This month, the European Journal of Human Genetics presents several studies identifying novel disease genes, expanding the phenotypic spectrum, and refining our understanding of mechanisms underlying rare disorders. CACNB1 variants are identified as a new cause of a congenital muscular disorder. Iturrate et al. report three cases presenting with early-onset muscle weakness, high creatine kinase levels, ptosis, and low body weight from two unrelated consanguineous families [1]. Muto et al. expand the spectrum of de novo ARF3 variants by describing five additional cases presenting with developmental delay, microcephaly, brain atrophy, epilepsy, and minor skeletal defects. They also provide functional analyses that reveal variant-specific effects on protein stability, Golgi integrity, and nervous system development [2]. Further highlighting the complexity of gene-disease relationships, Fowler syndrome, a severe and often lethal condition with microcephaly, skeletal deformities, and cerebrovascular defects, has been associated with recessive FLVCR2 variants, though pathogenic evidence remains limited. In this issue, Scala et al demonstrate that partial FLVCR2 deficiency can cause Fowler syndrome, suggesting that extragenetic factors may contribute to disease pathogenesis [3].

Beyond gene discoveries, understanding genotype-phenotype correlations and shared genetic mechanisms is crucial for developmental disorders. Correa et al. demonstrate a link between congenital hypogonadotrophic hypogonadism (CHH) and cleft lip/palate (CLP). Among 336 individuals with CHH, 6% had CLP, with pathogenic variants identified in shared developmental genes, most notably FGFR1 and CHD7 [4]. Another challenge in neurodevelopmental conditions concerns growth, which often deviates from typical trajectories, further complicating clinical assessment and management. In this issue, Low et al. present an efficient approach for generating gene-specific growth charts in rare neurodevelopmental disorders [5]. The proposed method promises a solution to address this issue in children with rare neurodevelopmental disorders.

Rapid genomic sequencing (rGS) in neonatal and paediatric intensive care units (ICUs) offers high diagnostic yield but may cause significant emotional and decisional burdens on families. Mackley et al. highlight the need for ICU-tailored approaches, including involving multiple consultations in the decision-making process and framing rGS as an element of care, to support families and informed genomic testing [6]. Extending this consideration to older age groups, predictive genetic testing (PT) for inherited cardiac conditions (ICCs) during adolescence also affects both individuals and their families. Mulhern et al. emphasise that personalised follow-up and family-centred education are essential to help adolescents navigate predictive testing effectively, regardless of their gene status [7].

Despite the advances, diagnosis of tetralogy of Fallot (TOF) can be particularly complex when accompanied by non-cardiac anomalies (TOF + ). Volpi et al. report that clinical exome sequencing (cES) improves diagnostic yield in TOF + . Their findings also highlight the low-penetrance, syndromic nature of TOF, primarily associated with pathogenic variants in DVL3, MED13L, PUF60, and MEIS2, supporting the use of cES when chromosomal microarray analysis is uninformative [8]. Mitochondrial aminoacyl-tRNA synthetase (mt-aaRS) disorders are another phenotypically diverse and diagnostically challenging condition. However, Ratnaike et al. uncover likely diagnoses or variants of uncertain significance in a total of 24 cases, including the ones missed by standard Exomiser pipelines [9]. Their approach, which quantifies phenotypic similarity to prioritise variants, underscores the value of individual-level genotype-phenotype analysis in interpreting variants in complex rare diseases.

Pharmacogenetic and cancer genomics studies, of course, enable more personalised care, guiding decisions from screening to therapeutic strategies. In this issue of the EJHG, the Dutch Pharmacogenetic Working Group (DPWG) provides guidance on tricyclic antidepressant dosing based on CYP2D6 and CYP2C19 metaboliser status to optimise efficacy and safety [10]. The current French guideline for hereditary renal cancers (PREDIR) recommends genetic testing for renal cell carcinoma (RCC) based on certain clinical criteria. Although hereditary RCC is rare and the utility of broad germline testing in sporadic cases is limited, Vibert et al. propose revising the guideline to better identify young or high-risk patients and to distinguish hereditary from sporadic cases [11]. Lastly, the unmet need for reproductive counselling in individuals with cancer predisposition syndromes is further highlighted. In this issue, ERN GENTURIS guidelines provide 16 recommendations to address this and other relevant issues [12].