Clinical outcomes following preimplantation genetic testing for monogenic conditions, a systematic review of observational studies.

OBJECTIVE: We aimed to report a summary of clinical outcomes following preimplantation genetic testing for monogenic conditions, by performing a systematic review of published literature on clinical pregnancy and live birth rates following preimplantation genetic testing due to a monogenic indication. Additionally, we aimed to undertake a subgroup analysis of clinical outcomes of concurrent monogenic and aneuploidy screening. DATA SOURCES (INCLUDING YEARS SEARCHED): Three electronic databases (MEDLINE, EMBASE and PubMed) were searched from inception to May 2024. STUDY ELIGIBILITY CRITERIA (STUDY DESIGN, POPULATIONS, AND INTERVENTIONS [IF APPLICABLE]): Quantitative data audits, observational studies and case series reporting clinical outcomes for individuals undergoing preimplantation genetic testing for a monogenic indication were included. Only studies using blastocyst biopsies with polymerase chain reaction-based or genome-wide haplotyping methods for molecular analysis were eligible to reflect current laboratory practice. STUDY APPRAISAL AND SYNTHESIS METHODS: Quality assessment was performed following data extraction using an adaptation of the Joanna Briggs critical appraisal tool for case series. Results were extracted, and pooled mean clinical pregnancy rates and birth rates were calculated with 95% confidence intervals. We compared outcomes between those with and without concurrent PGT-A. RESULTS: Our search identified 1372 publications; 51 were eligible for inclusion. Pooled data on 5305 cycles and 5229 embryo transfers yielded 1806 clinical pregnancies and 1577 births. This translated to clinical pregnancy and birth rates of 34.0% [95%CI: 32.8-35.3%] and 29.7% [95%CI: 28.5-31.0%] per cycle and 24.8% [95%CI: 23.6-26.0%] and 21.7% [95%CI: 20.8-23.1%] per embryo transfer. In studies with concurrent aneuploidy screening, clinical pregnancy and birth rates were 43.3% [95%CI: 40.2-46.5%] and 37.6% [95%CI: 34.6-40.8%] per cycle and 37.0% [95%CI: 33.9-40.3%] and 31.8% [95%CI: 28.8-35.0%] per embryo transfer. Studies without aneuploidy screening reported clinical pregnancy and birth rates of 32.5% [95%CI: 31.0-34.1%] and 28.1% [95%CI: 26.6-29.7%] per cycle and 21.2% [95%CI: 19.8-22.6%] and 18.6% [95%CI: 17.3-20.0%] per embryo transfer. CONCLUSIONS: This systematic review reveals promising clinical outcome figures for this indication group. Additionally, synthesizing the published scientific literature on clinical outcomes from preimplantation genetic testing for monogenic conditions provides a rigorous, non-commercial evidence base for counselling.

Whole exome sequencing in patients with childhood-onset systemic lupus erythematosus: Results from a Croatian national study.

The purpose of this study was to identify new and low-frequency gene variants using whole exome sequencing (WES) in patients with childhood-onset systemic lupus erythematosus (cSLE), that may be involved in the pathogenesis of SLE. We performed WES on selected 17 trios (in some cases including other informative family members) in which the proband presented with severe, atypical clinical features, resistance to conventional therapy, a family pattern of occurrence and/or syndromic characteristics. After performing WES and analysis of gene variants, 17 novel and/or low-frequency variants were identified in 7 patients. One variant was classified as pathogenic (KMT2D, NM_003482.3:c.8626delC, predicted to truncate the protein p.(Gln2876Serfs*34)) and two as likely pathogenic according to the American College of Medical Genetics and Genomics classification guidelines (ADAR, NM_001111.3:c.2815A>G, predicted to encode p.(Ile939Val); BLK, NM_001715.2:c.211G>A, predicted to encode p.(Ala71Thr)). The other variants remain of uncertain significance at this point of time. WES is an important diagnostic and research instrument, producing a growing list of likely genes and gene variants that may be of relevance in the pathogenesis of cSLE and potentially point to novel therapeutic targets.

The GENESIS database and tools: A decade of discovery in Mendelian genomics.

In the past decade, human genetics research saw an acceleration of disease gene discovery and further dissection of the genetic architectures of many disorders. Much of this progress was enabled via data aggregation projects, collaborative data sharing among researchers, and the adoption of sophisticated and standardized bioinformatics analyses pipelines. In 2012, we launched the GENESIS platform, formerly known as GEM.app, with the aims to 1) empower clinical and basic researchers without bioinformatics expertise to analyze and explore genome level data and 2) facilitate the detection of novel pathogenic variation and novel disease genes by leveraging data aggregation and genetic matchmaking. The GENESIS database has grown to over 20,000 datasets from rare disease patients, which were provided by multiple academic research consortia and many individual investigators. Some of the largest global collections of genome-level data are available for Charcot-Marie-Tooth disease, hereditary spastic paraplegia, and cerebellar ataxia. A number of rare disease consortia and networks are archiving their data in this database. Over the past decade, more than 1500 scientists have registered and used this resource and published over 200 papers on gene and variant identifications, which garnered >6000 citations. GENESIS has supported >100 gene discoveries and contributed to approximately half of all gene identifications in the fields of inherited peripheral neuropathies and spastic paraplegia in this time frame. Many diagnostic odysseys of rare disease patients have been resolved. The concept of genomes-to-therapy has borne out for a number of such discoveries that let to rapid clinical trials and expedited natural history studies. This marks GENESIS as one of the most impactful data aggregation initiatives in rare monogenic diseases.

Aligning genotyping and copy number data in single trophectoderm biopsies for aneuploidy prediction: uncovering incomplete concordance.

STUDY QUESTION: To what extent can genotype analysis aid in the classification of (mosaic) aneuploid embryos diagnosed through copy number analysis of a trophectoderm (TE) biopsy? SUMMARY ANSWER: In a small portion of embryos, genotype analysis revealed signatures of meiotic or uniform aneuploidy in those diagnosed with intermediate copy number changes, and signatures of presumed mitotic or putative mosaic aneuploidy in those diagnosed with full copy number changes. WHAT IS KNOWN ALREADY: Comprehensive chromosome screening (CCS) for preimplantation genetic testing has provided valuable insights into the prevalence of (mosaic) chromosomal aneuploidy at the blastocyst stage. However, diagnosis of (mosaic) aneuploidy often relies solely on (intermediate) copy number analysis of a single TE biopsy. Integrating genotype information allows for independent assessment of the origin and degree of aneuploidy. Yet, studies aligning both datasets to predict (putative mosaic) aneuploidy in embryos remain scarce. STUDY DESIGN SIZE DURATION: A single TE biopsy was collected from 1560 embryos derived from 221 couples tested for a monogenic disorder (n = 218) or microdeletion-/microduplication syndrome (n = 3). TE samples were subjected to both copy number and genotyping analysis. PARTICIPANTS/MATERIALS SETTING METHODS: Copy number and SNP genotyping analysis were conducted using GENType. Unbalanced chromosomal anomalies ≥10 Mb (or ≥20 Mb for copy number calls <50%) were classified by degree, based on low-range intermediate (LR, 30-50%), high-range intermediate (HR, 50-70%) or full (>70%) copy number changes. These categories were further subjected to genotyping analysis to ascertain the origin (and/or degree) of aneuploidy. For chromosomal gains, the meiotic division of origin (meiotic I/II versus non-meiotic or presumed mitotic) was established by studying the haplotypes. The level of monosomy (uniform versus putative mosaic) in the biopsy could be ascertained from the B-allele frequencies. For segmental aneuploidies, genotyping was restricted to deletions. MAIN RESULTS AND THE ROLE OF CHANCE: Of 1479 analysed embryos, 24% (n = 356) exhibited a whole-chromosome aneuploidy, with 19% (n = 280) showing full copy number changes suggestive of uniform aneuploidy. Among 258 embryos further investigated by genotyping, 95% of trisomies with full copy number changes were identified to be of meiotic origin. For monosomies, a complete loss of heterozygosity (LOH) in the biopsy was observed in 97% of cases, yielding a 96% concordance rate at the embryo level (n = 248/258). Interestingly, 4% of embryos (n = 10/258) showed SNP signatures of non-meiotic gain or putative mosaic loss instead. Meanwhile, 5% of embryos (n = 76/1479) solely displayed HR (2.5%; n = 37) or LR (2.6%; n = 39) intermediate copy number changes, with an additional 2% showing both intermediate and full copy number changes. Among embryos with HR intermediate copy number changes where genotyping was feasible (n = 25/37), 92% (n = 23/25) showed SNP signatures consistent with putative mosaic aneuploidy. However, 8% (n = 2/25) exhibited evidence of meiotic trisomy (9%) or complete LOH in the biopsy (7%). In the LR intermediate group, 1 of 33 (3%) genotyped embryos displayed complete LOH. Furthermore, segmental aneuploidy was detected in 7% of embryos (n = 108/1479) (or 9% (n = 139) with added whole-chromosome aneuploidy). These errors were often (52%) characterized by intermediate copy number values, which closely aligned with genotyping data when examined (94-100%). LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: The findings were based on single TE biopsies and the true extent of mosaicism was not validated through embryo dissection. Moreover, evidence of absence of a meiotic origin for a trisomy should not be construed as definitive proof of a mitotic error. Additionally, a genotyping diagnosis was not always attainable due to the absence of a recombination event necessary to discern between meiotic II and non-meiotic trisomy, or the unavailability of DNA from both parents. WIDER IMPLICATIONS OF THE FINDINGS: Interpreting (intermediate) copy number changes of a single TE biopsy alone as evidence for (mosaic) aneuploidy in the embryo remains suboptimal. Integrating genotype information alongside the copy number status could provide a more comprehensive assessment of the embryo's genetic makeup, within and beyond the single TE biopsy. By identifying meiotic aberrations, especially in presumed mosaic embryos, we underscore the potential value of genotyping analysis as a deselection tool, ultimately striving to reduce adverse clinical outcomes. STUDY FUNDING/COMPETING INTERESTS: L.D.W. was supported by the Research Foundation Flanders (FWO; 1S74621N). M.B., K.T., F.V.M., S.J., A.V.T., V.S., D.S., A.D., and S.S. are supported by Ghent University Hospital. B.M. was funded by Ghent University. The authors have no conflicts of interest.

Exploring the genetic basis of childhood monogenic diabetes.

Monogenic diabetes is caused by one or even more genetic variations, which may be uncommon yet have a significant influence and cause diabetes at an early age. Monogenic diabetes affects 1% to 5% of children, and early detection and genetically focused treatment of neonatal diabetes and maturity-onset diabetes of the young can significantly improve long-term health and well-being. The etiology of monogenic diabetes in childhood is primarily attributed to genetic variations affecting the regulatory genes responsible for beta-cell activity. In rare instances, mutations leading to severe insulin resistance can also result in the development of diabetes. Individuals diagnosed with specific types of monogenic diabetes, which are commonly found, can transition from insulin therapy to sulfonylureas, provided they maintain consistent regulation of their blood glucose levels. Scientists have successfully devised materials and methodologies to distinguish individuals with type 1 or 2 diabetes from those more prone to monogenic diabetes. Genetic screening with appropriate findings and interpretations is essential to establish a prognosis and to guide the choice of therapies and management of these interrelated ailments. This review aims to design a comprehensive literature summarizing genetic insights into monogenetic diabetes in children and adolescents as well as summarizing their diagnosis and management.

Clinical spectrum and outcome of children with deficiency of adenosine deaminase 2 (DADA2): multicentric experience from India.

OBJECTIVES: Deficiency of adenosine deaminase-2 (DADA2) is a monogenic disorder closely resembling polyarteritis nodosa (PAN) and can present to physicians across various specialties. Through this case series, we aim to describe the clinical spectrum and outcome of Indian children with DADA2. We aimed to study the clinical spectrum and outcome of Indian children with DADA-2. METHODS: The deidentified data from all participating centres were entered in an excel sheet, and the coordinating centre (All India Institute of Medical Sciences, New Delhi) screened the data for accuracy and completeness. RESULTS: We enrolled 16 children (11 females) in the study; the mean (SD) age at the time of onset of symptoms for males and females was 46.2 (47) and 73.6 (50.4) months, respectively. The most common clinical feature in this cohort was fever and rash in 80% of patients. More than half of children n, (%) [8, (53%)] had a CNS stroke. The other clinical features were hypertension [5(33%)], anaemia [3 (20%)] and arthralgia/arthritis in 4 (26%). These children were managed with various immunomodulators: steroids [13, (86%)], anti-TNF agents [(12, (80%)], cyclophosphamide [2 (13%)] and mycophenolate mofetil [3 (20%)]. The median (IQR) duration of follow-up for this cohort was 17 (10, 29) months. Fourteen children achieved remission and none had recurrent strokes after the initiation of anti-TNF drugs. CONCLUSION: DADA-2 closely resembles PAN; early age of onset and CNS stroke are striking differentiating features from classic PAN. Most children respond well to anti-TNF agents without serious adverse events during short-term follow-up.

Chapter 2: Non-invasive prenatal diagnosis.

Non-invasive prenatal diagnosis of monogenic disorders is becoming integrated into routine clinical care for many indications. This is carried out by testing cell-free DNA extracted from the plasma portion of a maternal blood sample. The cell-free DNA is low in concentration, and consists of a mixture of maternal and fetally-derived DNA which are not easy to separate. Methods used therefore need to be rapid, sensitive and specific, including real-time PCR, digital PCR and next generation sequencing with complex algorithms. Testing may be required for pregnancies with an increased chance of a monogenic disorder due to family history or carrier status, or where there are specific abnormalities identified by ultrasound scan. In these situations, testing is considered to be diagnostic and therefore does not require confirmation by invasive testing. With increased access to genomic technologies, and more diagnoses for rare disease patients, future demand for NIPD and possibilities during pregnancy will continue.

Technically feasible solutions to challenges in preimplantation genetic testing for thalassemia: experiences of multiple centers between 2019 and 2022.

PURPOSE: In clinical practice, the success of preimplantation genetic testing for monogenic diseases (PGT-M) for thalassemia was hindered by the absence of probands, incomplete family members, or failure in detecting embryonic gene mutation sites. This study aimed to address these issues. METHODS: This retrospective study included 342 couples undergoing PGT-M for α- or ß-thalassemia at three reproductive medicine centers from 2019 to 2022. Various methods were used to construct parental haplotypes. A total of 1778 embryos were analyzed and selected for transfer based on chromosomal ploidy and PGT-M results. Follow-up involved amniocentesis results and clinical outcomes. RESULTS: Haplotypes were established using DNA samples from probands or parents, as well as sibling blood samples, single sperm, and affected embryos, achieving an overall success rate was 99.4% (340/342). For α-thalassemia and ß-thalassemia, the concordance between embryo single nucleotide polymorphism (SNP) haplotype analysis results and mutation loci detection results was 93.8% (1011/1078) and 98.2% (538/548), respectively. Multiple annealing and looping-based amplification cycles (MALBAC) showed a higher whole genome amplification success rate than multiple displacement amplification (MDA) (98.8% (1031/1044) vs. 96.2% (703/731), p < 0.001). Amniocentesis confirmed PGT-M outcomes in 100% of cases followed up (99/99). CONCLUSION: This study summarizes feasible solutions to various challenging scenarios encountered in PGT-M for thalassemia, providing valuable insights to enhance success rate of PGT-M in clinical practice.

MODY calculator applied in patients with clinical diagnosis of type 1 diabetes mellitus: Is a higher cutoff needed?

Aim: This study aimed to evaluate the mean post-test probability (PTP) of the Maturity-onset diabetes of the young (MODY) calculator in a multiethnic cohort of patients previously diagnosed with type 1 diabetes (T1DM). Materials and methods: The MODY probability calculator proposed by Shields and colleagues (2012) was applied to 117 patients from a T1DM outpatient clinic at a tertiary hospital in Brazil. Additionally, two exons of the HNF1A gene were sequenced in eight patients who hadn't received insulin treatment within six months after the diagnosis. Results: 17.1 % of patients achieved PTP >10 %; 11.1 % achieved PTP >25 % (and all patients >30 %), and 7.7 % achieved PTP >40 %. Among the patients who were selected for genetic sequencing, 100 % presented PTP >30 %, with 66.6 % achieving PTP >40 % and 41.6 % achieving PTP >75 %. These cutoffs are as suggested for the Brazilian population, according to previous investigations. No mutation was observed in the sequenced exons. Conclusion: Considering that only around 10 % of the evaluated cases achieved PTP >30 %, it is highly probable that the most suitable cutoff to select patients for genetic sequencing in a Brazilian cohort of T1DM is higher than the cutoff used in Caucasian populations.

Good laboratory practice for PGT-M: Turkish Society of Reproductive Medicine guidelines.

This guideline was prepared by the Turkish Society of Reproductive Medicine to define the conditions and requirements for an outsourced preimplantation genetic testing (PGT) programme in line with the experience and needs of practitioners. This guideline is intended to be a reference document for assisted reproductive technology centres, genetic diagnosis centres, non-governmental organizations working on reproductive health, legal experts, consultants working on laboratory accreditation, academicians specializing in ethical issues, and policy makers. The Consortium aims to provide recommendations addressing the challenges of genetic testing, especially PGT for monogenic diseases (PGT-M) due to the high rate of consanguineous marriage in Turkey. For this purpose, this summary document specifically includes challenges and recommendations regarding PGT-M practice, and aims to identify and aid in prevention of errors leading to misdiagnosis. The recommendations can be modified to fit other locations.

Loss of tolerance to dietary proteins: From mouse models to human model diseases.

The critical importance of the immunoregulatory mechanisms, which prevent adverse responses to dietary proteins is demonstrated by the consequences of their failure in two common but distinct human pathological conditions, food allergy and celiac disease. The mechanisms of tolerance to dietary proteins have been extensively studied in mouse models but the extent to which the results in mice can be extrapolated to humans remains unclear. Here, after summarizing the mechanisms known to control oral tolerance in mouse models, we discuss how the monogenic immune disorders associated with food allergy on the one hand, and celiac disease, on the other hand, represent model diseases to gain insight into the key immunoregulatory pathways that control immune responses to food antigens in humans. The spectrum of monogenic disorders, in which the dysfunction of a single gene, is strongly associated with TH2-mediated food allergy suggests an important overlap between the mechanisms that regulate TH2 and IgE responses to food antigens in humans and mice. In contrast, celiac disease provides a unique example of the link between autoimmunity and loss of tolerance to a food antigen.

The Genetics of Obesity.

Understanding the genetic causes of obesity permits anticipatory guidance and targeted treatments. Children with hyperphagia and severe early-onset obesity should receive genetic testing for rare monogenic and syndromic disorders caused by pathogenic variants involving a single gene or single chromosomal region. Gene panels covering the leptin pathway, the key regulator of energy balance, are becoming more widely available and at lower cost. Polygenic obesity is much more common and involves multiple genes throughout the genome, although the overlap in genes for rare and common disorders suggests a spectrum of severity and the potential of shared precision medicine approaches for treatment.

Clinically Meaningful Outcomes after 1 Year of Treatment with Setmelanotide in an Adult Patient with a Variant in SH2B1.

INTRODUCTION: Monogenic obesity is caused by a unique genetic dysfunction, often appears in childhood, and can be accompanied by neuroendocrine, skeletal, developmental, and behavioral disorders, among other manifestations. Some variants in the SH2B1 gene have been suggested as strong candidates for the development of autosomal dominant obesity. CASE PRESENTATION: We describe here the clinical response after 1 year of setmelanotide treatment in a 22-year-old patient with an SH2B1 variant. After 3 months of treatment, our patient lost 5.4% of body weight. This period was followed by a 3-month period of noncompliance, in which the patient gained 4% body weight. After reinstating daily drug administration, the patient showed a 19.5% reduction in body weight and a clear improvement in all hunger scales after 1 year of treatment. CONCLUSION: These results indicate that the changes seen are drug dependent and provide positive evidence for the administration of setmelanotide in adult patients with heterozygous variants in the SH2B1 gene.

Examining the clinical and genetic spectrum of maturity-onset diabetes of the young (MODY) in Iran.

Maturity-onset diabetes of the young (MODY) is an uncommon monogenic type of diabetes mellitus. Detecting genetic variants for MODY is a necessity for precise diagnosis and treatment. The majority of MODY genetic predisposition has been documented in European populations and a lack of information is present in Iranians which leads to misdiagnosis as a consequence of defects in unknown variants. In this study, using genetic variant information of 20,002 participants from the family-based TCGS (Tehran Cardiometabolic Genetic Study) cohort, we evaluated the genetic spectrum of MODY in Iran. We concentrated on previously discovered MODY-causing genes. Genetic variants were evaluated for their pathogenicity. We discovered 6 variants that were previously reported in the ClinVar as pathogenic/likely pathogenic (P/LP) for MODY in 45 participants from 24 families (INS in 21 cases, GCK in 13, HNF1B in 8, HNF4A, HNF1A, and CEL in 1 case). One potential MODY variant with Uncertain Risk Allele in ClinVar classification was also identified, which showed complete disease penetrance (100%) in four subjects from one family. This is the first family-based study to define the genetic spectrum and estimate the prevalence of MODY in Iran. The discovered variants need to be investigated by additional studies.

Categorizing Monogenic Epilepsies by Genetic Mechanisms May Predict Efficacy of the Ketogenic Diet.

BACKGROUND: The ketogenic diet (KD) is an effective treatment for epilepsy. In recent years, studies have shown favorable efficacy of KD in epilepsy from genetic disorders. In this study, we propose an approach to KD in monogenic epilepsy: we evaluate the utility of categorizing genetic variants based on rational associations with the known mechanisms of KD. METHODS: Patients with monogenic epilepsy treated with KD were reviewed. The genetic etiologies were categorized into five groups: (1) conditions causing cellular energy impairment, (2) GABA-pathies, (3) mToR-pathies, (4) ion channelopathies, and (5) no known mechanisms associated with KD mechanisms. Treatment response was defined as a median reduction in seizure frequency of greater than 50%. RESULTS: Of 35 patients, 24 (69%) were responders at three months. Based on categories, Group 1 had the highest response rate with seven of seven (100%), followed by Group 2, six of seven (86%), and Group 3, two of three (67%). Patients in Groups 4 and 5 had poorer responses with three of seven (43%) and four of 11 (36%) response rates, respectively (P < 0.01). Median percentage of seizure reduction showed Group 1 with the highest reduction of 97.5%, Group 2 at 94%, and Groups 3, 4, and 5 at 62.5%, 30%, and 40%, respectively (P = 0.036). CONCLUSION: Our findings show a favorable response to KD in patients with monogenic epilepsy (69% at three months) with the highest response in patients with conditions involving cellular energy impairment and GABA-pathies. The KD, therefore, should be considered early in patients with monogenic epilepsy, especially those involving genes associated with cellular energy impairment or GABA-pathies.

The systemic complexity of a monogenic disease: the molecular network of spinal muscular atrophy.

Monogenic diseases are well-suited paradigms for the causal analysis of disease-driving molecular patterns. Spinal Muscular Atrophy (SMA) is one such monogenic model caused by mutation or deletion of the Survival of motor neuron 1 (SMN1) gene. Although several functions of the SMN protein have been studied, single functions and pathways alone do not allow to identify critical disease-driving molecules. Here, we analyzed the systemic characteristics of SMA employing proteomics, phosphoproteomics, translatomics and interactomics from two mouse models with different disease-severities and genetics. This systems approach revealed sub-networks and proteins characterizing commonalities and differences of both models. To link the identified molecular networks with the disease-causing SMN protein, we combined SMN-interactome data with both proteomes creating a comprehensive representation of SMA. By this approach, disease hubs and bottlenecks between SMN and downstream pathways could be identified. Linking a disease-causing molecule with widespread molecular dysregulations via multiomics is a concept for analyses of monogenic diseases.

Profile of juvenile systemic lupus erythematosus patients with a special reference to monogenic lupus and lupus nephritis: a cross-sectional study.

To study the clinical, laboratory profile and outcome of juvenile Systemic Lupus Erythematosus (jSLE) patients at a tertiary care centre in South India. A retrospective review of the medical records of all jSLE patients visiting the Pediatric Immunology and Rheumatology Unit, Aster CMI Hospital, India from February 2017 to December 2023 was performed. The clinical characteristics, treatment and outcomes were recorded and tabulated. Seventy patients diagnosed with jSLE were included in the study. The female-to-male ratio was 4.4:1. Mean age at onset and delay in diagnosis were 120.1 (+/- 56.8) and 11.7 (+/- 22.7) months respectively. The median follow-up period was 13 months (range 4, 29 months). Nine patients presented with early onset SLE (< 5 years). Most common manifestations were constitutional symptoms (n = 56), followed by haematologic (n = 55), and mucocutaneous(n = 50) involvement. Immunological workup showed SLE-specific antibody positivity in 38 patients, hypocomplementemia in 40 patients, and anti-phospholipid antibody positivity in 13 patients. Mortality was observed in five patients with LN while there was no mortality in the non-nephritis group (p 0.004). C1q deficiency was the most common cause of monogenic lupus seen in 5/9 patients; protein kinase C delta (PRKCD) defect and chronic granulomatous disease (CYBB mutation) were seen in one patient each. We describe a large cohort of jSLE from Southern India. Lupus nephritis was noted in 35.7% of our cohort and had a direct correlation with mortality. 10% of patients had monogenic lupus. Serious infections were more frequent in patients with monogenic lupus.

In steroid-resistant nephrotic syndrome that meets the strict definition, monogenic variants are less common than expected.

BACKGROUND: In patients with steroid-resistant nephrotic syndrome (SRNS), the presence of monogenic variants influences therapeutic strategies. Large cohort studies reported the detection of monogenic variants in approximately 30% of patients with SRNS. However, these cohorts included many patients, such as those with symptomatic proteinuria, who did not meet the strict diagnostic criteria for pediatric nephrotic syndrome (NS). Therefore, we investigated the proportion of causative monogenic variants detected in patients who strictly met the diagnostic criteria of SRNS and explored their clinical characteristics. METHODS: We examined pediatric SRNS cases with genetic analysis conducted in our hospital. Cases satisfying all of the following criteria were included: (1) age at onset 1-18 years, (2) serum albumin at onset ≤ 2.5 g/dl, (3) persistent heavy proteinuria, and (4) no complete remission after 4 weeks of steroid monotherapy. RESULTS: The proportion of detected monogenic variants was 12% (22/185) among all patients. The proportion was only 7% (9/129) in patients with edema at disease onset compared with 38% (9/24) in those without (p < 0.0001). Monogenic variants were rare in patients with acute kidney injury associated with NS (1% (1/11)) or a history of complete remission (4% (2/51)). CONCLUSIONS: Our study revealed a monogenic cause in 12% of individuals with strictly defined SRNS, a much smaller proportion than previously reported. The presence or absence of edema at the onset was an important factor to distinguish SRNS with monogenic cause from SRNS without. Our results provide further evidence of the SRNS types attributable to monogenic causes.

Identification of KSR2 Variants in Pediatric Patients with Severe Early-Onset Obesity from Qatar.

The kinase suppressor of Ras 2 (KSR2) gene is associated with monogenic obesity, and loss-of-function variants in KSR2 have been identified in individuals with severe early-onset obesity. This study investigated KSR2 variants in 9 pediatric patients with severe early-onset obesity in Qatar using whole genome sequencing among a cohort of 240 individuals. We focused on KSR2 variants with a minor allele frequency (MAF) below 1% and a Combined Annotation Dependent Depletion (CADD) score above 13 to identify potential causative variants. Our analysis identified four KSR2 variants: one intronic (c.1765-8G>A) and three missense variants (c.1057G>A, c.1673G>A, and c.923T>C) in nine patients. The intronic variant c.1765-8G>A was the most frequent (seen in six individuals) and had a CADD score of 21.10, suggesting possible pathogenicity. This variant showed a significantly higher allele frequency in the Qatari population compared to the Genome Aggregation Database (gnomAD), indicating a possible founder effect. Molecular modeling of the missense variants revealed structural changes in the protein structure. The study concludes that these four KSR2 variants are associated with monogenic obesity, with an autosomal dominant inheritance pattern. The c.1765-8G>A variant's prevalence in Qatar underscores its importance in genetic screening for severe obesity. This research advances the understanding of genetic factors in severe early-onset obesity and may inform better management strategies.