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Background Imprinting disorders are rare diseases resulting from altered expression of imprinted genes, which exhibit parent-of-origin-specific expression patterns regulated through differential DNA methylation. A subgroup of patients with imprinting disorders have DNA methylation changes at multiple imprinted loci, a condition referred to as multi-locus imprinting disturbance (MLID). MLID is recognised in most but not all imprinting disorders and is also found in individuals with atypical clinical features; the presence of MLID often alters the management or prognosis of the affected person. Some cases of MLID are caused by trans-acting genetic variants, frequently not in the patients but their mothers, which have counselling implications. There is currently no consensus on the definition of MLID, clinical indications prompting testing, molecular procedures and methods for epigenetic and genetic diagnosis, recommendations for laboratory reporting, considerations for counselling, and implications for prognosis and management. The purpose of this study is thus to cover this unmet need. Methods A comprehensive literature search was conducted resulting in identification of more than 100 articles which formed the basis of discussions by two working groups focusing on clinical diagnosis (n = 12 members) and molecular testing (n = 19 members). Following eight months of preparations and regular online discussions, the experts from 11 countries compiled the preliminary documentation and determined the questions to be addressed during a face-to-face meeting which was held with the attendance of the experts together with four representatives of patient advocacy organisations. Results In light of available evidence and expert consensus, we formulated 16 propositions and 8 recommendations as interim guidance for the clinical and molecular diagnosis of MLID. Conclusions MLID is a molecular designation, and for patients with MLID and atypical phenotypes, we propose the alternative term multi-locus imprinting syndrome. Due to the intrinsic variability of MLID, the guidelines underscore the importance of involving experts from various fields to ensure a confident approach to diagnosis, counselling, and care. The authors advocate for global, collaborative efforts in both basic and translational research to tackle numerous crucial questions that currently lack answers, and suggest reconvening within the next 3–5 years to evaluate the research advancements and update this guidance as needed.

BackgroundComplications are frequently reported after hypospadias repair and there is a need to understand the factors that influence their occurrence.MethodsData from boys with hypospadias born between 2000 and 2020 were obtained from the International Disorders of Sex Development (I-DSD) Registry. Logistic regressions, fisher’s exact tests and spearman’s correlation tests were performed on the data to assess associations between clinical factors and complication rates.ResultsOf the 551 eligible boys, data were available on 160 (29%). Within the cohort, the median (range) External Masculinization Score (EMS) was 6 (2, 9). All presented with one or more additional genital malformation and 61 (38%) presented with additional extragenital malformations. Disorders of androgen action, androgen synthesis and gonadal development were diagnosed in 28 (18%), 22 (14%) and 9 (6%) boys, respectively. The remaining 101 (62%) patients were diagnosed as having non-specific 46,XY Disorders of Sex Development. Eighty (50%) boys had evidence of abnormal biochemistry, and gene variants were identified in 42 (26%). Median age at first hypospadias surgery was 2 years (0, 9), and median length of follow-up was 5 years (0, 17). Postsurgical complications were noted in 102 (64%) boys. There were no significant associations with postsurgical complications.ConclusionsBoys with proximal hypospadias in the I-DSD Registry have high rates of additional comorbidities and a high risk of postoperative complications. No clinical factors were significantly associated with complication rates. High complication rates with no observable cause suggest the involvement of other factors which need investigation.

The RhoGEF TRIO is known to play a major role in neuronal development by controlling actin cytoskeleton remodeling, primarily through the activation of the RAC1 GTPase. Numerous de novo mutations in the TRIO gene have been identified in individuals with neurodevelopmental disorders (NDDs). We have previously established the first phenotype/genotype correlation in TRIO-associated diseases, with striking correlation between the clinical features of the individuals and the opposite modulation of RAC1 activity by TRIO variants targeting different domains. The mutations hyperactivating RAC1 are of particular interest, as they are recurrently found in patients and are associated with a severe form of NDD and macrocephaly, indicating their importance in the etiology of the disease. Yet, it remains unknown how these pathogenic TRIO variants disrupt TRIO activity at a molecular level and how they affect neurodevelopmental processes such as axon outgrowth or guidance. Here we report an additional cohort of individuals carrying a pathogenic TRIO variant that reinforces our initial phenotype/genotype correlation. More importantly, by performing conformation predictions coupled to biochemical validation, we propose a model whereby TRIO is inhibited by an intramolecular fold and NDD-associated variants relieve this inhibition, leading to RAC1 hyperactivation. Moreover, we show that in cultured primary neurons and in the zebrafish developmental model, these gain-of-function variants differentially affect axon outgrowth and branching in vitro and in vivo, as compared to loss-of-function TRIO variants. In summary, by combining clinical, molecular, cellular and in vivo data, we provide compelling new evidence for the pathogenicity of novel genetic variants targeting the TRIO gene in NDDs. We report a novel mechanism whereby the fine-tuned regulation of TRIO activity is critical for proper neuronal development and is disrupted by pathogenic mutations.

Purpose Disorders/differences of sex development (DSD) result from variants in many different human genes but, frequently, have no detectable molecular cause. Methods Detailed clinical and genetic phenotyping was conducted on a family with three children. A Sec31a animal model and functional studies were used to investigate the significance of the findings. Results By trio whole-exome DNA sequencing we detected a heterozygous de novo nonsense SEC31A variant, in three children of healthy non-consanguineous parents. The children had different combinations of disorders that included complete gonadal dysgenesis and multiple pituitary hormone deficiency. SEC31A encodes a component of the COPII coat protein complex, necessary for intracellular anterograde vesicle-mediated transport between the endoplasmic reticulum (ER) and Golgi. CRISPR-Cas9 targeted knockout of the orthologous Sec31a gene region resulted in early embryonic lethality in homozygous mice. mRNA expression of ER-stress genes ATF4 and CHOP was increased in the children, suggesting defective protein transport. The pLI score of the gene, from gnomAD data, is 0.02. Conclusions SEC31A might underlie a previously unrecognised clinical syndrome comprising gonadal dysgenesis, multiple pituitary hormone deficiencies, dysmorphic features and developmental delay. However, a variant that remains undetected, in a different gene, may alternatively be causal in this family.

ABSTRACT Background A genetic neurodevelopmental disorder (GND) impacts all aspects of a child's and family's life. GNDs are rare; most have limited natural history data. We aimed to understand the impacts, obstacles, information barriers and coping strategies developed through parents' experience of receiving and living with a child's diagnosis. Design and Participants This analysis is part of the UK multicentre observational study of children with rare GNDs (GenROC). We conducted 17 semi‐structured online interviews with parents of children with GNDs (aged 0–15 years) from November 2023 to March 2024. Data were analysed following the principles of thematic analysis. Results We identified five themes. (1) Impact on the family around a genetic diagnosis: Distress begins well before a diagnosis is received; there is an impact upon the receipt itself and the ongoing impact on the family thereafter. (2) Impact of uncertainty, lack of data and ‘rareness’. The experience of parenting when so little is known about your child's condition. (3) Relationships with health professionals. Positive where parents are empowered and feel part of the team; negative where parents feel not heard/believed due to a professional lack of expertise/understanding. (4) Parent mental health: GNDs can be a significant burden to family life. The need to advocate for services has a negative impact. Feelings of isolation through rareness. (5) Coping strategies and factors that help: Support/Facebook groups are considered highly beneficial. Parents develop new positive identities, including that of advocate, professional and educator. Conclusions GNDs represent a major challenge for families, clinicians and service providers. Distressed parents are struggling to cope with challenges and suffer from poor mental health. Psychosocial support, better signposting and health professional education may help. Patient Contribution Patient Participant Involvement group (comprising five mothers and one father of children with varying GNDs, one young person with a GND, and one genetics family charity representative) contributed to topic guide development and methodology and provided feedback on results.

Hypospadias is characterised by a displacement of the urethral orifice affecting approximately 1 in 200-300 boys and may be an isolated finding or occur together with other developmental problems including learning disability. Its aetiology has been investigated for decades with environmental, endocrine and genetic factors felt to contribute to its development. Current knowledge regarding the genetic causes of hypospadias is scarce and in at least half of the hypospadias cases no molecular diagnosis is established. The UK-wide Deciphering Developmental Disorders (DDD) Study enabled clinicians to undertake complementary analysis projects (CAPs) using phenotype data collected from recruiting clinical geneticists and genotype information generated by the DDD Study researchers. The aims of this study were to detect new and known variants in genes already linked to hypospadias and to explore the possibility of discovering new genetic associations with this condition. Additional aims were to describe the frequency of genital abnormalities in DDD participants and to describe associated clinical features while investigating whether there is a common combination of features observed in this group of patients. The hypothesis was that VCF file re-analysis of selected DDD participants with similar constellation of associated clinical features would facilitate identification of potentially causative variants in the same gene or genetic pathway. Investigations were started with a preliminary analysis describing the range and prevalence of genital abnormalities in DDD participants and assessing reported variants in the first 1133 families recruited into the DDD study. This analysis showed that genital abnormalities are present in approximately 6% of DDD patients, with hypospadias being the second most common genital problem. A review of reported variants in the first 1133 families demonstrated that it is possible to extend the clinical spectrum of known syndromes by reporting associated genital abnormalities. In order to select a group of patients with the highest reporter certainty, individuals with hypospadias were chosen as the study group. An analysis of associated features of DDD participants with hypospadias compared to those without hypospadias identified that cardiovascular and growth abnormalities are more likely to occur in individuals with hypospadias. To remove neurodevelopmental delay as a confounding factor from the analysis, associated malformations of a subset of DDD participants with hypospadias and co-existing neurodevelopmental delay were compared to those with a genital abnormality other than hypospadias but again with co-existing neurodevelopmental delay. This analysis showed that cardiovascular and structural brain abnormalities occurred at a significantly higher rate in individuals with hypospadias compared to the 'no hypospadias' group. In addition, in a number of patients, these features occurred as a constellation. Both studies mentioned above showed that cardiovascular abnormalities are more likely to occur together with hypospadias, and in order to remove ascertainment bias, DDD participants with associated neurodevelopmental delay were considered for the next step of the investigations which was VCF file re-analysis of DDD patients with hypospadias, neurodevelopmental delay and cardiovascular abnormalities. VCF files of 22 trio and 11 singleton cases were available for re-analysis. A bioinformatic analysis pipeline was created and applied to perform variant filtering and analysis of the trio cases and likely causative variants in four genes (MID1, ADNP, CTNND1 and TRIO), already linked to developmental disorders have been identified. This is the first report to describe hypospadias as an associated clinical feature in relation to the TRIO, CTNND1 and ADNP genes. Additionally, a new multiple malformation syndrome caused by a likely pathogenic variant in the PKN2 gene is delineated. Three (CTNND1, TRIO, and PKN2) of the five genes identified in the family trios are directly interacting with or regulate the function of Rho GTPases. Singleton analysis using a modified bioinformatics pipeline detected a causative alteration in an epigenetic regulator gene (HIST1H1E). In summary, the application of whole-exome sequencing was deemed a powerful tool in establishing molecular diagnoses for patients with hypospadias and in the discovery of new gene associations. Additional research into the role of Rho GTPases in the development of hypospadias might facilitate our understanding of the mechanisms driving genital development.

Abstract Disclosure: I.A. Bacila: None. R. Welch: None. S. Adam: None. S.F. Ahmed: None. M. Alimussina: None. E. Chinnasamy: None. E.C. Crowne: None. J.H. Davies: None. A. Davis: None. J. Davis: None. M. Debono: None. S. Elford: None. Y. Elhassan: None. G. Gazdagh: None. H. Gleeson: None. L. James: None. M. Korbonits: None. S. Llanaha: None. J.M. Lynch: None. S. McGeoch: None. A. Mitchell: None. R.D. Murray: None. S. Nedelcu: None. G. Okoro: None. M.W. O'Reilly: None. A. Rees: None. R. Scott: None. R.H. Stimson: None. A. Thankamony: None. J.W. Tomlinson: None. B. Vaidya: None. N.P. Krone: None. Background: Congenital adrenal hyperplasia (CAH) is one of the commonest forms of primary adrenal insufficiency with an incidence of about 1 in 15,000. Previous studies have highlighted the suboptimal health status and care provision in adults with CAH and these were associated with significant co-morbidities. In 2023, we implemented CaHASE2 (https://www.endocrinology.org/clinical-practice/research-projects/cahase-2/) to develop a strategy for prospective collection of longitudinal data. Our recent CAH service evaluation suggested significant differences in the approach to CAH patients. Aim: To identify specific unmet needs in the care of people living with CAH, through standardised phenotyping across all participating centres. Methods: In September 2023, PIs agreed a minimal dataset for the collection of real-world data for participating centres. The data is collected using the international CAH registry (I-CAH; https://sdmregistries.org/). CaHASE2 was launched in November 2023. Results: To date, 351 adults (213 females, 138 males) with CAH have been recruited and 1213 clinic visits were available for analysis. There is a preponderance of younger to middle-aged adults in the currently available datasets (median age 42 years, range 23-88). Preliminary analysis suggests a temporal change in glucocorticoid choice over time with an increased use of hydrocortisone and a decreased use of prednisolone. Analysis of 17OHP concentrations shows that a significant proportion of patients are overtreated. A significant proportion of patients are overweight or obese. Currently 18 centres are actively recruiting and 5 are awaiting local approval to use the I-CAH registry. The data will be analysed in 12-month cycles, to assess the current level of care provision and inform the development of CAH standards. In addition, we will establish a report that will provide centres with information about their local care provision in relation to other centres. Conclusions: The CaHASE2 project will provide important information about the health status of adults with CAH and how this might be related to differences in health care provision. Ultimately, such data should lead to a higher degree of equality of service provision in all parts of the UK and Ireland. Presentation: Saturday, July 12, 2025

Complications are frequently reported after hypospadias repair and there is a need to understand the factors that influence their occurrence.BackgroundComplications are frequently reported after hypospadias repair and there is a need to understand the factors that influence their occurrence.Data from boys with hypospadias born between 2000 and 2020 were obtained from the International Disorders of Sex Development (I-DSD) Registry. Logistic regressions, fisher's exact tests and spearman's correlation tests were performed on the data to assess associations between clinical factors and complication rates.MethodsData from boys with hypospadias born between 2000 and 2020 were obtained from the International Disorders of Sex Development (I-DSD) Registry. Logistic regressions, fisher's exact tests and spearman's correlation tests were performed on the data to assess associations between clinical factors and complication rates.Of the 551 eligible boys, data were available on 160 (29%). Within the cohort, the median (range) External Masculinization Score (EMS) was 6 (2, 9). All presented with one or more additional genital malformation and 61 (38%) presented with additional extragenital malformations. Disorders of androgen action, androgen synthesis and gonadal development were diagnosed in 28 (18%), 22 (14%) and 9 (6%) boys, respectively. The remaining 101 (62%) patients were diagnosed as having non-specific 46,XY Disorders of Sex Development. Eighty (50%) boys had evidence of abnormal biochemistry, and gene variants were identified in 42 (26%). Median age at first hypospadias surgery was 2 years (0, 9), and median length of follow-up was 5 years (0, 17). Postsurgical complications were noted in 102 (64%) boys. There were no significant associations with postsurgical complications.ResultsOf the 551 eligible boys, data were available on 160 (29%). Within the cohort, the median (range) External Masculinization Score (EMS) was 6 (2, 9). All presented with one or more additional genital malformation and 61 (38%) presented with additional extragenital malformations. Disorders of androgen action, androgen synthesis and gonadal development were diagnosed in 28 (18%), 22 (14%) and 9 (6%) boys, respectively. The remaining 101 (62%) patients were diagnosed as having non-specific 46,XY Disorders of Sex Development. Eighty (50%) boys had evidence of abnormal biochemistry, and gene variants were identified in 42 (26%). Median age at first hypospadias surgery was 2 years (0, 9), and median length of follow-up was 5 years (0, 17). Postsurgical complications were noted in 102 (64%) boys. There were no significant associations with postsurgical complications.Boys with proximal hypospadias in the I-DSD Registry have high rates of additional comorbidities and a high risk of postoperative complications. No clinical factors were significantly associated with complication rates. High complication rates with no observable cause suggest the involvement of other factors which need investigation.ConclusionsBoys with proximal hypospadias in the I-DSD Registry have high rates of additional comorbidities and a high risk of postoperative complications. No clinical factors were significantly associated with complication rates. High complication rates with no observable cause suggest the involvement of other factors which need investigation.

Introduction XYdisorders of sex development (DSD) result from variants in many different human genes but frequently have no detectable molecular cause. In approximately 25% of cases of XY DSD, the index case may have associated malformations. Genetic disorders of endoplasmic reticulum (ER) function are increasingly being recognised but have not been associated with DSD or pituitary disorders. Clinical case Three siblings (with unaffected non-consanguineous parents) were reviewed at the tertiary endocrine clinic. Child I was noted at birth to have cliteromegaly. Imaging and examination under anaesthetic revealed a normal vagina and uterus but gonads of indeterminate origin. She was 46,XY and basal endocrine investigations at the age of 4 years showed a low AMH for male but otherwise normal gonadal and thyroid function and normal IGF-1. She had a laparoscopic bilateral gonadectomy aged 5 years. Pathology demonstrated bilateral testicular tissue, with substantial fibrotic atrophic change and occasional placental alkaline phosphatase (PLAP) positive cells, suggestive of germ cell tumours. Aged 8 years she developed obesity and later hypertension. Child II was reviewed due to short stature and diagnosed with GH deficiency aged 2 years. She has normal adrenal and thyroid function and gonadotrophins. MRI demonstrated an ectopic posterior pituitary. Child III presented with perineal hypospadias, a small phallus, bilateral undescended testes and craniofacial abnormalities. Endocrine investigations revealed hypogonadotrophic hypogonadism, with no testosterone response to hCG stimulation, a low normal AMH and no response of LH or FSH on LHRH stimulation. He has panhypopituitarism with an ectopic posterior pituitary gland on MRI and is currently on treatment with GH, hydrocortisone and levothyroxine. His BP is on the 98th centile for age and height. Child I and Child III have mild developmental delay but are in mainstream school with additional educational support. High-throughput DNA sequencing revealed, in all three siblings, a heterozygous truncating variant in the SEC31A gene that encodes a component of the COPII-complex that coats the vesicles mediating ER to Golgi transport. CRISPR-Cas9 targeted knockout of the corresponding Sec31a region resulted in embryonic lethality in homozygous mice. mRNA phenotyping of ER-related genes demonstrated increased mRNA expression of ATF4 and CHOP in the affected children, genes encoding key ER stress-related proteins, associated with defective protein transport. Conclusions Dysregulation ofanterograde and retrograde COPII-coated-vesicle ER-Golgi transport is increasingly recognised to underlie human developmental disorders, including Craniolenticulosutural dysplasia (OMIM 607812) and Saul-Wilson syndrome (OMIM 618150). The de novo SEC31A nonsense variant in all three affected siblings, the ER stress response, plus reported developmental syndromes with dysfunction of this transport mechanism and evidence from the preclinical mouse model suggest that SEC31A might underlie a previously unrecognised clinical syndrome comprising DSD, endocrine abnormalities, dysmorphic features and developmental delay. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.