International Genetics and Genomics of Diseases

Clusters of metabolic dysfunction-associated steatotic liver disease for precision medicine Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogeneous disease regarding its pathophysiology and clinical outcomes. Two novel studies suggest that different clusters of people with MASLD exist, explaining part of this heterogeneity. These findings and future research applying data dimensionality reduction approaches might be beneficial for implementing precision medicine in MASLD. The basic, translational and clinical content in Nature Reviews Gastroenterology & Hepatology is written by internationally renowned basic and clinical academics and researchers and targeted towards readers in the biological and medical sciences, from postgraduate level upwards. While intended to be read by practising doctors, researchers and academics within a specialty, we aim to make all our articles accessible to readers working in any biological or medical discipline. In-depth Revi...

Rare disease gene association discovery in the 100,000 Genomes Project Up to 80% of rare disease patients remain undiagnosed after genomic sequencing 1 , with many probably involving pathogenic variants in yet to be discovered disease–gene associations. To search for such associations, we developed a rare variant gene burden analytical framework for Mendelian diseases, and applied it to protein-coding variants from whole-genome sequencing of 34,851 cases and their family members recruited to the 100,000 Genomes Project 2 . A total of 141 new associations were identified, including five for which independent disease–gene evidence was recently published. Following in silico triaging and clinical expert review, 69 associations were prioritized, of which 30 could be linked to existing experimental evidence. The five associations with strongest overall genetic and experimental evidence were monogenic diabetes with the known β cell regulator3,4 UNC13A, schizophrenia with GPR17, epilepsy with...

Making Gene Therapy Faster And Better With Fuse Vectors Moorfields Eye Hospital in London made international headlines last week. Doctors announced they had saved the sight of four young children suffering from a rare genetic condition that rapidly causes blindness. The toddlers were treated using gene therapy, through which patients are given a harmless virus containing healthy versions of a defective gene in order to remedy the problem. “Gene therapy sounds like science fiction, but it is beginning to have a huge impact,” says Benjamin Blaha, co-founder of the gene therapy-focused Danish biotechnology start-up Fuse Vectors, which is today announcing a $5.2 million pre-seed fundraising round. “We desperately need to develop more of these treatments as quickly as possible, because they can save lives and transform patient outcomes.” Fuse hopes to play a significant role in doing exactly that. Blaha and co-founders Jordan Turnbull and Henrik Stage believe that the bottleneck for gene th...

Top in cardiology: Atherosclerosis common in lung cancer; treating amyloidosis Patients beginning lung cancer treatment demonstrated a high prevalence of atherosclerosis, which suggests that they may benefit from calcium scoring, new data showed. According to a presentation given at the American College of Cardiology’s Advancing theCardiovascular Care of the Oncology Patient course, more than three-quarters of patients entering lung cancer treatment who underwent chest CT imaging showed evidence of atherosclerosis. White patients who smoked appeared most likely to have atherosclerosis on CT out of all the subgroups examined, researchers found. “What this study confirms is that tobacco use is a shared risk factor for both diseases and at the time of lung cancer diagnosis these patients should be considered for additional evaluation by a cardiologist or cardio-oncologist, as it is likely they already have CV disease,” Christopher Malozzi, DO, director of cardio-oncology services at the U...

International Conference on Genetics and Genomics of Diseases

Rare genetic disorder treated in womb for the first time A two-and-a-half-year-old girl shows no signs of a rare genetic disorder, after becoming the first person to be treated for the motor-neuron condition while in the womb. The child’s mother took the gene-targeting drug during late pregnancy, and the child continues to take it. The “baby has been effectively treated, with no manifestations of the condition,” says Michelle Farrar, a paediatric neurologist at UNSW Sydney in Australia. The results were published in the New England Journal of Medicine yesterday. The child was conceived with a genetic condition known as spinal muscular atrophy, which affects motor neurons that control movement, and leads to progressive muscle weakening. About one in every 10,000 births have some form of the condition — making it a leading genetic cause of death in infants and children. In its most severe form, as in the case of this child, individuals lack both copies of the SMN1 gene, and have only one...

Characterizing the spectrum of mitochondrial DNA deletion disease syndromes Researchers from the Mitochondrial Medicine Program at Children's Hospital of Philadelphia (CHOP) have better characterized a spectrum of what were classically considered discrete mitochondrial DNA deletion disease syndromes. The findings offer new insights into genetic causes, potential symptoms, and disease progression, and may inform future clinical trial development. The findings were published today in the journal Genetics in Medicine. Mitochondrial disease refers to a group of disorders that affect the mitochondria, which are tiny compartments present in almost every cell of the body that generate most of our energy. Certain forms of mitochondrial disease – Pearson syndrome, Kearns-Sayre syndrome (KSS) and chronic progressive external ophthalmoplegia (CPEO) – are each caused by single large-scale mitochondrial DNA (mtDNA) deletions (SLSMD), which involve the loss of a large segment within the small DN...

Characteristic of Chromosomal Disorder Objective: Jacobsen syndrome is an infrequent contiguous gene syndrome that involves the deletion of the long arm of chromosome 11. It is mostly accompanied by intellectual disability and other abnormalities. The majority of the patients are hospitalized or lost within the first two years of life. Case(s): We report a case of a fetus at 21 weeks of gestation with Jacobsen syndrome who presented with a conotruncal cardiac defect. Amniocentesis was performed, and karyotype analysis revealed that there was a de novo deletion of chromosome 11. The family decided to terminate the pregnancy. Conclusion: Prenatal diagnosis of Jacobsen syndrome is not always possible, since the characteristic ultrasound findings vary greatly between patients. Additionally, existing symptoms and signs may not always be found with imaging techniques. However, if present, certain ultrasonographic findings should lead clinicians to consider the syndrome. The study aims to p...

From Flies to Families: How a Gene Variant May Shield Against Seizures Researchers identified a genetic modifier of PIGA-CDG, a rare disorder that results in seizures, in a family carrying the genetic mutation and in a fruit fly model. Gregor Mendel’s studies of inheritance patterns in pea plants helped shape researchers’ understanding of single-gene diseases, which can run in families. Some of the diseases that follow a Mendelian pattern include cystic fibrosis, color blindness, and rare seizure disorders such as phosphatidylinositol glycan class A congenital disorder of glycosylation (PIGA-CDG). Clement Chow, a geneticist at the University of Utah Health, and his team study the role of genetic variants on disease outcomes, especially in rare diseases. Chow focused on PIGA-CDG when he and his team noticed a family carrying the PIGA mutation where some members remained unaffected by the disease. This finding led them to search for a genetic modifier that might contribute to this observ...

Functional analysis of cancer-associated germline risk variants Single-nucleotide variants (SNVs) in regulatory DNA are linked to inherited cancer risk. Massively parallel reporter assays of 4,041 SNVs linked to 13 neoplasms comprising >90% of human malignancies were performed in pertinent primary human cell types and then integrated with matching chromatin accessibility, DNA looping and expression quantitative trait loci data to nominate 380 potentially regulatory SNVs and their putative target genes. The latter highlighted specific protein networks in lifetime cancer risk, including mitochondrial translation, DNA damage repair and Rho GTPase activity. A CRISPR knockout screen demonstrated that a subset of germline putative risk genes also enables the growth of established cancers. Editing one SNV, rs10411210, showed that its risk allele increases rhophilin RHPN2 expression and stimulus-responsive RhoA activation, indicating that individual SNVs may upregulate cancer-linked pathway...

She suspected a heart attack, but was diagnosed with broken heart syndrome If you've ever had a scary experience, when your adrenaline is pumping, as you deal with a threat or shock, you may relate to Maria Carraballo's experience. While on vacation in Puerto Rico, Carraballo, 75, was swimming with her two young grandsons, when the current began to pull them away from the shore. "I was holding the boys, trying to keep their heads above the water," she recalls. "It was such desperation," she thought they were going to drown. Fortunately, a nearby swimmer came to help, and once safely back to shore she thought the event was over. But several hours later she ended up in the emergency room with chest pain and shortness of breath. She was diagnosed with stress cardiomyopathy, also known as broken heart syndrome. You may think of a broken heart as a metaphorical idea, but this is a real condition that can bring on a sudden and dramatic weakening of the heart muscl...

Genetic heritage from the Stone Age protects against today's chronic inflammatory bowel diseases In Europe alone, approximately 2 million people live with chronic inflammatory bowel diseases (IBD), and their incidence has been rising steadily in recent decades. However, a small proportion of the European population carries a genetic variant that provides natural protection against IBD. A newly published study in the journal eBioMedicine explores how this protective variant can be leveraged to develop modern therapies, demonstrating the potential of evolutionary medicine in addressing chronic diseases of the modern era. The study, led by the Institute of Clinical Molecular Biology (IKMB) at Kiel University, brought together researchers from genetics, medicine, and archaeology. "We have demonstrated that this gene variant, which offers protection against inflammatory bowel diseases, was prevalent among the first sedentary farmers in Anatolia and was introduced to Europe through ...

Scientists uncover 'root cause' of Alzheimer's disease in breakthrough study Using a new animal model of Alzheimer’s disease, the study highlights a potential breakthrough in treatment strategies. Unlike current therapies that primarily target a single toxic protein linked to the disease, this research explores a more comprehensive approach. A research team from the Institut de Neurociències at the Universitat Autònoma de Barcelona (INc-UAB) has identified how the two primary hallmarks of Alzheimer’s disease—tau protein and beta-amyloid—affect brain circuits in distinct yet complementary ways, particularly those involved in memory and emotions. The study, conducted in collaboration with the Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED) and the Universidad Pablo de Olavide (UPO), provides new insights into the mechanisms underlying the disease. Published in Molecular Psychiatry, the research shows that tau accumulation in the hippocampus...

Yale Scientists Reprogram Genetic Code To Create Revolutionary Synthetic Organism Yale researchers have created “Ochre,” a genomically recoded organism that enables the production of synthetic proteins with novel properties, paving the way for groundbreaking applications in medicine, biotechnology, and industry. Synthetic biologists from Yale successfully rewrote the genetic code of an organism—a novel genomically recoded organism (GRO) with a single stop codon—using a cellular platform they developed that enables the production of new classes of synthetic proteins. Researchers say these synthetic proteins offer the promise of innumerable medical and industrial applications that can benefit society and human health. A new study published in the journal Nature describes the creation of the landmark GRO, known as “Ochre,” which fully compresses redundant (or “degenerate”) codons into a single codon. A codon is a sequence of three nucleotides in DNA or RNA that codes for a specific amino ...