DECIPHER: Improving Genetic Diagnosis Through Dynamic Integration of Genomic and Clinical Data.

DECIPHER (Database of Genomic Variation and Phenotype in Humans Using Ensembl Resources) shares candidate diagnostic variants and phenotypic data from patients with genetic disorders to facilitate research and improve the diagnosis, management, and therapy of rare diseases. The platform sits at the boundary between genomic research and the clinical community. DECIPHER aims to ensure that the most up-to-date data are made rapidly available within its interpretation interfaces to improve clinical care. Newly integrated cardiac case-control data that provide evidence of gene-disease associations and inform variant interpretation exemplify this mission. New research resources are presented in a format optimized for use by a broad range of professionals supporting the delivery of genomic medicine. The interfaces within DECIPHER integrate and contextualize variant and phenotypic data, helping to determine a robust clinico-molecular diagnosis for rare-disease patients, which combines both variant classification and clinical fit. DECIPHER supports discovery research, connecting individuals within the rare-disease community to pursue hypothesis-driven research.

Recent Therapeutic Gene Editing Applications to Genetic Disorders.

Recent years have witnessed unprecedented progress in therapeutic gene editing, revolutionizing the approach to treating genetic disorders. In this comprehensive review, we discuss the progression of milestones leading to the emergence of the clustered regularly interspaced short palindromic repeats (CRISPR)-based technology as a powerful tool for precise and targeted modifications of the human genome. CRISPR-Cas9 nuclease, base editing, and prime editing have taken center stage, demonstrating remarkable precision and efficacy in targeted ex vivo and in vivo genomic modifications. Enhanced delivery systems, including viral vectors and nanoparticles, have further improved the efficiency and safety of therapeutic gene editing, advancing their clinical translatability. The exploration of CRISPR-Cas systems beyond the commonly used Cas9, such as the development of Cas12 and Cas13 variants, has expanded the repertoire of gene editing tools, enabling more intricate modifications and therapeutic interventions. Outstandingly, prime editing represents a significant leap forward, given its unparalleled versatility and minimization of off-target effects. These innovations have paved the way for therapeutic gene editing in a multitude of previously incurable genetic disorders, ranging from monogenic diseases to complex polygenic conditions. This review highlights the latest innovative studies in the field, emphasizing breakthrough technologies in preclinical and clinical trials, and their applications in the realm of precision medicine. However, challenges such as off-target effects and ethical considerations remain, necessitating continued research to refine safety profiles and ethical frameworks.

The metabolic basis of inherited neutropenias.

Neutrophils are the shortest-lived blood cells, which requires a prodigious degree of proliferation and differentiation to sustain physiologically sufficient numbers and be poised to respond quickly to infectious emergencies. More than 107 neutrophils are produced every minute in an adult bone marrow-a process that is tightly regulated by a small group of cytokines and chemical mediators and dependent on nutrients and energy. Like granulocyte colony-stimulating factor, the primary growth factor for granulopoiesis, they stimulate signalling pathways, some affecting metabolism. Nutrient or energy deficiency stresses the survival, proliferation, and differentiation of neutrophils and their precursors. Thus, it is not surprising that monogenic disorders related to metabolism exist that result in neutropenia. Among these are pathogenic mutations in HAX1, G6PC3, SLC37A4, TAFAZZIN, SBDS, EFL1 and the mitochondrial disorders. These mutations perturb carbohydrate, lipid and/or protein metabolism. We hypothesize that metabolic disturbances may drive the pathogenesis of a subset of inherited neutropenias just as defects in DNA damage response do in Fanconi anaemia, telomere maintenance in dyskeratosis congenita and ribosome formation in Diamond-Blackfan anaemia. Greater understanding of metabolic pathways in granulopoiesis will identify points of vulnerability in production and may point to new strategies for the treatment of neutropenias.

Biallelic hypomorphic variants in CAD cause uridine-responsive macrocytic anaemia with elevated haemoglobin-A2.

Biallelic pathogenic variants in CAD, that encode the multienzymatic protein required for de-novo pyrimidine biosynthesis, cause early infantile epileptic encephalopathy-50. This rare disease, characterized by developmental delay, intractable seizures and anaemia, is amenable to treatment with uridine. We present a patient with macrocytic anaemia, elevated haemoglobin-A2 levels, anisocytosis, poikilocytosis and target cells in the blood smear, and mild developmental delay. A next-generation sequencing panel revealed biallelic variants in CAD. Functional studies did not support complete abrogation of protein function; however, the patient responded to uridine supplement. We conclude that biallelic hypomorphic CAD variants may cause a primarily haematological phenotype.

GATA2 deficiency syndrome: A compensatory mechanism gone awry?

In their paper, using zebrafish models, Gioacchino et al. have demonstrated the GATA2 haploinsufficiency, the genetic hallmark of GATA2 deficiency syndrome, promotes erythroid and myeloid cytopenia, and have discovered a self-regulatory mechanism to compensate GATA2 levels and protein function. Commentary on: Gioacchino et al. GATA2 heterozygosity causes an epigenetic feedback mechanism resulting in myeloid and erythroid dysplasia. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19585.

Comparative analysis of the diversity of trinucleotide repeats in bacterial genomes.

The human gut is the most favorable niche for microbial populations, and few studies have explored the possibilities of horizontal gene transfer between host and pathogen. Trinucleotide repeat (TNR) expansion in humans can cause more than 40 neurodegenerative diseases. Further, TNRs are a type of microsatellite that resides on coding regions can contribute to the synthesis of homopolymeric amino acids. Hence, the present study aims to estimate the occurrence and diversity of TNRs in bacterial genomes available in the NCBI Genome database. Genome-wide analyses revealed that several bacterial genomes contain different types of uninterrupted TNRs. It was found that TNRs are abundant in the genomes of Alcaligenes faecalis, Mycoplasma gallisepticum, Mycoplasma genitalium, Sorangium cellulosum, and Thermus thermophilus. Interestingly, the genome of Bacillus thuringiensis strain YBT-1518 contained 169 uninterrupted ATT repeats. The genome of Leclercia adecarboxylata had 46 uninterrupted CAG repeats, which potentially translate into polyglutamine. In some instances, the TNRs were present in genes that potentially encode essential functions. Similar occurrences in human genes are known to cause genetic disorders. Further analysis of the occurrence of TNRs in bacterial genomes is likely to provide a better understanding of mismatch repair, genetic disorders, host-pathogen interaction, and homopolymeric amino acids.

DOK7 congenital myasthenic syndrome: case series and review of literature.

BACKGROUND: Congenital myasthenic syndromes (CMS) are among the most challenging differential diagnoses in the neuromuscular domain, consisting of diverse genotypes and phenotypes. A mutation in the Docking Protein 7 (Dok-7) is a common cause of CMS. DOK7 CMS requires different treatment than other CMS types. Regarding DOK7's special considerations and challenges ahead of neurologists, we describe seven DOK7 patients and evaluate their response to treatment. METHODS: The authors visited these patients in the neuromuscular clinics of Tehran and Kerman Universities of Medical Sciences Hospitals. They diagnosed these patients based on clinical findings and neurophysiological studies, which Whole Exome Sequencing confirmed. For each patient, we tried unique medications and recorded the clinical response. RESULTS: The symptoms started from birth to as late as the age of 33, with the mean age of onset being 12.5. Common symptoms were: Limb-girdle weakness in 6, fluctuating symptoms in 5, ptosis in 4, bifacial weakness in 3, reduced extraocular movement in 3, bulbar symptoms in 2 and dyspnea in 2 3-Hz RNS was decremental in 5 out of 6 patients. Salbutamol was the most effective. c.1124_1127dupTGCC is the most common variant; three patients had this variant. CONCLUSION: We strongly recommend that neurologists consider CMS in patients with these symptoms and a similar familial history. We recommend prescribing salbutamol as the first-choice treatment option for DOK7 patients.

Dual inhibition of the endothelin and angiotensin receptor ameliorates renal and inner ear pathologies in Alport mice.

Alport syndrome (AS), a type IV collagen disorder, leads to glomerular disease and, in some patients, hearing loss. AS is treated with inhibitors of the renin-angiotensin system; however, a need exists for novel therapies, especially those addressing both major pathologies. Sparsentan is a single-molecule dual endothelin type-A and angiotensin II type 1 receptor antagonist (DEARA) under clinical development for focal segmental glomerulosclerosis and IgA nephropathy. We report the ability of sparsentan to ameliorate both renal and inner ear pathologies in an autosomal-recessive Alport mouse model. Sparsentan significantly delayed onset of glomerulosclerosis, interstitial fibrosis, proteinuria, and glomerular filtration rate decline. Sparsentan attenuated glomerular basement membrane defects, blunted mesangial filopodial invasion into the glomerular capillaries, increased lifespan more than losartan, and lessened changes in profibrotic/pro-inflammatory gene pathways in both the glomerular and the renal cortical compartments. Notably, treatment with sparsentan, but not losartan, prevented accumulation of extracellular matrix in the strial capillary basement membranes in the inner ear and reduced susceptibility to hearing loss. Improvements in lifespan and in renal and strial pathology were observed even when sparsentan was initiated after development of renal pathologies. These findings suggest that sparsentan may address both renal and hearing pathologies in Alport syndrome patients. © 2023 Travere Therapeutics, Inc and The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Adverse pregnancy outcome in fetuses with early increased nuchal translucency: prospective cohort study.

OBJECTIVES: An increased nuchal translucency (NT) ≥3.5mm is a well-established marker for congenital anomalies and adverse pregnancy outcome between 11 and 14 weeks of gestation. Little is known about its performance as a screening tool before 11 weeks of gestation. We aimed to investigate in a prospective setting whether fetuses with an increased NT before 11 weeks of gestation are at risk for an adverse pregnancy outcome. METHODS: This is a prospective cohort study including pregnant women with a viable fetus with a NT≥2.5mm and a crown-rump-length (CRL) <45mm. All women were referred to our fetal medicine unit (FMU) and scheduled for a follow-up scan where the NT was remeasured after one week when the CRL was >45mm. Two groups were evaluated: cases with a normalized NT(<3.5mm) and cases with a persistently increased NT (≥3.5mm). We monitored the cases until four weeks after delivery. The main outcome was a composite adverse outcome of aneuploidies, other genetic disorders, structural anomalies and pregnancy loss. We performed subgroup analyses of NT thickness at inclusion and normalized or persistently increased NT at follow-up. RESULTS: We included 109 cases of which 35.8% (39/109) had an adverse pregnancy outcome. Of these 64.1% (25/39) were aneuploidies which corresponds to 22.9% (25/109) aneuploidies in total. The subgroups of NT thickness at inclusion of 2.5-3.4, 3.5-4.4 and ≥4.5mm showed abnormal outcomes in 22.0% (9/41), 40.0% (18/45), 52.2% (12/23) respectively. In fetuses with a normalized NT and without ultrasound abnormalities at follow-up scan, the incidence of adverse outcome was 8.5% (5/59), of which 5.1% (3/59) were aneuploidies. CONCLUSION: Fetuses with an early increased NT thickness are at considerable risk of an adverse pregnancy outcome, even if the NT normalizes after 11 weeks. Not all congenital anomalies can be diagnosed with routine first-trimester screening such as non-invasive prenatal testing and/or a first-trimester anomaly scan. Therefore, expectant parents should always be referred to a FMU for detailed ultrasonography. Invasive prenatal testing should be offered if an increased nuchal translucency of ≥2.5mm is observed before 11 weeks of gestation. This article is protected by copyright. All rights reserved.

Whole-exome sequencing as the first-tier test for patients in neonatal intensive care unit: a Chinese single-center study.

BACKGROUND: Genetic disorders significantly affect patients in neonatal intensive care units, where establishing a diagnosis can be challenging through routine tests and supplementary examinations. Whole-exome sequencing offers a molecular-based approach for diagnosing genetic disorders. This study aimed to assess the importance of whole-exome sequencing for neonates in intensive care through a retrospective observational study within a Chinese cohort. METHODS: We gathered data from neonatal patients at Tianjin Children's Hospital between January 2018 and April 2021. These patients presented with acute illnesses and were suspected of having genetic disorders, which were investigated using whole-exome sequencing. Our retrospective analysis covered clinical data, genetic findings, and the correlation between phenotypes and genetic variations. RESULTS: The study included 121 neonates. Disorders affected multiple organs or systems, predominantly the metabolic, neurological, and endocrine systems. The detection rate for whole-exome sequencing was 52.9% (64 out of 121 patients), identifying 84 pathogenic or likely pathogenic genetic variants in 64 neonates. These included 13 copy number variations and 71 single-nucleotide variants. The most frequent inheritance pattern was autosomal recessive (57.8%, 37 out of 64), followed by autosomal dominant (29.7%, 19 out of 64). In total, 40 diseases were identified through whole-exome sequencing. CONCLUSION: This study underscores the value and clinical utility of whole-exome sequencing as a primary diagnostic tool for neonates in intensive care units with suspected genetic disorders. Whole-exome sequencing not only aids in diagnosis but also offers significant benefits to patients and their families by providing clarity in uncertain diagnostic situations.

Why do individuals with Williams syndrome or Down syndrome fail the Weather Prediction Task?

Williams syndrome (WS) and Down syndrome (DS) are two neurodevelopmental disorders with distinct genetic origins characterized by mild to moderate intellectual disability. Individuals with WS or DS exhibit impaired hippocampus-dependent place learning and enhanced striatum-dependent spatial response learning. Here, we used the Weather Prediction Task (WPT), which can be solved using hippocampus- or striatum-dependent learning strategies, to determine whether individuals with WS or DS exhibit similar profiles outside the spatial domain. Only 10% of individuals with WS or DS solved the WPT. We further assessed whether a concurrent memory task could promote reliance on procedural learning to solve the WPT in individuals with WS but found that the concurrent task did not improve performance. To understand how the probabilistic cue-outcome associations influences WPT performance, and whether individuals with WS or DS can ignore distractors, we assessed performance using a visual learning task with differing reward contingencies, and a modified WPT with unpredictive cues. Both probabilistic feedback and distractors negatively impacted the performance of individuals with WS or DS. These findings are consistent with deficits in hippocampus-dependent learning and executive functions, and reveal the importance of congruent feedback and the minimization of distractors to optimize learning in these two populations.

First case report of a successful delivery of a healthy boy by preimplantation genetic testing for Beckwith-Wiedemann syndrome.

PURPOSE: To showcase the successful use of ICSI with PGT-M to overcome Beckwith-Wiedemann syndrome (BWS)-related reproductive challenges, resulting in the birth of a healthy baby boy. By targeting the maternally inherited CDKN1C pathogenic gene variant, this report highlights the genetic interventions in BWS reproductive risk management. METHODS: This case report describes a 41-year-old woman seeking fertility assistance after a previous pregnancy revealed a fetal anomaly related to BWS. Families with BWS recurrence face challenges, as maternally inherited CDKN1C pathogenic variants contribute to approximately 40% of genetic alterations, with a potential recurrence risk as high as 50%. Genetic analysis identified a pathogenic variant in the CDKN1C gene of the fetus that was maternally inherited. The pregnancy was terminated due to the fetal anomalies. The couple underwent intra-cytoplasmic sperm injection (ICSI) combined with preimplantation genetic testing for monogenic diseases (PGT-M) and preimplantation genetic testing for aneuploidy (PGT-A). RESULTS: Two embryos from IVF with low-risk PGT-M and euploid status. One transferred via frozen embryo transfer (FET) in February 2023 resulted in the successful birth of a healthy baby boy. This study reports the first successful delivery of a healthy boy after PGT-M for the CDKN1C gene variant c.79_100delinsGTGACC, contributing to the limited literature on successful outcomes for BWS. CONCLUSION: Utilizing PGT-M in combination with IVF can lead to favorable outcomes in managing BWS-associated reproductive challenges, offering insights into potential genetic interventions and successful birth.

Significant haemoglobinopathies: A guideline for screening and diagnosis: A British Society for Haematology Guideline: A British Society for Haematology Guideline.

Antenatal screening/testing of pregnant women should be carried out according to the guidelines of the National Health Service (NHS) Sickle Cell and Thalassaemia Screening Programme. Newborn screening and, when necessary, follow-up testing and referral, should be carried out according to the guidelines of the NHS Sickle Cell and Thalassaemia Screening Programme. All babies under 1 year of age arriving in the United Kingdom should be offered screening for sickle cell disease (SCD). Preoperative screening for SCD should be carried out in patients from ethnic groups in which there is a significant prevalence of the condition. Emergency screening with a sickle solubility test must always be followed by definitive analysis. Laboratories performing antenatal screening should utilise methods that are capable of detecting significant variants and are capable of quantitating haemoglobins A2 and F at the cut-off points required by the national antenatal screening programme. The laboratory must ensure a provisional report is available for antenatal patients within three working days from sample receipt.

Phenotypic presentation of Mendelian disease across the diagnostic trajectory in electronic health records.

PURPOSE: To investigate the phenotypic presentation of Mendelian disease across the diagnostic trajectory in the electronic health record (EHR). METHODS: We applied a conceptual model to delineate the diagnostic trajectory of Mendelian disease to the EHRs of patients affected by 1 of 9 Mendelian diseases. We assessed data availability and phenotype ascertainment across the diagnostic trajectory using phenotype risk scores and validated our findings via chart review of patients with hereditary connective tissue disorders. RESULTS: We identified 896 individuals with genetically confirmed diagnoses, 216 (24%) of whom had fully ascertained diagnostic trajectories. Phenotype risk scores increased following clinical suspicion and diagnosis (P < 1 × 10-4, Wilcoxon rank sum test). We found that of all International Classification of Disease-based phenotypes in the EHR, 66% were recorded after clinical suspicion, and manual chart review yielded consistent results. CONCLUSION: Using a novel conceptual model to study the diagnostic trajectory of genetic disease in the EHR, we demonstrated that phenotype ascertainment is, in large part, driven by the clinical examinations and studies prompted by clinical suspicion of a genetic disease, a process we term diagnostic convergence. Algorithms designed to detect undiagnosed genetic disease should consider censoring EHR data at the first date of clinical suspicion to avoid data leakage.

Economic evaluation of next-generation sequencing techniques in diagnosis of genetic disorders: A systematic review.

In recent years, massively parallel sequencing or next generation sequencing (NGS) has considerably changed both the research and diagnostic fields, and rapid developments have led to the combination of NGS techniques in clinical practice, ease of analysis, and detection of genetic mutations. This article aimed at reviewing the economic evaluation studies of the NGS techniques in the diagnosis of genetic diseases. In this systematic review, scientific databases (PubMed, EMBASE, Web of Science, Cochrane, Scopus, and CEA registry) were searched from 2005 to 2022 to identify the related literature on the economic evaluation of NGS techniques in the diagnosis of genetic diseases. Full-text reviews and data extraction were all performed by two independent researchers. The quality of all the articles included in this study was evaluated using the Checklist of Quality of Health Economic Studies (QHES). Out of 20 521 screened abstracts, 36 studies met the inclusion criteria. The mean score of the QHES checklist for the studies was 0.78 (high quality). Seventeen studies were conducted based on modeling. Cost-effectiveness analysis, cost-utility analysis, and cost-minimization analysis were done in 26 studies, 13 studies, and 1 study, respectively. Based on the available evidence and findings, exome sequencing, which is one of the NGS techniques, could have the potential to be used as a cost-effective genomic test to diagnose children with suspected genetic diseases. The results of the present study support the cost-effectiveness of exome sequencing in diagnosing suspected genetic disorders. However, the use of exome sequencing as a first- or second-line diagnostic test is still controversial. Most studies have been conducted in high-income countries, and research on the cost-effectiveness of NGS methods is recommended in low- and middle-income countries.

Combined-modality treatment for locally advanced cervical cancer in a woman with Bloom-like syndrome: A case report and review of the literature.

We report the case of a 46-year-old woman with Bloom-like syndrome affected with locally advanced cervical cancer. She was treated with induction chemotherapy and radical radiation therapy concurrent with chemotherapy (carboplatin and paclitaxel). She was able to complete treatment, but grade III toxicities were observed. The limited relevant literature is presented. We conclude that the management of patients with DNA repair deficiency is challenging for the team in charge because of the potentially high sensitivity to treatment and the lack of clear recommendations in the literature. The main objective remains to deliver the optimal treatment while reducing toxicities.

The social phenotype associated with Wiedemann-Steiner syndrome: Autistic traits juxtaposed with high social drive and prosociality.

The aim of this study was to provide a descriptive overview of the social characteristics associated with Wiedemann-Steiner syndrome (WSS). A total of 24 parents of children/adults with WSS (11F, mean age = 12.94 years, SD = 8.00) completed the Social Responsiveness Scale 2nd Edition (SRS-2); Colorado Learning Difficulties Questionnaire (CLDQ) and Strengths and Difficulties Questionnaire (SDQ). Almost half our sample reported a diagnosis of autism spectrum disorder (ASD) and 70% had intellectual disability. On the SDQ, over 90% of participants were rated in borderline/clinical ranges in Peer Problems, yet the majority fell within normal limits in Prosocial Behaviors. Most fell in the moderate/severe difficulties ranges across SRS-2 Social Cognition, Communication, and Restricted/Repetitive Behaviors scales (all >70%); whereas substantially less participants met these ranges for deficits in Social Awareness (50%) and Social Motivation (33.33%). A pattern of relatively strong prosocial skills and social drive in the context of difficulties with inflexible behaviors, social cognition, and communication was observed, regardless of gender, ASD or intellectual disability diagnosis. The social phenotype associated with WSS is characterized by some autistic features paired with unusually high social motivation and prosocial tendencies.

Anxiety in Wiedemann-Steiner syndrome.

This study examined anxiety in Wiedemann-Steiner syndrome (WSS). Eighteen caregivers and participants with WSS completed the parent- and self-report versions of the Screen for Child Anxiety Related Disorder or the adapted version of the Screen for Adult Anxiety Related Disorder. Approximately 33.33% of parents and 65% of participants with WSS rated in the clinical range for overall anxiety. Across anxiety subtypes, parents primarily indicated concerns with Separation Anxiety (72%), which was also endorsed by the majority of participants with WSS (82%). The emergent trend showed Total Anxiety increased with age based on parent-informant ratings. The behavioral phenotype of WSS includes elevated anxiety. Clinical management should include incorporating early behavioral interventions to bolster emotion regulation given the observed risk of anxiety with age.

Integrative omics approaches to advance rare disease diagnostics.

Over the past decade high-throughput DNA sequencing approaches, namely whole exome and whole genome sequencing became a standard procedure in Mendelian disease diagnostics. Implementation of these technologies greatly facilitated diagnostics and shifted the analysis paradigm from variant identification to prioritisation and evaluation. The diagnostic rates vary widely depending on the cohort size, heterogeneity and disease and range from around 30% to 50% leaving the majority of patients undiagnosed. Advances in omics technologies and computational analysis provide an opportunity to increase these unfavourable rates by providing evidence for disease-causing variant validation and prioritisation. This review aims to provide an overview of the current application of several omics technologies including RNA-sequencing, proteomics, metabolomics and DNA-methylation profiling for diagnostics of rare genetic diseases in general and inborn errors of metabolism in particular.

Individuals with Wiedemann-Steiner syndrome show nonverbal reasoning and visuospatial defects with relative verbal skill sparing.

OBJECTIVES: Wiedemann-Steiner syndrome (WSS) is a rare Mendelian disorder of the epigenetic machinery caused by heterozygous pathogenic variants in KMT2A. Currently, the specific neurocognitive profile of this syndrome remains unknown. This case series provides insight into the cognitive phenotype of WSS. METHODS: This study involves a retrospective medical chart review of 10 pediatric patients, each with a molecularly confirmed diagnosis of WSS who underwent clinical neuropsychological evaluation at an academic medical center. RESULTS: The majority of patients performed in the below average to very low ranges in Nonverbal Reasoning, Visual/Spatial Perception, Visuoconstruction, Visual Memory, Attention, Working Memory and Math Computation skills. In contrast, over half the sample performed within normal limits on Receptive Vocabulary, Verbal Memory, and Word Reading. Wilcoxon signed rank test showed weaker Nonverbal versus Verbal Reasoning skills (p = .005). Most caregivers reported deficits in executive functioning, most notably in emotion regulation. CONCLUSIONS: Nonverbal reasoning/memory, visuospatial/construction, attention, working memory, executive functioning, and math computation skills are areas of weakness among those with WSS. These findings overlap with research on Kabuki syndrome, which is caused by variants in KMT2D, and suggest disruption in the neurogenesis of the hippocampal formation may drive shared pathogenesis of the two syndromes.