Mosaic RASopathies are a group of rare developmental disorders arising from post-zygotic variants in members of the RAS/MAPK signalling pathway and with a cancer predisposition. Their phenotypic manifestations are highly variable and depend on the extent and distribution of tissue involvement. Ocular features typically include epibulbar dermoids, although structural eye anomalies are also less commonly reported. We describe a girl with microphthalmia and coloboma whose extraocular features were suggestive of the mosaic RASopathy, EncephaloCranioCutaneous Lipomatosis (ECCL). Genetic analyses of affected tissues revealed a missense variant in the RAS pathway gene KRAS (p.[Ala146Pro]), located in a recurrent hotspot for mosaic RASopathies. The variant was absent in blood, confirming a tissue-restricted distribution. The identification of this mosaic KRAS variant genetically confirmed the clinical diagnosis of ECCL and prompted appropriate tumour surveillance. This case highlights mosaic RASopathies as a cause of developmental eye anomalies.

Pathogenic variants in RNU4-2, encoding for a critical component of the major spliceosome, cause a newly recognized autosomal dominant disorder. Patients with RNU4-2/ReNU syndrome exhibit global developmental delay, microcephaly, dysmorphic features, seizures, hypotonia, and multi-organ involvement. Here, we detailed clinical findings and laboratory evaluation of a 3-year-old girl harboring a common RNU4-2 pathogenic variant. Her clinical presentation and disease course were similar to previously described. Furthermore, akin to other cases, an undiagnosed mitochondrial disorder was initially suspected because of hypoglycemia and lactic acidosis during metabolic stresses and abnormalities in circulating mitochondrial markers. The patient's muscle biopsy suggested mild mitochondrial abnormalities. We employed untargeted metabolomics to further characterize the patient; to our knowledge, this is the first report including metabolomic data in a ReNU syndrome patient. Clinically relevant changes were detected in several lipids, including low concentrations of several plasmalogen species. Plasmalogen deficiency, confirmed by a targeted biochemical assay, was comparable to defects of peroxisomal plasmalogen biosynthesis. Laboratory evaluation of mitochondrial and peroxisomal function in other ReNU syndrome patients is paramount for assessing the role of these organelles, if any, in the pathophysiology of this condition.

Cutis laxa comprises a group of rare connective tissue disorders characterized by loose, inelastic skin due to defects in elastic fiber formation, with autosomal recessive forms presenting early with multisystem involvement. Recently, biallelic variants in the LOX gene have been proposed to cause a severe form of autosomal recessive cutis laxa (ARCL), although evidence remains limited. We report a neonate with generalized cutis laxa, dysmorphic features, and extensive vascular abnormalities. Imaging revealed marked tortuosity of the aortic arch, descending thoracic aorta, cervical arteries, and pulmonary arteries, along with involvement of the systemic venous system. Whole exome sequencing identified a homozygous start-loss variant in the LOX gene, predicted to result in loss-of-function. The patient remained under cardiology follow-up but succumbed at 2 years of age. Lysyl oxidase plays a critical role in collagen and elastin cross-linking within the extracellular matrix, and its disruption provides a plausible mechanism for the observed phenotype. While previously reported cases have described predominantly arterial involvement, the additional presence of venous tortuosity in our patient expands the phenotypic spectrum of this emerging entity. This report adds to the limited evidence supporting LOX as a candidate gene for ARCL and highlights the importance of molecular diagnostics in delineating rare connective tissue disorders.

Dilated cardiomyopathy (DCM) is a severe cardiac condition characterized by the enlargement and impaired contraction of the heart's ventricles. Pediatric cases often present unique challenges due to their rarity and the complexity of underlying genetic causes. This study presents the first documented case of a Colombian patient with neonatal DCM, bilateral congenital cataracts, focal epilepsy, and hyperlactatemia. Genetic testing identified a pathogenic variant in the RRAGC gene, establishing the diagnosis of Long-Olsen-Distelmaier syndrome, a rare mTOR-related disorder characterized by syndromic cardiomyopathy and multisystem involvement. Additionally, we review the clinical and molecular characteristics of previously reported cases in the literature.

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.

We report a 19-month-old girl with molecularly confirmed Perrault syndrome type 4 (PRLTS4), due to a homozygous LARS2 variant (c.457A>C, p.Asn153His), who developed dilated cardiomyopathy (ejection fraction 21%) at 2 months of age despite a normal neonatal echocardiogram, alongside bilateral profound sensorineural hearing loss and global developmental delay. No second causative cardiac variant was identified. To our knowledge, this is the first reported case of dilated cardiomyopathy in molecularly confirmed LARS2-related PRLTS4, expanding the recognised phenotypic spectrum of this disorder and supporting cardiac surveillance in affected infants.

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.

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.

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.

CBX1-related syndrome is characterized by developmental delay, hypotonia, autistic features, and mild dysmorphic features. This syndrome is caused by heterozygous missense variants in CBX1, which encodes heterochromatin protein 1 beta (HP1β). These variants are situated within the chromodomain of HP1β, a critical region that mediates the interaction between HP1β and trimethylated H3K9. While a prior study identified three individuals with pathogenic CBX1 variants, the variant and clinical spectrum of CBX1-related syndrome remain largely unknown. Here we report three patients with novel de novo heterozygous variants in CBX1. Patients with CBX1 p.(Leu40Pro) and p.(Cys60Arg) manifested with global developmental delay, while the patient with CBX1 p.(Cys60Gly) primarily exhibited speech delay without concurrent motor developmental delay. All variants reside within the chromodomain of the HP1β protein. Interestingly, in vitro cellular assays revealed that the CBX1 p.(Cys60Gly) variant showed an intermediate cellular phenotype between the wild type and the CBX1 p.(Leu40Pro) and p.(Cys60Arg) variants, suggesting a possible genotype-phenotype correlation. This report provides further evidence that missense variants within the chromodomain of HP1β cause a syndromic neurodevelopmental disorder, CBX1-related syndrome.

Congenital heart disease (CHD) is the most common type of birth defect with tremendous genetic heterogeneity. The aim of our study was to unravel the molecular pathology and the magnitude of recessive genotypes (RGs) in a cohort of CHD from our consanguineous population. In probands with CHD who were consecutively recruited, genetic analysis was conducted based on the most likely etiology to either copy number variants (CNVs) analysis, multigene panel, whole exome sequencing (WES), or whole genome sequencing (WGS). A total of 201 families were recruited, of whom 59.7% were consanguineous. The overall diagnostic yield of genetic testing was 34.8%, with significantly higher yield in syndromic compared to isolated CHD (48.8% vs. 11.8%, respectively, ***p < 0.0001). Pathogenic CNV were identified in 12.4% and single-nucleotides variants in 22.4%, with biallelic variants in only 6.5% of probands. In negative cases, analysis of WES/WGS data did not reveal plausible variants. The tremendous genetic heterogeneity with a minority of homozygous variants in our cohort suggests that RG may be considered a rare cause of CHD even in consanguineous population. Our findings support the integration of next-generation sequencing into routine clinical care of CHD and provide relevant ingredients for genetic counseling in consanguineous population.

To our knowledge, we report the first combined homozygous deletion of ALCAM and CBLB at 3q13.11-q13.12. The patient, a 14-year-old boy born to consanguineous parents, had a multisystem phenotype with severe congenital ocular and craniofacial anomalies, early-onset osteoporosis, progressive scoliosis, growth failure, congenital heart defect, humoral immunodeficiency, and chronic inflammatory findings. SNP array identified a 2.5-Mb homozygous deletion spanning ALCAM and CBLB, and expression studies confirmed complete absence of ALCAM and CBLB expression. Whole-exome sequencing did not identify an alternative molecular diagnosis. The clinical presentation is likely attributable to combined ALCAM and CBLB loss. Previous animal-model studies support interpretation of the individual phenotypic components by linking loss of these genes to craniofacial developmental abnormalities, skeletal findings, and immune dysregulation. We propose that this deletion may represent a candidate novel contiguous gene deletion syndrome. This case is the first human phenotype associated with complete ALCAM loss in a contiguous deletion and expands the clinical spectrum associated with disruption of ALCAM and CBLB.

Pathogenic variants in MITF (Microphthalmia Transcription Factor) gene are associated with a spectrum of disorders, including Waardenburg syndrome type II and Tietz syndrome. Rare reports suggest that biallelic loss-of-function variants may result in a severe multisystem phenotype. We report an infant presenting with a phenotype consistent with COMMAD-like syndrome (Coloboma, Οsteopetrosis, Μicrophthalmia, Μacrocephaly, Αlbinism, and Deafness) who died in the early neonatal period. In addition to the core COMMAD features, the proband exhibited ectopic ossification, cardiac fibrosis and fibroelastosis, interstitial lung disease, ectopic renal tissue, liver steatosis, and hemosiderosis. Whole-exome sequencing identified two heterozygous truncating MITF variants, the previously reported c.961C>T (p.Arg321Ter) and a novel c.1135A>T (p.Lys379Ter) variant, both predicted to result in impaired MITF function. Parental testing was declined, precluding determination of the phase of the variants. To date, only one study has reported an association between biallelic MITF disruption and a severe clinical phenotype. Our findings provide additional evidence for this genotype-phenotype relationship and further expand the clinical spectrum of COMMAD syndrome. The present case further supports a role for impaired MITF function in the pathogenesis of a severe multisystem phenotype.

A three-year-old girl with attenuated protein-losing enteropathy carried compound-heterozygous missense PLVAP variants inherited from unaffected non-consanguineous parents. The case supports residual PLVAP function in missense-associated DIAR10 and expands its genetic and clinical spectrum.

Heterozygous ACAN variants are a major monogenic cause of short stature (SS). We reported a 7 years and 11 months Chinese girl with SS, advanced bone age (BA), and asymptomatic knee osteochondritis dissecans. Targeted next generation sequencing identified a novel paternally inherited heterozygous ACAN missense variant c.547G>C within the G1 domain, classified as likely pathogenic per ACMG standards. Recombinant human growth hormone (rhGH) induced robust early catch up growth followed by reduced growth velocity, and the patient remains under follow up. This case expands the aggrecanopathy variant spectrum and supports routine ACAN screening in children with unexplained SS, accelerated BA, and osteochondral lesions.