Genetic Investigations Research Articles

8486 Age at diagnosis in Prader Willi Syndrome (PWS)

Abstract Disclosure: R. Sritharan: None. J. Lodge: None. S. Tadros: None. L. Menzies: None. E.F. Gevers: None. PWS is a complex neurodevelopmental disorder characterised by neonatal hypotonia,failure to thrive, hypothalamic and endocrine dysfunction, behavioural and learning difficulties and hyperphagia. It is caused by absence of expression of paternally imprinted genes on chromosome 15q11-q13. PWS is confirmed by genetic methylation analysis of this region. Most patients with PWS are referred for genetic investigations in the first months of life due to severe hypotonia and/or failure to thrive. However, it is known that some patients are still only diagnosed in adulthood, with resulting missed opportunities for prompt early treatments for PWS, such as growth hormone therapy. Little information is available on age of diagnosis of PWS, and whether opportunities to request genetic investigation are missed in childhood. We therefore aimed to study age at diagnosis of PWS in the UK. To do so, we assessed data as reported to the UK patient association PWSA-UK from 1968-2023, and additionally audited PWS genetic testing by the North Thames Genomics Laboratory Hub from 2019-22. Of 1145 people registered at PWSA as having PWS, 945 had an age of diagnosis recorded. Of these, 254 (28%) were diagnosed over 1 year of age. From March 2021 to Sept 2023, 13 were diagnosed over 1 year of age with a mean age at diagnosis of 9.27 yr (95% CI 4.15 to 14.4) and with 8 patients below 5 years of age. We assessed PWS diagnoses made in blocks of 4 years from 1968, and the number of PWS diagnoses in people over age 1 year in those time blocks. The number of diagnoses in people over 1 year of age appeared to decrease since 1996 to 7 but from 2015 this has been fluctuating. North Thames Genomics Laboratory Hub provides testing for around 10 million people in and around London. Over a 3-year period between 2019-2022, there were 59 requests for PWS testing. 28 of these were positive (a 47% diagnostic yield). 20/28 (71%) of patients were diagnosed under 1 month of age, 7% were diagnosed at 1-24 months of age, 3.5% at 2-5 yrs and 18% at >5 yrs of age (one at age 9, two at age 18, one at age 29 and one at 33 yrs of age). Most tests were performed in children under1 month of age (91% yield), followed by those over 5 yrs of age (30% yield). For 10 individuals, microarray was requested, however methylation studies would have been more appropriate. All patients diagnosed over 5 years of age had hypotonia and were described as hyperphagic and having intellectual disability, and 75% were obese. Patients diagnosed after age 8were described as having neonatal hypotonia and may have been eligible for genetic testing soon after birth. These data suggest that a considerable percentage of patients are diagnosed with PWS after the first year of life in the UK. Further root analysis, interventions, and education is required to reduce age at diagnosis in patients with PWS to allow for optimal management starting in the first few months of life. Presentation: 6/1/2024

Monogenic Kidney Diseases in Adults With Chronic Kidney Disease (CKD).

According to current evidence, every 10th to 11th adult with chronic kidney disease (CKD) has a monogenic disease of the kidney. This review is based on reported studies in which molecular genetic diagnostic techniques were used to investigate monogenic kidney diseases in adults with CKD. The studies were identified by a selective literature search using predefined criteria. In 12 selected studies, diagnostic variants of 179 different genes were identified in 1467 out of 6607 study participants with CKD (22.2%). More than 60% of these variants affected 8 genes (PKD1, PKD2, COL4A3, COL4A4, COL4A5, UMOD, MUC1, HNF1B). Three diseases are associated with these genes: autosomal dominant polycystic kidney disease (ADPKD), Alport syndrome, and autosomal dominant tubulo-interstitial kidney disease (ADTKD). Physicians treating patients with CKD should be alert to the presence of any red flags, such as onset at a young age, a positive family history, or hematuria of unknown cause. When a genetic etiology is suspected, a specialized work-up is indicated, often including a molecular genetic investigation. A positive genetic finding usually leads to a modification of the patient's specific diagnosis and/or treatment. Awareness of the high prevalence of monogenic kidney diseases in adults with CKD and alertness to their suggestive clinical features are crucial for the timely initiation of targeted diagnostic testing. The molecular genetic identification of these diseases is a prerequisite for appropriate patient management.

Investigating Concomitant RAG-2 and LRBA Mutations in SCID and Autoimmunity.

Inborn errors of immunity (IEI) are a large heterogenous group of diseases characterized by immunodeficiency, immune dysregulation, allergy, auto-inflammation and predisposition for malignancies. Most are inherited in an autosomal recessive trait. We studied a patient with severe combined immunodeficiency (SCID) and immune dysregulation who harbored two distinct bi-allelic IEI-associated genetic mutations. Clinical, immunological and genetic data were collected. Genetic investigation included whole exome sequencing on DNA extracted from skin fibroblasts. Family segregation was performed by Sanger sequencing. Immunological evaluation included absolute and functional evaluation of lymphocytes and chimerism analysis post hematopoietic stem cell transplantation (HSCT). Treg subsets, LRBA and CTLA4 expression levels were measured by flow-cytometric analysis. A nineteen-year-old female patient from a consanguine background underwent unconditioned matched sibling related HSCT during infancy due to clinical presentation of SCID with an Omenn phenotype. At that time her underlying genetic defect was not defined. Years after HSCT, severe auto-immune phenomena were noted, including a systemic lupus erythematosus-like syndrome and ophthalmic manifestations. Genetic evaluation revealed bi-allelic homozygous mutations in RAG-2 (c.685C>T, p.Arg229Trp) and a previously undescribed mutation in LRBA (c.3325G>T, p.Asp1109Tyr). LRBA and CTLA4 expression levels were normal, suggesting that the LRBA variant identified in these kindred is unlikely to be pathogenic. Multiple genetic defects causing complex IEIs may be identified in the same individual in highly consanguineous populations. Functional immunological testing is essential for evaluation of novel genetic variants.

Heterozygous DSP in-frame deletion in a poodle with syndromic ichthyosis involving additional hair and tooth abnormalities.

Ichthyoses comprise a large heterogeneous group of skin disorders, characterized by generalized scaly and hyperkeratotic skin. We investigated a miniature poodle with early onset generalized scaling, dry and irregularly thickened skin, paw pad hyperkeratosis and abnormalities in hair and teeth. The clinical signs of ichthyosis were confirmed by histopathological examination, which revealed mild epidermal hyperplasia and lamellar orthokeratotic hyperkeratosis. A hereditary condition was suspected and a genetic investigation was initiated. We sequenced the whole genome of the affected dog and searched for potentially causative variants in functional candidate genes for the observed phenotype. The analysis revealed a heterozygous in-frame deletion in DSP, NC_049256.1:g.8804542_8804544del resulting from a de novo mutation event as evidenced by genotyping leukocyte DNA from both parents. The 3 bp deletion is predicted to remove one aspartic acid without disrupting the open reading frame (XM_038584124.1:c.1821_1823del, XP_038440052.1:p.(Asp608del)). The DSP gene encodes desmoplakin, a desmosomal plaque protein, responsible for cell-cell adhesion to provide resistance to mechanical stress in epidermal and cardiac tissues. We hypothesize that the deletion of one amino acid in the N-terminal globular head domain acts in a dominant negative manner and thus impairs the proper connection with other proteins. Several variants in DSP in humans and cattle have been described to result in different phenotypes associated with hair and skin abnormalities, sometimes in combination with variable cardiac and/or dental manifestations. In conclusion, we characterized a new syndromic ichthyosis phenotype in a dog and identified a de novo 3 bp deletion in the DSP gene as causal variant.

Genetic Polymorphisms of Immunity Regulatory Genes and Alopecia Areata Susceptibility in Jordanian Patients

Background and Objectives: Alopecia areata (AA) is a tissue-specific immune-mediated disorder that affects hair follicles and the nail apparatus. Due to the collapse of hair follicle immune privilege in AA, hair loss ranges in severity from small, localized patches on the scalp to the loss of entire body hair. Although AA is of uncertain etiology, the disease has a common genetic basis with a number of other autoimmune diseases. Materials and Methods: To identify candidate genes that confer susceptibility to AA in the Jordanian population and further understand the disease background, we performed DNA genotyping using case–control samples of 152 patients and 150 healthy subjects. Results: While no significant result was observed in the ten single-nucleotide polymorphisms (SNPs), CLEC4D rs4304840 variants showed significant associations with AA development within our cohort (p = 0.02). The strongest associations were for the codominant and recessive forms of rs4304840 (p = 0.023 and p = 0.0061, respectively). Conclusions: These findings suggest that CLEC4D gene variants may contribute to AA pathogenesis among Jordanians. Further advanced genetic analysis and functional investigations are required to elucidate the genetic basis of the disease.

Hierarchical Genomic Analysis of Susceptibility to Schizophrenia in Sudanese multi-case families

Background Schizophrenia, with its diverse and complex presentation, is a prime candidate for genetic investigation. Its heritability in both familial and sporadic cases, clinical overlap with other psychiatric conditions, and individual variations in response to treatment contribute to its complexity. Numerous genes and associated biochemical pathways show significant differences at the population, familial, and individual levels. Additionally, schizophrenia may represent an evolutionary trade-off for human brain development, creativity, and intellectual performance. Material and Methods This case pseudo-control study analyzed the whole genomes/exomes of seven Sudanese families with multiple siblings affected by schizophrenia. We examined shared variants among family members, including both cases and controls, and unique variants shared between patients but not controls. These variants were filtered based on their impact on protein function, expression levels, allele frequencies, ACMG classification for rare variants, and disease associations. Networks were created to identify central genes and common biological pathways. Results and Discussion The examination of this complex disorder in Sudanese families revealed numerous variants, both common and rare, showing differences between families and between our population and those reported in the literature. This highlights the challenge of accounting for the known heritability of the disease. Our hierarchical approach demonstrates that schizophrenia’s etiology involves the cumulative effect of various interacting variants in an ascending order of influence. Common variants are shared among all samples, while rare variants are shared among two or three families, most of which are associated with schizophrenia. In conclusion The significance lies not merely in the number of detected variants but in understanding their interactive roles, step by step, to reveal the complete picture of the disease’s phenotype.

Utilizing non-invasive prenatal test sequencing data for human genetic investigation

Non-invasive prenatal testing (NIPT) employs ultra-low-pass sequencing of maternal plasma cell-free DNA to detect fetal trisomy. Its global adoption has established NIPT as a large human genetic resource for exploring genetic variations and their associations with phenotypes. Here, we present methods for analyzing large-scale, low-depth NIPT data, including customized algorithms and software for genetic variant detection, genotype imputation, family relatedness, population structure inference, and genome-wide association analysis of maternal genomes. Our results demonstrate accurate allele frequency estimation and high genotype imputation accuracy (R2>0.84) for NIPT sequencing depths from 0.1× to 0.3×. We also achieve effective classification of duplicates and first-degree relatives, along with robust principal-component analysis. Additionally, we obtain an R2>0.81 for estimating genetic effect sizes across genotyping and sequencing platforms with adequate sample sizes. These methods offer a robust theoretical and practical foundation for utilizing NIPT data in medical genetic research.

Serratia marcescens outbreak at a neonatal intensive care unit in an acute care tertiary hospital in Singapore

To report the epidemiological, diagnostic, and genetic investigation of an outbreak of neonatal patients infected or colonized with Serratia marcescens (S. marcescens) including the infection control interventions. Outbreak investigation report. 28-bedded neonatal unit in an acute care tertiary hospital in Singapore divided into three areas: two negative-pressure airborne infection isolation rooms with a shared anteroom, 10 neonatal intensive care unit (NICU) beds, and 16 high dependency beds. A total of five neonates were involved in this outbreak. Screening of in-flight patients and their immediate environment for S. marcescens to determine probable environmental sources, whole genome sequencing (WGS) analysis of resulting isolates to determine clone-relatedness and possible transmission patterns. Implementation of infection control interventions included prompt isolation of cases, enhanced equipment and environmental disinfection, use of alcohol-based hand rub as the preferred hand hygiene mode, enhanced infection prevention orientation for parents, review of practices, audits, and immediate feedback on non-compliance. Five neonates infected or colonized with S. marcescens were involved in this outbreak. Four were infection cases whilst one identified through contact tracing. Three NICU sinks and the milk preparation room sink were tested positive for S. marcescens. WGS confirmed clonality of strains from two NICU sinks, and milk preparation room sink with that of the five neonates. Multiprong strategy was required to contain this outbreak. WGS analysis showed association of biofilms in sinks with the outbreak.

Characteristics and Survival of Patients with WHO Grade 4 Diffuse Glioma in Dharmais National Referral Cancer Hospital

Background: The WHO grade 4 diffuse glioma are extremely aggressive and account for over 60% of adult Central Nervous System (CNS) tumors. The diagnosis and management pose significant challenges due to the need for comprehensive evaluation and holistic treatment approaches. This study aims to determine the clinical characteristics of WHO grade 4 diffuse glioma in Indonesia and the overall survival as a secondary goal. Methods: This is a retrospective cohort study of all WHO grade 4 glioma patients from 2017 to 2022 at Dharmais National Cancer Hospital, Jakarta, Indonesia. Demographic characteristics were presented descriptively. Kaplan-Meier plot was used to evaluate the median survival. Results: Twenty-eight patients were eligible for this study. The median age group is 45 years old, with equal male and female prevalence. Headache was the most prevalent primary symptom. The therapy following surgery was radiotherapy (RT) with chemosensitizer (82.1%) and RT alone (14.3%) with both followed by adjuvant chemotherapy. There was one patient (3.6%) underwent palliative therapy. The median survival of all patients was 10 months, whereas 10 months in RT with the chemo-sensitizer group and 1 month in RT only group. There was no statistically significant difference between RT with and without chemotherapy sensitizer in terms of survival rates. Conclusions: Our study reports a younger median age of WHO Grade 4 diffuse glioma. Male subjects were equivalent to females. Median OS was 10 months and were longer in RT with the chemosensitizer group. Further multicentered and at the genetic level investigation was needed, to achieve optimal outcomes.

Storytelling of Hypertrophic Cardiomyopathy Discovery.

The discovery of hypertrophic cardiomyopathy (HCM) dates back to 1958, when the pathologist Donald Teare of the St. George's Hospital in London performed autopsies in eight cases with asymmetric hypertrophy of the ventricular septum and bizarre disorganization (disarray) at histology, first interpreted as hamartoma. Seven had died suddenly. The cardiac specimens were cut along the long axis, similar to the 2D echo. In the same year, at the National Institute of Health U.S.A., Eugene Braunwald, a hemodynamist, and Andrew Glenn Morrow, a cardiac surgeon, clinically faced a patient with an apparently similar morbid entity, with a systolic murmur and subaortic valve gradient. "Discrete" subaortic stenosis was postulated. However, at surgery, Dr. Morrow observed only hypertrophy and performed myectomy to relieve the obstruction. This first Braunwald-Morrow patient underwent a successful cardiac transplant later at the disease end stage. The same Dr. Morrow was found to be affected by the familial HCM and died suddenly in 1992. The term "functional subaortic stenosis" was used in 1959 and "idiopathic hypertrophic subaortic stenosis" in 1960. Years before, in 1957, Lord Brock, a cardiac surgeon at the Guy's Hospital in London, during alleged aortic valve surgery in extracorporeal circulation, did not find any valvular or discrete subaortic stenoses. In 1980, John F. Goodwin of the Westminster Hospital in London, the head of an international WHO committee, put forward the first classification of heart muscle diseases, introducing the term cardiomyopathy (dilated, hypertrophic, and endomyocardial restrictive). In 1995, the WHO classification was revisited, with the addition of two new entities, namely arrhythmogenic and purely myocardial restrictive, the latter a paradox of a small heart accounting for severe congestive heart failure by ventricular diastolic impairment. A familial occurrence was noticed earlier in HCM and published by Teare and Goodwin in 1960. In 1989-1990, the same family underwent molecular genetics investigation by the Seidman team in Boston, and a missense mutation of the β-cardiac myosin heavy chain in chromosome 14 was found. Thus, 21 years elapsed from HCM gross discovery to molecular discoveries. The same original family was the source of both the gross and genetic explanations of HCM, which is now named sarcomere disease. Restrictive cardiomyopathy, characterized grossly without hypertrophy and histologically by myocardial disarray, was found to also have a sarcomeric genetic mutation, labeled "HCM without hypertrophy". Sarcomere missense mutations have also been reported in dilated cardiomyopathy (DCM) and non-compaction cardiomyopathy. Moreover, sarcomeric gene defects have been detected in some DNA non-coding regions of HCM patients. The same mutation in the family may express different phenotypes (HCM, DCM, and RCM). Large ischemic scars have been reported by pathologists and are nowadays easily detectable in vivo by cardiac magnetic resonance with gadolinium. The ischemic arrhythmic substrate enhances the risk of sudden death.

Clinical characteristics of gastrointestinal stromal tumors with hypoglycemia.

The development of tyrosine-kinase inhibitors has improved survival rates for patients with gastrointestinal stromal tumors (GISTs). Despite the progress, not all the patients can universally receive the benefit from treatment due to the individual underlying conditions in a real-world setting. The present study focused on the well-known but understudied condition of GIST with hypoglycemia. Hypoglycemia in GIST is characterized by hypoglycemic symptoms such as dizziness, sweating and confusion. It is caused by several factors such as multiple liver metastases, drug adverse effects, postoperative complications and paraneoplastic syndrome [non-islet cell tumor hypoglycemia (NICTH)]. Comprehensive analysis of this condition has been hindered due to its rarity, and has been mostly limited to case reports. In the present study, a single-institution retrospective analysis of GIST with hypoglycemia was conducted to investigate its prevalence and prognosis, and the cause of this condition. The present study identified that the prevalence of hypoglycemic episodes of GIST was 4.1% in all patients with GIST, and recurrent hypoglycemic cases had a poor prognosis. The present study identified 1 case with recurrent hypoglycemia due to NICTH. Since NICTH is a rare hypoglycemic cause and requires further evaluation, an autopsy and genetic sequencing were performed using the available clinical materials. Through this histological and genetic investigation, the histological diversity of NICTH-GIST was revealed and insulin-like growth factor II (IGF-II) amplification was identified. Furthermore, a chronological analysis was performed using multiple resected archived samples from the same case, and revealed that diffuse IGF-II expression may have occurred in the early phase of tumor development. The present study catalogued the characteristics of GIST with hypoglycemia with a focus on NICTH-GIST.

The Kids Heart BioBank: supporting 20 years of patient care and research into CHD.

The cause of most CHD is unknown and considered complex, implicating genetic and environmental factors in disease causation. The Kids Heart BioBank was established in 2003 to accelerate genetic investigations into CHD. Recruitment includes patients undergoing interventions for CHD at The Children's Hospital at Westmead. Informed consent is obtained from parents/guardians, and blood is collected at the time of cardiac intervention from which DNA is extracted and stored. Associated detailed clinical information and a family history are stored in the purpose-designed database. To date, the Kids Heart BioBank contains biospecimens and associated clinical information from over 4,900 patients with CHD and their families. Two-thirds (64.1%) of probands have been included in research studies with 28.9% of participants who underwent genomic sequencing receiving a molecular diagnosis with direct clinical utility. The value of this resource to patients and families is highlighted by the high consent rate (94.6%) and the low withdrawal of consent rate (0.4%). The Kids Heart BioBank has supported many large national and international collaborations and contributed significantly to CHD research. The Kids Heart BioBank is an invaluable resource and, together with other similar resources, the resulting research has paved the way for clinical genetic testing options for CHD patients, previously not possible. With research in the field moving away from diagnosing monogenic disease, the Kids Heart BioBank is ideally placed to support the next chapter of research efforts into complex disease mechanisms, requiring large patient cohorts with detailed phenotypic information.

Antenatal unilateral upper limb acromesomelic dysplasia.

Acromesomelic dysplasia (AMD) is an umbrella term given to a heterogeneous group of progressive skeletal disorders characterized by short limbed dwarfism associated with disproportionate shortening of middle and distal segments of the upper as well as lower limbs. Although specific skeletal anomalies are difficult to diagnose antenatally, but because of their antenatal and postnatal implications and a possibility of reoccurrence in following pregnancies, such skeletal anomalies need to be actively addressed. A combination of radiologic, pathologic, genetic and molecular investigation prenatally as well as postnatally is required to classify a specific congenital skeletal dysplasia. Once the genetic make-up of fetal skeletal dysplasia is deciphered, a meaningful genetic counselling could be offered for future pregnancies of affected families. We describe a case of primigravida diagnosed with fetal unilateral upper limb AMD on antenatal ultrasound done at early second trimester. The radius and ulna of left upper limb were abnormally short (less than 5th centile of the mean for that gestational age). The left hand was also hypoplastic. Rest of the sonographic anomaly scan was normal. To the best of our knowledge, AMD limited to unilateral upper limb diagnosed antenatally as an isolated finding is not described in the medical literature so far.

Taxonomic identification of Nigerian Terminalia superba and Terminalia ivorensis Combretaceae) using AFLP molecular markers

Terminalia superba and T. ivorensis are difficult to identify with morphological markers. Molecular characterization is very effective to correct the delimitation of timber species, especially when the discriminatory power of morphological markers is weak. In this study, four amplified fragment length polymorphism (AFLP) marker combinations were used to determine the taxonomic relationship among a total of 33 accessions of the genus Terminalia, consisting of two species, Terminalia ivorensis (12 accessions) and T. superba (21). The primer combinations produced a total of 740 fragments out of which 619 (83.6%) were polymorphic. Among all the primer combinations used, E-ACT/M-CTC was the most informative, which generated 11 unique markers for clear identification of the two species. The average polymorphic information content (PIC) ranged from 0.24 (E-ACT/M-CAT) to 0.28 (E-ACT/M-CTC) while the resolving power (RP) varied from 40.73 (E-AAC/M-CTA) to 63.76 (E-ACT/M-CTC). The genetic difference between the two species was significant (PhiPT = 0.610, p<0.001). All 33 accessions were delimited by both the UPGMA cluster and principal component analysis. Based on the results, it was concluded that E-ACT/M-CTC is the best among the marker combinations used for molecular study of the two tree species and used significantly to distinguish them. STRUCTURE analysis identified two accessions of Terminalia superba with alleles derived from T. ivorensis as well as revealed five putative hybrid accessions, which requires further genetic investigation to substantiate the finding.

Estimation of Heterosis for Plant Growth, Oil Content and Yield Related Traits in Indian Mustard [Brassica juncea (L.) Czern and Coss] Using Half Diallel

Genetic investigation was carried out diallel design for heterosis analysis studies the experimental material comprised with eight parents with two checks was carried out to identify high heterotic crosses and their relationship in Indian mustard. Several hybrids exhibited heterobeltiosis and standard heterosis for seed yield per plant and other characters. The heterosis analysis revealed substantial hybrid vigor across 28 hybrid crosses, with noteworthy improvements in traits such as earlier flowering, earlier maturity, and increased seed weight. The seed yield per plant exhibited better parent heterosis ranging from -20.71% to 16.28%, with five crosses yielding more seeds than their better parents. P3 (PM-22) X P8 (RH-749) was the best cross, with a 16.28% increase. Standard heterosis ranged from -38.72% to 35.14%, with ten crosses showing significant positive heterosis. The findings from this investigation provide crucial insights into the genetic performance and breeding potential of Indian mustard genotypes. The identified parental lines and cross combinations with desirable heterosis effects offer valuable resources for breeding programs aimed at developing high-yielding and resilient mustard varieties, contributing to the advancement of agricultural practices and crop improvement. The above best parent and best crosses can be used in hybridization and heterosis breeding respectively.

Genetic investigations on singleton school aged children reveal novel variants and new candidate genes for hearing loss

Hearing loss affects around 5% of the global population. Two preliminary studies have described genetic variants in sporadic individuals with hearing loss from Pakistan. Here we extend these studies to determine the spectrum of variants in a cohort of individuals with no previous history of hearing loss. Individuals with hearing loss born to consanguineous couples were identified from special schools. Audiograms were assessed. DNA from participants negative for GJB2 pathogenic variants was subjected to exome sequencing. Data were filtered to include variants with frequencies < 0.01 in the public databases. The effects of the missense variants on respective amino acids were analyzed by using PyMol software. Among the 44 participants, hearing loss was moderate for two individuals; 14 exhibited moderately-severe hearing loss while 25 had a severe degree of hearing loss. Hearing loss was reported to have been progressive in four participants and was currently profound in three participants. Variants were unambiguously identified in 17 genes, of which the majority affected SLC26A4. CDH23, MYO15A and OTOF were other significant contributors. Deleterious variants detected in two genes suggest new associations for hearing loss. Molecular characterization of hearing loss in our cohort revealed high genetic heterogeneity with a 75% diagnostic rate.

An observational and genetic investigation into the association between psoriasis and risk of malignancy

The relationship between psoriasis and site-specific cancers remains unclear. Here, we aim to investigate whether psoriasis is causally associated with site-specific cancers. We use observational and genetic data from the UK Biobank, obtaining GWAS summary data, eQTL analysis data, TCGA data, and GTEx data from public datasets. We perform PheWAS, polygenic risk score analysis, and one-sample and two-sample Mendelian randomization analyses to investigate the potential causal associations between psoriasis and cancers. In the unselected PheWAS analysis, psoriasis is associated with higher risks of 16 types of cancer. Using one-sample Mendelian randomization analyses, it is found that genetically predicted psoriasis is associated with higher risks of anal canal cancer, breast cancer, follicular non-Hodgkin’s lymphoma and nonmelanoma skin cancer in women; and lung cancer and kidney cancer in men. Our two-sample Mendelian randomization analysis indicates that psoriasis is causally associated with breast cancer and lung cancer. Gene annotation shows that psoriasis-related genes, such as ERAP1, are significantly different in lung and breast cancer tissues. Taken together, clinical attention to lung cancer and breast cancer may be warranted among patients with psoriasis.

Polymorphic microsatellite markers for genetic analysis of Berkeleyomyces rouxiae, a causal agent of black root rot

AbstractBerkeleyomyces rouxiae, a soil-borne fungal pathogen, causes black root rot on various plant species including carrot, okra, tobacco, lettuce, and other important crops. Here we analyzed the entire genome sequence of a Japanese isolate of B. rouxiae and discovered 25 microsatellite sequences. These sequences were amplified from the genomic DNA of several Japanese isolates by PCR and sequenced, revealing that the microsatellite sequences were polymorphic among isolates. These markers are useful for phylogenetic analysis, epidemiological population analysis, identification of specific isolates, and other genetic investigation of B. rouxiae.

Helsmoortel-Van der Aa syndrome in a 13-year-old girl with autistic spectrum disorder, dysmorphism, a right solitary kidney, and polycystic ovaries: a case report

BackgroundHelsmoortel-Van der Aa syndrome was officially documented in 2014. Helsmoortel-Van der Aa syndrome is an extremely rare complex neurodegenerative disorder characterized by reduced intellectual capacity, motor dysfunction, facial dysmorphism, impaired development, and an increased predisposition to autism spectrum disorder. In addition, many patients also present with neuropsychiatric disorders, including attention deficit hyperactivity disorder, anxiety disorders, and various behavioral abnormalities. Helsmoortel-Van der Aa syndrome is challenging to identify solely on the basis of symptoms, and genetic investigations, including exome sequencing, may facilitate diagnosis.Case presentationWe report a case of 13-year-old Saudi patient who presented with dysmorphic features as illustrated in Fig. 1, severe intellectual disability, autism spectrum disorder, and attention deficit hyperactivity disorder. Initial genetic testing was unremarkable; thus, a clinical exome analysis was performed to identify the genetic basis of the condition.ConclusionsClinical exome analysis indicated an autosomal dominant Helsmoortel-Van der Aa syndrome with a likely pathogenic de novo variant within the activity-dependent neuroprotector homeobox (ADNP) gene not previously reported in Helsmoortel-Van der Aa syndrome. The patient had a right-sided solitary kidney and polycystic ovaries, conditions that were not previously associated with HVDAS.

Deciphering genetic and nongenetic factors underlying tumour dormancy: insights from multiomics analysis of two syngeneic MRD models of melanoma and leukemia

BackgroundTumour dormancy, a resistance mechanism employed by cancer cells, is a significant challenge in cancer treatment, contributing to minimal residual disease (MRD) and potential relapse. Despite its clinical importance, the mechanisms underlying tumour dormancy and MRD remain unclear. In this study, we employed two syngeneic murine models of myeloid leukemia and melanoma to investigate the genetic, epigenetic, transcriptomic and protein signatures associated with tumour dormancy. We used a multiomics approach to elucidate the molecular mechanisms driving MRD and identify potential therapeutic targets.ResultsWe conducted an in-depth omics analysis encompassing whole-exome sequencing (WES), copy number variation (CNV) analysis, chromatin immunoprecipitation followed by sequencing (ChIP-seq), transcriptome and proteome investigations. WES analysis revealed a modest overlap of gene mutations between melanoma and leukemia dormancy models, with a significant number of mutated genes found exclusively in dormant cells. These exclusive genetic signatures suggest selective pressure during MRD, potentially conferring resistance to the microenvironment or therapies. CNV, histone marks and transcriptomic gene expression signatures combined with Gene Ontology (GO) enrichment analysis highlighted the potential functional roles of the mutated genes, providing insights into the pathways associated with MRD. In addition, we compared “murine MRD genes” profiles to the corresponding human disease through public datasets and highlighted common features according to disease progression. Proteomic analysis combined with multi-omics genetic investigations, revealed a dysregulated proteins signature in dormant cells with minimal genetic mechanism involvement. Pathway enrichment analysis revealed the metabolic, differentiation and cytoskeletal remodeling processes involved in MRD. Finally, we identified 11 common proteins differentially expressed in dormant cells from both pathologies.ConclusionsOur study underscores the complexity of tumour dormancy, implicating both genetic and nongenetic factors. By comparing genomic, transcriptomic, proteomic, and epigenomic datasets, our study provides a comprehensive understanding of the molecular landscape of minimal residual disease. These results provide a robust foundation for forthcoming investigations and offer potential avenues for the advancement of targeted MRD therapies in leukemia and melanoma patients, emphasizing the importance of considering both genetic and nongenetic factors in treatment strategies.Graphical