We are saying goodbye to summer with an issue that explores the genetic, molecular, and clinical spectrum of neurodevelopmental and neuromuscular disorders. Although DDX3X is a known genetic cause of intellectual disability in females, limited data are available for affected males. In this issue, Kennis et al. shed light on this gap, reporting 32 affected males through a combination of their cohort and published cases, expanding the clinical and genetic understanding of DDX3X-related disorders in males [1]. Another large cohort study broadens our understanding of CNOT3-related neurodevelopmental disorders. Engel et al. present 51 cases from across the world, delineating developmental and behavioural features, particularly language delay and intellectual disability and highlighting the absence of genotype-phenotype correlation despite a wide range of novel variants. Their findings help to characterize the clinical spectrum and offer valuable guidance for diagnosis and counselling, while underscoring the need for further research [2].

In contrast to the typical early and severe presentations of mitochondrial disorders, Fontaine et al. report two adult siblings who presented with pure spastic paraplegia with onset in childhood. This first report linking COQ9 variants to hereditary spastic paraplegia broadens the clinical spectrum of CoQ10 deficiency. Moreover, exogenous CoQ10 may even be a promising treatment option [3]. Tedesco et al. report three novel HSPB8 frameshift variants producing distinct C-terminal extensions, further expanding the disease spectrum. Affected individuals showed myopathy, often accompanied by neuropathy, respiratory problems, or cardiomyopathy. Their findings support the inclusion of HSPB8 in genetic testing not only for neuromuscular disorders but also for cardiomyopathy [4]. Additionally, Bergès et al. describe a novel heterozygous pathogenic variant in HEY2, associated with non-syndromic Tetralogy of Fallot (TOF), underscoring the role of monogenic contributions and supporting the inclusion of HEY2 in gene panels, particularly for familial or isolated TOF cases [5].

Distinguishing true disease variability from coexisting or misdiagnosed conditions can be tricky and requires comprehensive clinical and genetic evaluation. Puma et al. demonstrate that most facioscapulohumeral muscular dystrophy Type I (FSHD1) patients with atypical clinical features, such as uncommon muscle involvement of the face and limbs beyond the typical pattern, or blood CPK levels over four times the normal value, actually have alternative genetic diagnoses. Among those without comorbidities explaining these presentations, genetic conditions were identified, including myotonic dystrophy types 1 and 2, mitochondrial disorders, Huntington’s disease, limb-girdle muscular dystrophy, and spinocerebellar ataxia, underscoring the importance of WGS or targeted panels for those presenting with atypical features of neuromuscular and neurological disorders [6]. Also highlighting the importance of rapid genetic diagnosis, Roach et al. report a case of profound hypotonia in an infant with δ-aminolevulinic acid dehydratase–deficient porphyria (ADP), successfully managed with early intervention. Their findings highlight the potential of rapid WGS in preventing severe outcomes in rare metabolic conditions [7]. In addition, WGS offers valuable insights into population-specific immune responses and susceptibility, helping to uncover genetic diversity across populations. In this issue Liu et al. uncover genetic diversity and admixture of British Africans with HLA alleles inferred from whole genome sequencing data in the UK Biobank [8].

As genomic testing becomes common in healthcare, it’s clear that expanding access and managing the complexities of delivering additional genetic findings are two sides of the coin, and both are essential to making genomic medicine effective for patients. Stafford-Smith presents insights from 45 National Health Service (NHS) professionals who went above and beyond to return additional findings (AFs), recognizing patient benefits but also facing practical and emotional challenges. They emphasize caution and call for further research and planning before AFs are routinely integrated into care [9]. Meanwhile, publicly funded genetic testing in Australia has grown significantly over the past decade, yet its integration into clinical practice remains limited. Schilling et al. highlight both the progress made and the ongoing challenges in translating genomic research into healthcare policy [10].

One of the major goals of genomic medicine is personalised treatment for rare diseases. Somatic pathogenic variants in PIK3CA are associated with a range of overgrowth phenotypes. Alpelisib is a selective PIK3CA inhibitor, undergoing evaluation as a treatment for PIK3CA related overgrowth. There are concerns around the impact on fertility of Alpelisib. In this issue, Morin et al. report successful pregnancy after cessation of Alpelisib, and track clinical response to ceasing and restarting the medication, with no evidence of loss of effectiveness [11].

Rezai Jahromi et al. investigate the presence of cancer-type somatic mutations in saccular cerebral aneurysms and report that over half of the patients carried nonsynonymous somatic variants, highly enriched in cancer-related genes, with the majority predicted to be deleterious [12].

Beyond system-level challenges, this issue also explores how genetic information is perceived, interpreted, and how it influences individuals’ health behaviours. Mertens et al. explore the reflexive effects of predictive testing and how such information can shape behaviour in self-fulfilling or self-defeating ways [13]. Tutty et al. also indicate that individuals who received increased chance results in reproductive genetic carrier screening agreed on the benefits of knowing their risks despite the high anxiety levels, and this emotional impact could persist [14]. Hence, understanding these psychological mechanisms becomes essential for effective counselling and ethical oversight, as access to genetic testing grows.