ABSTRACT Next‐generation sequencing has radically transformed the diagnostic capability of rare neurodevelopmental disorders (RNDDs), yet translating these molecular insights into viable therapeutics remains a hurdle. While gene‐directed modalities, specifically viral‐mediated supplementation, antisense oligonucleotides (ASOs), and CRISPR‐based activation or precision editing, offer a means to rescue loss‐of‐function phenotypes, successful clinical implementation requires moving past the reductive framework of merely increasing the expression of the target gene towards approaches that account for spatial, developmental, and therapeutic windows. This review uses HNRNPU‐related rare neurodevelopmental disorder (HNRNPU‐RNDD), a condition marked with global developmental delay and refractory epilepsy, as an exemplar to discuss these translational hurdles. We discuss the homeostatic boundaries of this scaffold attachment factor, where unregulated overexpression risks localised cytotoxicity, and altered chromatin dynamics compromise editing safety. Furthermore, we assess how cell‐type sensitivity and narrow developmental windows may dictate clinical efficacy. By using HNRNPU‐RNDD to critically analyse the challenges of using each therapeutic platform, we hope to inform the creation of gene‐directed therapies that aim to treat disorders resulting from structural pleiotropic dosage‐sensitive proteins.
ABSTRACT Chromosome 15q11–q13 duplication syndrome (Dup15q) is a rare copy‐number disorder with marked phenotypic heterogeneity. This scoping review characterized its clinical spectrum and genotype–phenotype correlations. Following PRISMA‐ScR and Joanna Briggs Institute methodology, PubMed, Web of Science, and Google Scholar were searched through December 1, 2025. Ninety‐two studies comprising 395 molecularly confirmed patients were included. Cohen's kappa was 0.73, indicating substantial inter‐reviewer agreement. Neurodevelopmental manifestations predominated, particularly developmental delay, intellectual disability, autism spectrum disorder, epilepsy, hypotonia, motor and language impairment, and psychobehavioral abnormalities. Compared with interstitial duplications, supernumerary marker chromosomes were associated with higher odds of epilepsy (OR = 7.14, 95%, CI = 4.39–11.61; p < 0.001), intellectual disability (OR = 2.20, 95%, CI = 1.34–3.66; p = 0.002), and motor delay (OR = 1.70, 95%, CI = 1.02–2.84; p = 0.040), but lower odds of psychobehavioral manifestations (OR = 0.21, 95%, CI = 0.13–0.35, p < 0.001). Among 186 patients with reported parental origin, 155 (83%) were maternal and 31 (17%) paternal. Maternal duplications showed higher odds of seizures (OR = 4.26, 95%, CI = 1.42–12.79; p = 0.006) and motor delay (OR = 5.93, 95%, CI = 1.35–25.90; p = 0.006) than paternal duplications. Co‐occurrence analysis identified global developmental delay as the principal phenotypic hub. These findings refine the clinical spectrum of Dup15q and highlight associations with cytogenetic subtype and parental origin.
ABSTRACT Fetal cerebral ventriculomegalies are brain anomalies with potentially poor neurodevelopmental prognosis. They are amenable to prenatal imaging, isolated or associated with other cerebral and/or extra‐cerebral abnormalities. Most are obstructive due to a focal or diffuse dysgenesis of the ventricular system, disturbing the cerebro‐spinal fluid outflow. Triventricular dilatation is the most common, predicting a lesion at the level of the aqueduct of Sylvius (AS). Although variants in several genes have recently been linked to ventriculomegaly, their role remains unclear, compromising our ability to predict the impact of such variations when detected prenatally. To go further, we report here a monocentric cohort of 51 fetuses with cerebral ventriculomegaly linked to dysgenetic AS and discuss phenotype/genotype correlations after neuropathological study. A genetic cause has been identified in 15 cases (29.4%) using different genetic methods available between 1992 and 2021: standard karyotyping, targeted mutation screening (Sanger sequencing), and Next Generation Sequencing. Dysgeneses of the AS are still controversial in their nosology and etiology; most are discussed on the basis of brain imaging findings alone. In this series, complete fetal and neuropathological examination allowed detection of key clinical and histopathological clues, allowing the orientation of molecular screenings and the identification of cellular mechanisms involved in triventricular dilatations.
ABSTRACT Thauvin–Robinet–Faivre syndrome (TROFAS, OMIM #617107) is a recently identified autosomal recessive disorder characterised by syndromic overgrowth, facial dysmorphism, mild intellectual disability, variable congenital anomalies, and occasional tumour occurrence. TROFAS results from homozygous or compound heterozygous variants in the FIBP gene, encoding the intracellular binding protein for acidic fibroblast growth factor. This protein plays a role in the fibroblast growth factor (FGF) signalling pathway, which is involved in cell proliferation and contributes to the development of several structures, such as the nervous system, optic vesicles, and blood vessels. Prior to the present report, TROFAS has been described in 10 patients from seven families, four of which are of Turkish origin. We report two additional Turkish siblings from a previously unreported family harbouring the recurrent homozygous c.412‐3_415dupCAGTTTG likely pathogenic variant in FIBP . Both presented with typical TROFAS features; however, the male sibling exhibited a more severe neurodevelopmental profile and additional malformations, including postaxial polydactyly and upper lip vascular malformation, which, to our knowledge, have not previously been reported in association with TROFAS. A detailed clinical characterisation of these two new cases contributes to a more comprehensive delineation of the syndrome, adding potentially novel phenotypic features requiring confirmation in additional patients.
