be, therapy in susceptible individuals, working towards the prevention of tragic deaths in affected families. The registry will also give insights into possible preceding warning signs and symptoms of SCDY regardless of whether the underlying cause is a rare genetic disease or not.

Heterogenous atrial conduction in patients with hypertrophic cardiomyopathy and atrial fibrillation

Abstract Background/Introduction Hypertrophic cardiomyopathy (HCM) is characterised by myocardial thickening, fibrosis, and disarray, affecting both ventricles and atria. This pathology extends to atrial tissue, potentially influencing conductivity and contributing to arrhythmias, notably atrial fibrillation (AF). Pulmonary vein isolation to treat AF in HCM patients yields less satisfactory results compared to other patient groups. Improved understanding of the pathophysiology of AF in HCM patients could improve treatment stratification and delivery. Purpose This study aims to analyse atrial conduction properties in HCM patients with AF, compared to age, body mass index and sex-matched control patients. Methods Pre-ablation electroanatomic mapping data from 10 HCM patients and a matched control group of patients with structurally normal hearts undergoing AF ablation was retrospectively analysed. All patients underwent pre-ablation electroanatomic mapping during proximal coronary sinus pacing. This data was analysed using OpenEP software to quantify voltage mapping, conduction velocity and wave collision points. Conduction velocity was calculated using both plane fitting and triangulation methods. Wave collisions were identified by calculating the percentage of points with conduction velocity field divergence values less than -1.5. Results HCM patients exhibited significantly reduced mean left atrial bipolar voltage and greater low voltage burden <0.5mV than matched control patients (1.43mV vs. 2.14mV, p=0.0177; and 38.28% vs. 15.68%, p<0.0001), (Figure 1A and B). Wave collision points were significantly more prevalent in the HCM group (5.4% vs. 1.6%, p=0.0004), indicating more heterogeneous conduction (Figure 1C). Figure 2 shows example of divergence map with local electrograms around wave collision points. Both methods of quantifying conduction velocity showed comparable results. While average conduction velocity showed no statistically significant difference (plane fitting method - 0.61m/s in HCM group vs. 0.64m/s in control group, p = 0.465; triangulation method - 0.61m/s in HCM group, 0.64m/s in control group, p=0.393), a trend toward lower velocities in HCM patients was observed (Figure 1D and 1E). Conclusion HCM patients demonstrate significantly lower bipolar voltage and significantly greater low voltage areas than matched control patients. Atrial conduction in patients with HCM is significantly more heterogenous than matched control patients. These findings highlight marked conduction abnormalities in HCM patients which are likely to contribute to AF pathogenesis.

#1468 Alport syndrome family screening and management—experience of a tertiary center

Abstract Background and Aims Alport syndrome (AS) is the most common cause of inherited chronic kidney disease. This disorder is caused by deleterious variants on COL4A3, COL4A4 or COL4A5 genes. These genes codify the proteins that constitute collagen type IV of the glomerular basement membrane (GBM). Importantly, AS patients can develop chronic kidney disease (CKD) kidney disease that can be delayed or possibly prevented by timely initiation of therapy. The identification of at-risk relatives and their genetic testing allow to identify AS patients and initiate appropriate renal care and avoid unnecessary vigilance if the test is negative. Our aim was to assess the outcomes of Alport Syndrome cascade family screening in a tertiary hospital. Method In this study, we retrospectively assessed familial relatives at risk of AS index cases in our Nephrogenetics consult, from January 2018 to November 2023. After referral, routine tests to detect renal disease were done and AS gene panel was performed. Demographic and clinical data were also compiled. Results A total of 75 at-risk relatives were assessed, belonging to 26 families with a COL4A variant identified in the index case. Relatives at risk were mostly referred by primary care doctors (n = 52, 69.3%), with other 15 patients (20%) directly scheduled for consultation, and 8 (10.7%) referred by a nephrology clinic. In this cohort, an AS diagnosis was confirmed in 43 relatives (57.3%), with an additional 13 (17.3%) of the at-risk relatives with ongoing biochemical or molecular analyses. In 19 (25.4%) relatives the molecular study allowed the exclusion of AS. In the subgroup of patients diagnosed with AS (n = 43): median age at molecular diagnosis was 40.5 years (IQR 20.2-56.5years) and 26 (60.5%) were female. Thirty-five patients (81.4%) patients had autosomal dominant AS: 32 had a variant in COL4A3 (6 different variants were found: 4 were pathogenic or likely pathogenic and 2 were of uncertain significance) and 3 patients on COL4A4. COL4A5 variants were identified in 8 patients, 5 of them were female. Three (7%) patients presented with intermittent hematuria, 14 (32.6%) patients presented isolated hematuria, 10 (23.2%) patients had urinary protein/creatine (Up/cr) <0,3g/g, 7 (16.2%) presented Up/cr between 0.3g/g and 1g/g, 3 (7%) patients had Up/cr >1g/g; Six (14%) had CKD. Twenty-two (51.2%) patients were started on a renin angiotensin system inhibitor (RASi) and 5 (11.6%) were already under a RASi. At the last visit in this group of AS patients, the mean epiTFG was 104.2 ml/min (IQ 85.6-120-5 ml/min) and 6 (14%%) patients had epiTFG below 60 ml/min; mean Uprot/creat was 0.11g/g (IQR 0.06-0.32), 12 (28%) patients had no proteinuria. In the subgroup of relatives at risk were AS excluded (n = 19): median age was 38.5 years (IQR 20.2-56.0) and 11 (58%) were female. One patient had CKD, 7 (36.8%) had no signs of renal disease and 8 (42%) patients had intermittent hematuria. Conclusion Our retrospective review showed that the systematic screening of relatives at risk in our hospital was met with a high discovery rate of AS patients. Since there is clinical benefit in an early AS diagnosis, namely through improved renal care and prevention of disease progression, timely genetic/biochemical screening of at-risk relatives is advisable. Additionally, by discharging the relatives with a negative test, this is a more cost-effective approach than providing continuous vigilance to all.

#2781 Renal cortical necrosis—a rare cause of acute kidney injury

Abstract Background and Aims Renal cortical necrosis (RCN) is a rare and catastrophic cause of acute kidney injury (AKI). It is characterized by ischemic destruction of all the elements of renal cortex due to marked reduction in renal arterial perfusion of renal cortex due to vascular spasm and microvascular injury. It can be patchy or diffuse depending upon the cause and extent of hypoperfusion. Snake bite is rare cause of RCN. Incidence of RCN following snake bite has been reported to be as high as in 25% of the bitten patients to <1%. Lack or delay in receiving anti snake venom (ASV) has been observed to be a contributing factor in development of RCN following snake bite. Method A 45-year-old female had an unknown bite on foot while returning to home at twilight. She had intense pain at site of bite with slight ooze of blood. Overnight she had vomiting and pain abdomen. Subsequently she developed progressive fall in urine output and dyspnoea. After about 36 hours of bite at the time of admission in hospital she had anuria, prolonged whole blood clotting time, tachypnoea, hypoxemia and required oxygen (O2) to maintain normal O2 saturation. She was given two doses of polyvalent ASV 6 hours apart which corrected her coagulation defect. Investigations showed: haemoglobin—9 gm/dl, total leucocyte count—18700/mcl, platelet—1.15 lakh/mcl, blood urea—88 mg/dl and serum creatinine—10.5 mg/dl. She was managed with haemodialysis and supportive care. Even after 3 weeks of onset of AKI, she had anuria so a kidney biopsy was done. Results kidney biopsy on light microscopy examination showed 9 glomeruli; 8 revealing global tuft necrosis along with necrosis of adjacent tubules and vasculature and necrotic process affected around 60% of sampled cortical area consistent with cortical necrosis (Fig. 1). She was continued with haemodialysis support and urine output and pre-dialysis serum creatinine were monitored. Her urine output after 3 months of onset of AKI is around one litre per day but her pre-dialysis serum creatinine stays in the range of 9-10 mg/dl and so she continues to receive biweekly haemodialysis. Conclusion In our index case, there was delay in getting ASV which may have contributed to development of RCN. So, early treatment of snake bite is important to prevent this catastrophic complication.

#2199 Kidney involvement aspects in women with Fabry disease from the Romanian cohort

Abstract Background and Aims Fabry disease (FD) is an X-linked rare lysosomal storage disease causing progressive nervous system, kidney and heart disorders. Progressive kidney impairment is common, and an important cause of morbidity and mortality. In FD females, treatment guidelines recommend therapy initiation when there is evidence of organ involvement, but determining the proper moment to start FD specific treatment could be a real challenge in the cases. The aim of our retrospective study is to investigate clinical and histological aspects of kidney involvement in female patients with genetically confirmed FD evaluated in our Expert Center for Rare Diseases of the Reno-Urinary System between 2015–2023, with focus on the clinical phenotype and initiation of FD specific treatment. Method All patients had comprehensive assessment for target organ manifestations of Fabry disease. Renal function was assessed using serum creatinine, albumin creatinine ratio and proteinuria. Also, 14 (40%) FD females underwent kidney biopsy (KB) in order to reveal the FD specific lesions and/or to establish the indication for FD pathogenic therapy. Kidney biopsy specimens were analyzed by light and electron microscopy. Results Our study included 35 heterozygous adult females with FD from 25 unrelated families. Most females (91.4%) were diagnosed through family screening, while 3 females (8.6%) were index cases. The mean age at diagnosis was 43.8 ± 15.3 years (range 17-73 years), although mean age of symptoms onset was 34.3 ± 13.5 years (range 14-61 years). Six women from our cohort were considered healthy carriers, three females presented only neurological manifestations, nine patients had combined renal and neurological involvement, one patient had cardiac and renal involvement and the others presented multiple organ involvement. Significant co-morbidities were: arterial hypertension in 13 patients, diabetes mellitus in 2 patients, and obesity in 9 patients. Overall baseline mean eGFR was 79.9 ± 28.2 (range 25-135) ml/min/1.73 m2. Eleven patients had no obvious kidney involvement, 10 patients presented chronic kidney disease (CKD) stage 2, 11 patients CKD stage 3, one CKD stage 4 and 1 was hemodialyzed. Seventeen patients presented normal UACR, thirteen patients showed microalbuminuria, and four patients presented macroalbuminuria. Overt proteinuria (> 0.3 g/24 h) was noticed in 8 patients. Thirteen females performed KB before the initiation of FD specific treatment, and one patient was already treated. At the moment of KB, five patients had normal biologic kidney assessment, three patients presented CKD stage 2 (microalbuminuria in 2 cases and proteinuria in 1 case), and five patients presented CKD stage 3 (normoalbuminuria in 1 case, microalbuminuria in 1 case and overt proteinuria in 3 cases). All KBs showed lysosomal accumulation in the podocytes, 92.8% showed inclusions in the parietal cells of the Bowman capsule, 85.7% in the tubules, while vascular inclusions were found in 78.5% of cases. Also, we observed segmental glomerular sclerosis in 5 cases, interstitial fibrosis and tubular atrophy in 3 cases, each. Only 2 patients were treated with pathogenic therapy before the first evaluation in our center. After multidisciplinary evaluation, 22 patients (62.8%) from our cohort received recommendation to initiate FD specific treatment, and 11 patients entered in our follow-up program. Evidence of specific FD lesions in KB was a strong reason to support the recommendation to initiate FD specific treatment. Conclusion Our results showed that kidney involvement in FD females can vary from asymptomatic or mildly symptomatic, to severely symptomatic, with end stage kidney disease. Thus, females should be carefully evaluated and monitored in a multidisciplinary team, in order to diagnosed FD affected organs. Also, we underline that a normal standard assessment of the kidney cannot rule out kidney involvement in female patients with FD, and strengthen the importance of KB for detection of early kidney involvement and for additional support for early initiation of FD specific therapy.

Hidradenitis suppurativa (HS), systemic inflammatory response syndrome and sepsis: a database study.

Hidradenitis suppurativa (HS) has unclear pathophysiology and etiology, but it is not an infectious disease. However, HS is frequently mistaken for an infection and HS patients are treated for recurrent bacterial abscesses, or admitted for sepsis. A systematic literature search that is published as a separate paper did not identify an index case that demonstrates that sepsis can originate in an HS lesions.1 However, since HS patients get admitted for sepsis anyway, we wanted to characterize them.

#958 Development and Validation of a Score Estimating the Probability of obtaining a genetic diagnosis in adults with CKD of uncertain origin

Abstract Background and Aims We aim to derive and validate a score estimating the probability of identifying a variant explicative of the renal phenotype using Exome Sequencing (ES) in adults with CKD of uncertain origin. Method Participants: prospective cohort study including all consecutive index patients with a CKD from uncertain origin in three French nephrology units (metropolitan: Sorbonne University Hospitals, Paris, and Conception Hospital, Marseille; overseas: La Réunion University Hospital, Réunion island) who underwent ES between October 11th, 2017 and May 31st, 2023. Outcome measure: identification of a causal variant using ES data, according to the American College of Medical Genetics and Genomics diagnostic criteria. Candiate variables and feature engineering: raw data regarding patients’ phenotypes was prospectively entered in a collection form at the time of ES by the prescribing physician. Structured data (yes/no questions and lists) was mapped to Human Phenotype Ontology (HPO) terms. Unstructured data (free text) was manually translated into HPO terms by the same investigator (nephrologist), which was blinded to ES results. First, second and third-order ancestor HPO terms were included in the analysis. Score's derivation: an optimal weighted average of multiple models (“ensemble model”) was specified, following guidelines provided in a recently published article (PMID:36905602). Score's validation: internal validation using 10-fold cross validation, followed by internal-external validation (data from 2/3 centers was used to develop a model which was then tested using data from the remaining center; this process was repeated in each center). Results We included 2,490 patients, 560/2,490 (22.5%) of whom had a causal variant identified by ES. We collected 1,028 distinct HPO terms describing the patients’ phenotypes. The most common term was “Hypertension”, occurring in 2,079/2,490 (83.5%) patients. In internal validation, the score showed accurate calibration and discrimination (area under the receiver operating characteristics curve (AUC): 0.71, 95% CI 0.68 to 0.73; index of precision accuracy (IPA): 0.11, 95% CI 0.09 to 0.13). Performances were moderately diminished in internal-external validation but remained satisfactory (Tenon: AUC 0.64, IPA 0.04; Marseille: AUC 0.67, IPA 0.04; La Réunion: 0.68, IPA 0.09). Conclusion We derived, internally and internally-externally validated a clinical score which accurately predicts the probability of obtaining a genetic diagnosis using Exome Sequencing. Feature engineering could further increase the score's performances. Automatic computation by clinicians using an interactive tool is achievable and could be of clinical utility, especially to guide resource allocation in case of a low pretest probability.

#2412 Monoallelic NEK8-related polycystic kidney disease in an Irish ADPKD cohort

Abstract Background and Aims Autosomal dominant polycystic kidney disease (ADPKD), commonly caused by pathogenic variants in PKD1 and PKD2 genes, leads to enlarged cystic kidneys and typically present in adulthood where ∼70% of affected patients progress to kidney failure by their 7th decade of life. Recently, new genes have been reported that appear to explain some of the previously unresolved ADPKD-like cases. An example is the NEK8 gene, where monoallelic variants are reported to cause early-onset ADPKD with progressive phenotype. We are reporting 4 Irish families with monoallelic NEK8 variants. Method In-depth clinical and radiological evaluations were conducted on 250 families with polycystic kidney disease referred to the Irish Kidney Gene Project. All patients underwent genomic testing using gene-panel and exome Next Generation Sequencing (NGS), while multiple ligation probe amplification analysis of PKD1 or PKD2 was utilized in genetically unresolved families. The American College of Medical Genetics and Genomics guidelines were applied to assess variant pathogenicity. Results To date, 471 individuals representing 250 distinct families (F) have been studied, including 105 (42%) families with two or more individuals (326 individuals). 55.2% have reached end-stage kidney failure, with an average age of 49.1 ± 14.3 years. We identified pathogenic / likely pathogenic variants in 76% (190/250) of families, with variants in PKD1 accounting for 76.8% (146/190) and PKD2 accounting for 15.3% (29/190) of families, respectively. In familial cases with non-PKD1/PKD2 variants, we identified pathogenic variants in a small proportion of families with ADPKD-like phenotypes: IFT140 variants (n = 4), ALG5 (n = 2), 17q12 microdeletion (n = 2) and DNAJB11, ALG8, and ALG9 variants (n = 1 each). Upon thorough review of all genetically unresolved PKD families, 4 (6.7%) families were identified with monoallelic protein-kinase domain NEK8 variants [NM_178170.3]: p.R45W (in 2 families) and two other missense variants: p.N69D and p.R140L, none of which contained a second NEK8 variant despite extensive analysis. Autosomal dominant segregation was confirmed in two parent-child pairs, whereas the remaining two index patients reported no family history of kidney disease. The median age at the initial presentation was 12 years (IQR: 2.5–27.3), with a median follow-up period of 22.5 years at the last evaluation. The phenotype of all patients was consistent with polycystic kidney disease with the absence of liver and pancreatic cysts. All patients were diagnosed with hypertension at an average age of 15.3 ± 12.2 years. Cerebral aneurysms were detected in two patients (F1: at age 61 years and F4: at age 54 years), while F3 was reported to have childhood-onset frontal bossing, prominence cerebrospinal fluid, and large arachnoid cysts. Approximately 67% [4/6] patients progressed to end-stage kidney failure by the 3rd decade of life. Compared to families with PKD1/PKD2 variants, families with NEK8 variants were characterized by earlier average age at initial presentation (14.5 versus 29.9 years; p 0.01) and progression to end-stage kidney failure (15.5 versus 49.6 years; p < 0.0001). Table 1 summarizes the clinical and genetic characteristics of the reported families. Conclusion We provide further evidence that monoallelic NEK8 variants cause early presentation and progressive ADPKD-like phenotype. Sequencing for monoallelic NEK8 variants in patients with childhood and early-adulthood cystic kidney disease can inform renal prognosis, treatment planning, familial screening and reproductive choices.

#1854 Prevalence of Fabry disease in chronic hemodialysis patients: a multicenter screening approach

Abstract Background and Aims Fabry disease (FD), an X-linked lysosomal storage disorder caused by alpha-galactosidase A (α-Gal A) deficiency, leads to significant morbidity and early mortality due to progressive organ failure. Given the availability of enzyme replacement therapy, early identification of FD is crucial for improving patient outcomes. Method A multicenter screening was conducted among chronic hemodialysis patients across six centers. We utilized a two-tiered diagnostic approach. Initially, α-Gal A activity was measured from dried blood spots on filter paper. Subsequently, those with reduced enzyme levels underwent GLA gene mutation analysis. Results Out of 428 patients, 255 (102 females and 153 males) were selected for testing, leading to the analysis of 239 patients. In the male cohort, the average α-Gal A activity was 21.84 ± 11.9 µmol/L/h, with 34 males below the cut-off value (<15.3 µmol/L/h) but with normal lyso-Gb3 levels and no mutations. Among females, α-Gal A levels were typically within the normal range. Notably, one female was found to have a heterozygous variant of uncertain significance in the GLA gene [p.(Asp313Tyr)] in exon 6, with normal α-Gal A and lyso-Gb3 levels. Screening of other family members was not possible, as they resided abroad although we recommended it. Conclusion Screening for AFD in high-risk groups, such as hemodialysis patients, is challenging yet essential. Implementing α-Gal A measurement as a standard procedure for newly registered hemodialysis patients could prospectively identify potential Fabry carriers, offering more excellent utility than our cross-sectional study. While identifying index patients at a late disease stage may not benefit the patients themselves, it is crucial for early detection of family members, potentially altering their disease course. This proactive approach, supported by national and international guidelines, could significantly impact the management and outcomes of AFD.

Phenotypic spectrum of the first Belgian MYBPC3 founder: a large multi-exon deletion with a varying phenotype

BackgroundVariants in the MYBPC3 gene are a frequent cause of hypertrophic cardiomyopathy (HCM) but display a large phenotypic heterogeneity. Founder mutations are often believed to be more benign as they prevailed despite potential negative selection pressure. We detected a pathogenic variant in MYBPC3 (del exon 23-26) in several probands. We aimed to assess the presence of a common haplotype and to describe the cardiac characteristics, disease severity and long-term outcome of mutation carriers.MethodsProbands with HCM caused by a pathogenic deletion of exon 23-26 of MYBPC3 were identified through genetic screening using a gene panel encompassing 59 genes associated with cardiomyopathies in a single genetic center in Belgium. Cascade screening of first-degree relatives was performed, and genotype positive relatives were further phenotyped. Clinical characteristics were collected from probands and relatives. Cardiac outcomes included death, heart transplantation, life-threatening arrhythmia, heart failure hospitalization or septal reduction therapy. Haplotype analysis, using microsatellite markers surrounding MYBPC3, was performed in all index patients to identify a common haplotype. The age of the founder variant was estimated based on the size of the shared haplotype using a linkage-disequilibrium based approach.ResultsWe identified 24 probands with HCM harbouring the MYBPC3 exon 23-26 deletion. Probands were on average 51 ± 16 years old at time of clinical HCM diagnosis and 62 ± 10 years old at time of genetic diagnosis. A common haplotype of 1.19 Mb was identified in all 24 probands, with 19 of the probands sharing a 13.8 Mb haplotype. The founder event was estimated to have happened five generations, or 175–200 years ago, around the year 1830 in central Flanders. Through cascade screening, 59 first-degree relatives were genetically tested, of whom 37 (62.7%) were genotype positive (G+) and 22 (37.3%) genotype negative (G-). They were on average 38 ± 19 years old at time of genetic testing. Subsequent clinical assessment revealed a HCM phenotype in 19 (51.4%) G+ relatives. Probands were older (63 ± 10 vs. 42 ± 21 years; p < 0.001) and had more severe phenotypes than G+ family members, presenting with more symptoms (50% vs. 13.5%; p = 0.002), arrhythmia (41.7% vs. 12.9%, p = 0.014), more overt hypertrophy and left ventricular outflow tract obstruction (43.5% vs. 3.0%; p < 0.001). Male G+ relatives more often had a HCM phenotype (78.6% vs. 34.8%; p = 0.010) and were more severely affected than females. At the age of 50, a penetrance of 78.6% was observed, defined as the presence of HCM in 11 of 14 G+ relatives with age ≥50 years. Overall, 20.3% of all variant carriers developed one of the predefined cardiac outcomes after a median follow-up of 5.5 years with an average age of 50 (±21) years.ConclusionA Belgian founder variant, an exon 23-26 deletion in MYBPC3, was identified in 24 probands and 37 family members. The variant is characterized by a high penetrance of 78.6% at the age of 50 years but has variable phenotypic expression. Adverse outcomes were observed in 20.3% of patients during follow-up.

Simultaneous Detection of Common Founder Mutations Using a Cost-Effective Deep Sequencing Panel.

Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of diseases which cause visual loss due to Mendelian mutations in over 250 genes, making genetic diagnosis challenging and time-consuming. Here, we developed a new tool, CDIP (Cost-effective Deep-sequencing IRD Panel) in which a simultaneous sequencing of common mutations is performed. CDIP is based on simultaneous amplification of 47 amplicons harboring common mutations followed by next-generation sequencing (NGS). Following five rounds of calibration of NGS-based steps, CDIP was used in 740 IRD samples. The analysis revealed 151 mutations in 131 index cases. In 54 (7%) of these cases, CDIP identified the genetic cause of disease (the remaining were single-heterozygous recessive mutations). These include a patient that was clinically diagnosed with retinoschisis and found to be homozygous for NR2E3-c.932G>A (p.R311Q), and a patient with RP who is hemizygous for an RPGR variant, c.292C>A (p.H98N), which was not included in the analysis but is located in proximity to one of these mutations. CDIP is a cost-effective deep sequencing panel for simultaneous detection of common founder mutations. This protocol can be implemented for additional populations as well as additional inherited diseases, and mainly in populations with strong founder effects.

The Effect of Age and Comorbidities: Children vs. Adults in Their Response to SARS-CoV-2 Infection

While children have experienced less severe coronavirus disease (COVID-19) after SARS-CoV-2 infection than adults, the cause of this remains unclear. The objective of this study was to describe the humoral immune response to COVID-19 in child vs. adult household contacts, and to identify predictors of the response over time. In this prospective cohort study, children with a positive SARS-CoV-2 polymerase chain reaction (PCR) test (index case) were recruited along with their adult household contacts. Serum IgG antibodies against SARS-CoV-2 S1/S2 spike proteins were compared between children and adults at 6 and 12 months after infection. A total of 91 participants (37 adults and 54 children) from 36 families were enrolled. Overall, 78 (85.7%) participants were seropositive for anti-S1/S2 IgG antibody at 6 months following infection; this was higher in children than in adults (92.6% vs. 75.7%) (p = 0.05). Significant predictors of a lack of SARS-CoV-2 seropositivity were age ≥ 25 vs. < 12 years (odds ratio [OR] = 0.23, p = 0.04), presence of comorbidities (vs. none, adjusted OR = 0.23, p = 0.03), and immunosuppression (vs. immunocompetent, adjusted OR = 0.17, p = 0.02).

Snapshot of Anti-SARS-CoV-2 IgG Antibodies in COVID-19 Recovered Patients in Guinea.

Background: Because the regular vaccine campaign started in Guinea one year after the COVID-19 index case, the profile of naturally acquired immunity following primary SARS-CoV-2 infection needs to be deepened. Methods: Blood samples were collected once from 200 patients (90% of African extraction) who were recovered from COVID-19 for at least ~2.4 months (72 days), and their sera were tested for IgG antibodies to SARS-CoV-2 using an in-house ELISA assay against the Receptor Binding Domain (RBD) of the SARS-CoV-2 spike1 protein (RBD/S1-IH kit). Results: Results revealed that 73% of sera (146/200) were positive for IgG to SARS-CoV-2 with an Optical Density (OD) ranging from 0.13 to 1.19 and a median value of 0.56 (IC95: 0.51-0.61). The median OD value at 3 months (1.040) suddenly decreased thereafter and remained stable around OD 0.5 until 15 months post-infection. The OD median value was slightly higher in males compared to females (0.62 vs. 0.49), but the difference was not statistically significant (p-value: 0.073). In contrast, the OD median value was significantly higher among the 60-100 age group (0.87) compared to other groups, with a noteworthy odds ratio compared to the 0-20 age group (OR: 9.69, p-value: 0.044*). Results from the RBD/S1-IH ELISA kit demonstrated superior concordance with the whole spike1 protein ELISA commercial kit compared to a nucleoprotein ELISA commercial kit. Furthermore, anti-spike1 protein ELISAs (whole spike1 and RBD/S1) revealed higher seropositivity rates. Conclusions: These findings underscore the necessity for additional insights into naturally acquired immunity against COVID-19 and emphasize the relevance of specific ELISA kits for accurate seropositivity rates.