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Studies of rare growth disorders taken together with large-scale genetic studies of adult height variability have uncovered a large genetic network regulating childhood growth. Advances in technology and experimental model systems will help decipher the molecular mechanisms of this complex network and lead to novel treatment approaches for growth disorders.

A mutation leading to ubiquitous ectopic expression of agouti signaling protein, which is not picked up in conventional genetic screenings, is reported in patients with severe childhood obesity.

Yang et al. show that neuronatin (NNAT) can explain part of the phenotypic variation of complex traits, independently of genetics or the environment. Such NNAT-dependent variations can stratify human cohorts into four metabolic sub-types, including two distinct types of obesity.

Beckwith–Wiedemann syndrome is an overgrowth disorder characterized by variable clinical phenotypes and a complex molecular aetiology. This Consensus Statement summarizes recommendations for clinical indications, molecular diagnosis and management of the newly defined Beckwith–Wiedemann spectrum.

This article is the second part of the first-ever comprehensive, two-part, consensus guideline to cover the care of children and young people under 19 years of age with pituitary adenoma. Part 2 details 57 recommendations for CYP with prolactinomas, Cushing disease, growth hormone excess, clinically non-functioning adenomas and TSHomas.

Here, the authors describe the history of the efforts to expand knowledge of Wilms tumour biology, genetics, embryonal origin and associated syndromic and familial conditions, and to clinically apply prognostic biomarkers and development of preclinical models.

This Primer summarizes the molecular mechanisms of imprinting disorders, in addition to the diagnosis and treatment of these conditions. Moreover, this Primer provides an overview of future research avenues and the effect of these disorders on patient quality of life.

The biological clock model LifeClock predicts biological age across all life stages from routine clinical data, revealing distinct pediatric and adult disease risk patterns.

In a GWAS study of 32,438 adults, the authors discovered five novel loci for intracranial volume and confirmed two known signals. Variants for intracranial volume were also related to childhood and adult cognitive function and to Parkinson's disease, and enriched near genes involved in growth pathways, including PI3K-AKT signaling.

Using the lifespan brain chart and two large-scale cross-cultural consortia (ABIDE and CABIC), we disentangle the heterogeneity of brain morphology in ASD into two structural impairment pathways that could disrupt sensory to association functions.

The mTOR pathway is a key regulator of normal brain development. Here, the authors identify de novo mutations in RHEB, an mTOR activator protein, in patients with intellectual disability associated with megalencephaly and find a role for RHEB in regulating neuronal soma size and migration in vitro and in vivo.

While hepatoblastoma is the most common pediatric liver cancer, its molecular background has not been fully characterised. Here, the authors perform genomic and epigenomic profiling of 163 untreated pediatric liver tumours and suggest the upregulation of ASCL2 and methylation patterns of IGF2 promoters in driving hepatoblast carcinogenesis.

Despite frequent AKT/mTOR pathway activation in patient’s rhabdomyosarcoma (RMS), success of AKT inhibitors in the clinical has been limited. Here, using RMS patient-derived models, the authors demonstrate that the efficacy of the AKT inhibitor, ipatasertib, is in part due to its off-target effects on PRKG1, identifying PRKG1 as a potential biomarker for ipatasertib response.

Neurodevelopmental disorders (NDDs) are a heterogeneous group of diseases for which the genetic basis is still unknown in more than half of the cases. Here, the authors report a NDD associated with disruptive variants in the TANC2 gene and show that rols, the TANC2 homolog in flies, is required for synapse growth and function.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

Adolescent idiopathic scoliosis (AIS) is characterized by spinal curvature that develops early in adolescence. Although its causes are unknown, in this Primer, Cheng and colleagues discuss various hypotheses to explain the development and progression of AIS.

Gestational diabetes mellitus (GDM) is the most common complication in pregnancy and has short-term and long-term effects in both mother and offspring. This Primer discusses the definitions of GDM, diagnosis and management of the disease and areas requiring further research.

The authors analyzed the whole-exome sequences of over 16,000 individuals and found that very rare variants predicted to disrupt the SETD1A gene confer substantial risk for schizophrenia. Damaging variants in SETD1A were also associated with diverse, severe developmental disorders, providing an important genetic link between schizophrenia and other neurodevelopmental disorders.

This flagship study from the European Solve-Rare Diseases Consortium presents a diagnostic framework including bioinformatic analysis of clinical, pedigree and genomic data coupled with expert panel review, leading to 500 new diagnoses in a cohort of 6,000 families with suspected rare diseases.

Haploinsufficiency in three genes associated with risk of autism spectrum disorder—KMT5B, ARID1B and CHD8—in cell lines from multiple donors results in cell-type-specific asynchronous development of GABAergic neurons and cortical deep-layer excitatory projection neurons.

Neonates are thought to have impaired immune responses, yet, paradoxically, they can also demonstrate hyperinflammation. Ulas et al. show that a neonatal burst of the alarmins S100A8 and S100A9 activates a distinct innate immune response without dangerous hyperinflammation.

The cardiovascular benefits of weight loss in patients with obesity are well documented. Bariatric surgery is an effective and long-lasting strategy for weight loss, and can improve many cardiovascular risk factors such as hypertension and dyslipidaemia. In this Review, Beamish and colleagues highlight the effects of bariatric surgery on cardiovascular risk factors and outcomes.

The identification of mutations that underlie rare diseases has dramatically accelerated in recent years thanks to next-generation sequencing. This Review discusses strategies for further identification studies, insights into disease mechanisms and the clinical implications of the rapid progress in this field of research.

Autoinflammatory diseases are associated with abnormal activation of the innate immune system and resultant inflammation. Here, the authors provide a clinical and practical guide to autoinflammatory diseases, describing classification, insights into pathogenesis, diagnosis and management of these conditions.

In this era of rapidly expanding human genomics in research and healthcare, efficient data reuse is essential to maximize benefits for society. In response, the Federated European Genome–Phenome Archive (FEGA) was launched in 2022, and as of 2024, the FEGA network was composed of seven national nodes. Here we describe the complexities, challenges and achievements of FEGA, unravelling the dynamic interplay of regulatory frameworks, technical challenges and the shared vision of advancing genomic research.

Jan and Jan discuss various mechanisms by which neurons acquire their type-specific dendrite morphology. These have largely emerged from studies inDrosophila melanogaster, but are broadly applicable to vertebrates. The possible contribution of defects in dendrite morphogenesis to mental disorders such as autism is also considered.

Dysregulated immune features in a patient with a homozygous loss-of-function mutation in PDCD1 suggest that IL-6, IL-23, STAT3 and RORγT might be potential targets for treatment of PD-1 blockade-induced autoimmunity.

Congenital lung malformations are rare developmental anomalies of the lung that can lead to recurrent infections, pneumothorax and malignancy in some patients. This Primer summarizes the epidemiology, pathophysiology and diagnosis of this disorder, and discusses current disease management and quality of life of patients.

This Perspective outlines our current understanding of how the bone marrow niche contributes to both the initiation and the progression of haematological malignancies and suggests guidelines for the field which might help to overcome existing research challenges.

Silver–Russell syndrome (SRS) is an imprinting disorder that causes prenatal and postnatal growth retardation. This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with SRS, including the use of growth hormone and gonadotropin-releasing hormone analogues.

This Primer provides a general overview of the epidemiology, diagnosis, pathophysiology and treatment of the glycogen storage diseases. These genetic conditions are characterized by deficits in glycogenesis, glycogenolysis or glycolysis.

The neurobiology of autism spectrum disorder (ASD) is complex and heterogeneous. Although valuable insights into the neural substrates of ASD have been gained in the past decade, the low specificity of neuroimaging measures has hampered the development of ASD biomarkers that are suitable for efficient patient stratification and application in translational research. Ecker and Murphy review recent progress in developing more-specific neuroimaging markers for ASD, and argue for a multidisciplinary approach to enable integration of the findings into translational research.

Healthspan and healthy aging are areas of research with potential socioeconomic impact. Here, the authors present the Medical Genome Reference Bank (MGRB) which consist of over 4,000 individuals aged 70 years and older without a history of the major age-related diseases and report on results from whole-genome sequencing and association analyses.

Cystic fibrosis is caused by mutations in cystic fibrosis transmembrane conductance regulator (CFTR), which encodes a transmembrane ion channel on epithelial cells. Here, Ratjen et al. highlight that, although CFTR dysfunction affects many organs, lung disease is responsible for the vast majority of morbidity and mortality.

Jonathan Sebat and colleagues report the association of microduplication on chromosome 16p11.2 with schizophrenia, while the reciprocal microdeletion was associated with autism and developmental disorders.

Inactivating mutations in TGFBR2, encoding the transforming growth factor-β (TGFβ) type 2 receptor, may account for up to 10% of cases of Marfan syndrome. This finding has implications for a wider spectrum of disorders, including cancer, fibrosis and inflammatory and cardiovascular diseases, which are influenced by TGFβ.

Recent family-based genomic studies are providing a window into the incidence of new mutations in human genomes. This Review discusses our understanding of various types ofde novomutation, including the determinants and consequences of their occurrence rates, and the challenges both for their detection and for linking them to disease pathogenesis.

In this Consensus Statement, the pathology panel of the International Society of Paediatric Oncology–Renal Tumour Study Group (SIOP–RSTG) present the pathology and molecular biology protocol for Wilms tumours in the UMBRELLA SIOP-RTSG 2016 protocol.

Growth hormone, insulin-like growth factor I and insulin have potent growth-promoting and anabolic actions. Their potential involvement in tumor promotion and progression has been of concern for several decades. In this Review Peter Clayton and colleagues examine the complex evidence regarding growth hormone, the insulin-like growth factor axis, insulin and cancer risk.

This Review summarizes recent and compelling examples of microbiome-based interventions that are ripe for clinical adoption while also discussing the challenges and opportunities facing the field.