Abstract Joubert syndrome (JS) is a rare genetic disorder characterized by developmental abnormalities, particularly in the brainstem and cerebellar vermis, alongside multisystem manifestations such as kidney and liver anomalies, polydactyly, cleft lip or palate, and tongue defects. The underlying ciliopathy causing JS may also contribute to gastrointestinal symptoms and immune dysregulation via Wnt signaling and impaired epithelial maintenance. Dysmotility including Hirschsprung disease has been documented at increased rates in JS and in other ciliopathies. Our case series highlights how JS patients frequently exhibit feeding intolerance, vomiting, and poor growth, which may raise suspicion for an underlying gastrointestinal condition, such as eosinophilic esophagitis (EoE). Gastrointestinal symptoms often overlap with other chronic issues, delaying diagnosis and treatment, which can affect long‐term outcomes. These cases underscore the importance of thorough evaluations, including endoscopy, to investigate persistent symptoms suggestive of eosinophilic gastrointestinal diseases (EGIDs)/EoE. Such vigilance promotes early targeted therapies, improves quality of life, and decreases the risk of complications including formation of esophageal strictures.

ABSTRACTADAMTS9mutations cause the ciliopathies nephronophthisis and Joubert syndrome. Here we show that deletion of ADAMTS9 in the proximal nephron leads to polycystic kidney development in mice. In males,Adamts9deletion cause kidneys to become highly cystic but remain small without undergoing enlargement, causing early postnatal lethality. Female mice on the other hand, develop cystic kidneys but progress slowly. ADAMTS9 deletion disrupted ciliogenesis by the loss of ciliary transition zone (TZ) protein TMEM67 cleavage, leading to loss of the MKS/B9 module – a key component of the ciliary gate. Functional analysis of all eight ciliopathy patient variants ofADAMTS9identified to date, showed TMEM67 C-terminus failed to localize to the transition zone, thus disrupting a key regulatory mechanism in patient renal ciliogenesis. Modeling ADAMTS9-mediated TMEM67 cleavage utilizing our novel TMEM67-cleavage deficient mice revealed loss of TZ formation but not elevated canonical Wnt signaling as the underlying mechanism driving cystogenesis. We show thatAdamts9deletion leads to comparatively intense interstitial collagen deposition, which likely restricts kidney enlargement resulting in the characteristically small kidney phenotype in nephronophthisis and increased immune response. By comparative analysis of four interconnected polycystic kidney models in addition toPkd1andPkd2deleted kidneys, we identify differential collagen homeostasis is the principle determining factor deciphering cystic kidney size and type.

ABSTRACTNeuro‐ichthyosis is a rare group of disorders characterized by the coexistence of neurological dysfunction and ichthyotic skin changes. We report a 5‐year‐old girl born to consanguineous parents who presented with pharmacoresistant epilepsy, severe developmental delay, microcephaly, and ichthyosis. Family history revealed similarly affected siblings, suggesting a hereditary basis. Despite multiple antiepileptic drugs, seizures remained uncontrolled. Whole exome sequencing identified a homozygous CC2D2A variant consistent with Joubert syndrome type 9, along with heterozygous variants in ABCA12 and DOCK6, and a 14q31.3–q32.11 deletion. This unique combination represents an unprecedented multilocus pathogenic mechanism contributing to the complex neurocutaneous phenotype. The findings expand the known genotypic and phenotypic spectrum of neuro‐ichthyosis and highlight the importance of early whole exome sequencing for accurate diagnosis, genetic counseling, and management of patients with severe neurocutaneous disorders, especially in consanguineous populations where multilocus pathogenicity may underlie atypical or severe presentations.

Primary cilia in neural development and disease.

Cilia are essential cellular antennae that rely on precise motor-driven transport to assemble and function. Two kinesin-2 motors-kinesin-II and OSM-3 in Caenorhabditis elegans-cooperate to transport cargo along cilia, with kinesin-II operating in the middle segment and OSM-3 taking over distally. However, how kinesin-II is spatially confined to prevent its invasion into distal regions remains unclear. Here, we identify Joubert syndrome 26 protein (JBTS-26) as a critical regulator of this motor handover. JBTS-26 localizes to axonemal doublet microtubules in the ciliary middle segment, where it competes with kinesin-II for binding to the IFT-B subunit OSM-5/IFT88. This competition displaces kinesin-II from IFT particles, enabling OSM-3 to assume distal transport. Loss of JBTS-26 allows kinesin-II to invade the distal cilium and slows down IFT. Conversely, JBTS-26 overexpression accelerates IFT by prematurely releasing kinesin-II. Our findings reveal a mechanism for compartmentalized motor regulation and link defective motor handover to ciliopathy pathogenesis.

Centriolar protein PIBF1 is required for craniofacial and forebrain development.

Joubert syndrome (JS) is a rare autosomal recessive neurodevelopmental disorder characterized by the molar tooth sign (MTS) on brain magnetic resonance imaging (MRI), resulting from cerebellar vermis hypoplasia and elongated superior cerebellar peduncles. A 4-year-old female presenting with global developmental delay, hypotonia, oculomotor apraxia, and MTS on MRI underwent whole-exome sequencing (WES). Bioinformatic analysis, Sanger validation, and segregation studies were performed. Pathogenicity was assessed using ACMG/AMP guidelines and in silico tools. WES revealed a novel homozygous nonsense variant in AHI1 (c.2938A>T; p.Lys980Ter), absent in population databases. Segregation analysis confirmed autosomal recessive inheritance, with both parents as heterozygous carriers. Evolutionary conservation of Lys980 underscored its functional importance. This study expands the mutational spectrum of AHI1-related JS and highlights the utility of WES in consanguineous populations. The findings facilitate precise diagnosis, genetic counseling, and informed reproductive planning for at-risk families.

Oro-Facial-Digital Syndrome (OFDS) and Joubert syndrome are ciliary disorders. Fifteen individuals of consanguineous Bedouin kindred presented with global developmental delay with no speech, and a clear OFDS phenotype, combined with Joubert syndrome, with MRI showing hypoplastic corpus callosum and molar tooth sign. Renal and liver function tests and ultrasound were unremarkable. Within a 0.5 Mb disease-associated locus (LOD score 6.2), whole genome sequencing identified a single variant: CEP83 NG_051825.2:g.5774dupG, (NM_016122.3):c.-278dupG. Patient fibroblasts showed aberrantly long cilia, and alternative splicing of CEP83 5’UTR, skipping most of exon 1 of the canonical transcript, and frameshift, abrogating CEP83 mRNA and protein expression. CEP83 acts in primary cilium assembly. CEP83 biallelic missense or in-frame deletions, with presumed residual function, were previously associated with early-onset nephronophthisis culminating in end-stage renal disease. We now demonstrate that a biallelic complete loss-of-function CEP83 variant culminates in elongated primary cilia, causing OFDS with Joubert-like features without evident renal involvement.

Abstract Background Joubert Syndrome (JS) is a rare autosomal recessive neurodevelopmental disorder, characterised by hypotonia, developmental delay, and a “molar tooth sign” on MRI brain. Sleep disordered breathing (SDB) is common, although referral for polysomnography (PSG) is variable. The aim of this study was to collate overnight PSG results from a series of patients with JS, and monitor the pattern of SDB over time. Methods A retrospective analysis of children with JS in a tertiary paediatric hospital from 2010-2025. Progess to date Twenty-one children (16 males) with confirmed JS were identified during the study period. Fourteen had PSGs, at a median age of 4 years (1mo – 10 years), while 11 had repeat PSGs at a median age of 5 years. Genetic sequencing has been performed in 18. Initial and repeat PSGs have been analysed. The mean initial AHI was 9.4 events/hr, compared to 7.2 events/hr in the repeat. The mean OAHI in initial studies was 5.4 events/hr compared to 2.2 events/hr in repeat studies. Six children received treatment between studies, including adenotonsillectomy, non-invasive ventilation, or a combination of both. Objective improvement was seen in 7 children, while 3 had stable but persisting SDB. SDB worsened in 1 child. Intended outcome and impact Children with JS show a range of SDB, ranging from normal PSGs, to those showing severe OSA requiring varying levels of intervention. Patients with JS would benefit from serial PSGs during childhood, although not all are referred for sleep assessment. More awareness is required to ensure these children get adequate monitoring.

Joubert syndrome (JBTS) is a group of recessive neurodevelopmental disorders classified as a specific type of ciliopathy with genetic heterogeneity. JBTS23, a subtype of Joubert syndrome, is caused by variations in the KIAA0586 gene. In this study, we report a 9-month-old boy diagnosed with JBTS based on the presence of the molar tooth sign in the midbrain and global developmental delay. Whole-exome sequencing identified two pathogenic variants in KIAA0586 (c.3944 T>G and c.3686 + 3A>G), consistent with an autosomal recessive inheritance pattern. These findings were confirmed through Sanger sequencing of the proband and his parents. This study identifies two novel pathogenic variants in KIAA0586, provides a genetic diagnosis for this patient as JBTS23, and expands the variant spectrum of KIAA0586 associated with JBTS.

Joubert syndrome is a genetically heterogeneous ciliopathy characterized by cerebellar vermis hypoplasia and the distinctive molar tooth sign on neuroimaging, often accompanied by neurological impairment. Pathogenic CSPP1 variants account for approximately 3% of Joubert syndrome cases. While certain ciliopathies have been associated with metabolic dysfunction, this has not been described in CSPP1-related Joubert syndrome. We report a 16-year-old Honduran mestiza female patient with CSPP1-related Joubert syndrome who presented with insulin resistance, early onset diabetes, dyslipidemia, and metabolic dysfunction-associated steatotic liver disease. Notably, she lacked the typical neurological symptoms of Joubert syndrome. Brain magnetic resonance imaging revealed cerebellar vermis hypoplasia, confirming the diagnosis. Genetic testing identified a pathogenic heterozygous CSPP1 variant (c.3052C > T, p.Gln1018), supporting the diagnosis of CSPP1-related Joubert syndrome. This case expands the phenotypic spectrum of CSPP1-related Joubert syndrome and raises the possibility of a role for CSPP1 in metabolic homeostasis. Further research is needed to determine whether CSPP1 mutations contribute to metabolic dysfunction via ciliary or centrosome-associated mechanisms.

The relevance of primary cilia in neurological disorders.

BackgroundMeckel syndrome (MKS) is an embryonically lethal ciliopathy with severe clinical manifestations, including defects of the central nervous system, bilateral renal cystic dysplasia, and postaxial polydactyly. B9 domain-containing 1 (B9D1, NP_056496.1) is a member of a small family of proteins associated with basal bodies and primary cilia in mammalian cells. B9D1 variants are associated with MKS and Joubert syndrome. However, to date, only a few cases have been reported.MethodsIn this study, we investigated a prenatally diagnosed recurrent MKS pedigree. Two fetuses of different sexes were conceived by nonconsanguineous parents. Systematic color Doppler ultrasound revealed same malformations in both fetuses during the second trimester, which included meningoencephalocele, Dandy-Walker malformation, and postaxial polydactyly. Trio whole exome sequencing (WES) and WES reanalysis were performed. The presence and effects of these variants were further validated using Sanger sequencing, RT-PCR, and minigene splicing assay at the DNA and RNA levels.ResultsTwo compound heterozygous variants, c.341G>T (p.R114L) and c.405-308_405-304del, were identified in both probands, each inherited from one unaffected parent. Both variants led to abnormal splicing. Specifically, the missense mutation c.341G>T caused the skipping of exon 4, whereas the novel deep-intronic variant c.405-308_405-304del created a new and strong acceptor site at c.405-294_405-293. Pathogenicity analysis indicated that both variants were pathogenic.ConclusionThis report presents a rare pedigree of recurrent MKS, in which two novel mutations in B9D1 are identified. Our findings expand the mutation spectrum of B9D1 and provide an accurate molecular diagnosis for genetic counseling.

ABSTRACTCiliopathies are rare genetic disorders characterized by significant genetic and phenotypic variability. Over 140 proteins localized to primary cilia, which are sensory organelles essential for vertebrate development, are implicated. TMEM17 encodes a transmembrane protein at the ciliary transition zone and was previously proposed as a potential ciliopathy gene, based on reports of individuals from two families with orofaciodigital syndrome type 6 (OFD6) and Joubert syndrome (JS). Here, we report two unrelated fetuses with occipital encephalocele, polydactyly, and kidney cysts, in whom exome sequencing identified a founder homozygous missense variant (Arg94Trp) in TMEM17, affecting a highly conserved residue. This expands the TMEM17‐associated phenotypic spectrum to include Meckel syndrome (MKS). Comprehensive functional analyses of all known TMEM17 variants, using patient tissues/cells and a C. elegans model system, demonstrate a loss‐of‐function mechanism. Our study reveals severe functional consequences, including TMEM17 destabilization and mislocalization, anomalies in cilium composition and function, and abrogation of Sonic Hedgehog signaling. These experiments confirm the pathogenicity of all TMEM17 variants and underscore its essential role at the ciliary transition zone. Collectively, our findings establish TMEM17 as a bona fide ciliopathy gene, associated with a wide phenotypic spectrum ranging from viable syndromes (OFD6 and JS) to a fetal‐lethal condition (MKS).

Lipid-modified proteins are essential for ciliary signaling and structure, but their hydrophobic modifications hinder cytosolic transport and selective delivery. GDI-like solubilizing factors (GSFs), such as PDE6D and UNC119A/B, bind lipid moieties to shield cargo proteins and enable diffusion. However, the mechanisms that govern spatially restricted cargo release-particularly at the primary cilium-are not fully elucidated yet. In this Review, we highlight the central role of the small G protein ARL3 and its regulators in mediating selective release of lipidated cargoes. We discuss ARL13B, a ciliary-localized guanine nucleotide exchange factor (GEF) for ARL3, and BART, a co-GEF that enhances ARL3 activation by relieving autoinhibition. In contrast, RP2, a GTPase-activating protein (GAP) at the ciliary base, likely inactivates ARL3 outside the cilium, establishing a spatial ARL3·GTP gradient that restricts cargo release. Additional specificity arises from ARL2 exclusion from the cilium, differential GSF-cargo binding affinities, and putative docking platforms such as RPGR. Disruption of this pathway is implicated in ciliopathies, including Joubert syndrome. Current models and recent findings provide a framework for understanding spatial GTPase signaling in ciliary transport.

Genetic variants that introduce a premature termination codon (PTC) are often assumed equivalent and functionally null. Exceptions depend on the specific architectures of the affected mRNA and protein. Here we address phenotypic differences among early truncating variants of mouse Zfp423, whose phenotypes resemble Joubert Syndrome and Related Disorders. We replicate quantitative differences previously seen between presumptive null PTC variants based on their position in the coding sequence. We show with reciprocal congenic strains that large phenotype differences between two PTC variants with the same predicted stop and reinitiation codons are due to the specific allele rather than different strain backgrounds, with no evidence for induced exon skipping. Differences in RNA structure, however, could influence translation rate across the affected exon. Using a reporter assay, we find differences in translational reinitiation between 2 deletion variants that correlate with predicted RNA structure rather than distance from the canonical initiation codon. These results confirm and extend earlier evidence for differences among Zfp423 PTC variants, identify parameters for translational reinitiation after an early termination codon, and reinforce caution in the null interpretation of early PTC variants.

Molecular treatment options for patients carrying KIAA0586/TALPID3 variants

This study examines the quality of life, functional independence, and family impact of children diagnosed with Joubert Syndrome (JS) to address gaps in the literature on its developmental and psychosocial challenges. A descriptive, cross-sectional study was conducted with 49 parents of children with JS in Turkey. Data were collected using the Pediatric Quality of Life Inventory, Pediatric Functional Independence Measure, and Impact on Family Scale. Statistical analyses included descriptive and reliability assessments. Children with JS exhibited significant motor and cognitive delays, reduced functional independence, and lower quality of life. Feeding difficulties affected 38.8% of participants, highlighting the need for early nutritional interventions. Consanguineous marriage was reported by 61.2% of families, yet only 8.2% underwent genetic screening, emphasizing the importance of genetic counseling. Parents faced high psychosocial and economic burdens, underscoring the need for structured family support programs. The findings highlight the need for early, multidisciplinary interventions, including physical and speech therapy, nutritional support, and psychosocial care, to enhance functional independence and overall well-being. A comprehensive care model integrating neurology, pulmonology, rehabilitation, and genetic counseling is essential for improving outcomes in JS. A family-centered, multidisciplinary approach should be prioritized to improve patient care and caregiver support. Expanding rehabilitation services, genetic counseling, and structured family education can enhance long-term quality of life and independence in children with JS.

Production and characterisation of four Joubert syndrome patient-derived induced pluripotent stem cell (iPSC) lines with mutations in either RPGRIP1L or CPLANE1 genes.

Joubert Syndrome's rarity and diagnostic complexity, especially in Sudan, pose significant challenges in low-resource settings. Sibling cases with neurodevelopmental delays and MRI-confirmed molar tooth sign highlight the urgent need for heightened clinical suspicion, accessible neuroimaging, and genetic counseling to address underdiagnosis in underrepresented populations.