Search

Joubert Syndrome (JS) is a congenital cerebellar ataxia typically inherited in an autosomal recessive pattern, although rare X-linked inheritance can occur. It is characterized by hypotonia evolving into ataxia, global developmental delay, oculomotor apraxia, breathing dysregulation, and multiorgan involvement. To date, there are 40 causative genes implicated in JS, all of which encode proteins of the primary cilium. Primary cilia play a crucial role in the normal development and function of many organs, including parts of the brain (cerebellum and brainstem), kidneys, and the retina. This likely explains the multiorgan involvement seen in JS. In this report, we present the first genetically confirmed case of JS in two Filipino adolescent siblings who had early onset ataxia, hepatomegaly, and global developmental delay. A cranial CT scan revealed the Molar Tooth Sign (MTS). Whole Exome Sequencing (WES), performed via buccal swab, showed biallelic pathogenic variants at NM&#95;153704.6:c.2086 C > T (NP&#95;714915.3:p.Leu696Phe) and NM&#95;153704.6:c.431del (NP&#95;714915.3:p.Leu144CysfsTer19) in TMEM67, which are associated with Joubert Syndrome 6 (OMIM:610688) in a compound heterozygous state. The prevalence of NM&#95;153704.6:c.2086 C > T (NP&#95;714915.3:p.Leu696Phe) in TMEM67 variant is very rare (< 0.001%), and the NM&#95;153704.6:c.431del (NP&#95;714915.3:p.Leu144CysfsTer19) has not been recorded. This case contributes valuable information to the expanding knowledge of JS and its related disorders., Competing Interests: Declarations. Consent to participate: Informed consent was obtained from all involved family members. Counseling was provided before the genetic testing and during the discussion of the test results. Consent for publication: Patients’ guardians signed informed consent regarding publishing their data and photographs. Competing interests: The authors have no competing interests to declare that are relevant to this article’s content., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: Joubert syndrome (JS) is an autosomal recessive disorder with a distinctive mid-hindbrain malformation known as the "molar tooth sign" which involves the breathing control center and its connections with other structures. Literature has reported significant respiratory abnormalities which included hyperpnea interspersed with apneic episodes during wakefulness. Larger-scale studies looking at polysomnographic findings or subjective reports of sleep problems in this population have not yet been published., Objectives: The primary objectives were (1) compare a large group of children with JS and their unaffected siblings for caregiver-reported sleep difficulties. Secondary objectives were (1) present new polysomnography (PSG) data on our JS cohort; (2) review sleep disordered breathing (SDB) in other rare congenital hindbrain anatomic abnormalities., Design: We conducted a cross-sectional study on a cohort of 109 families affected by JS., Methods: Pediatric Sleep Questionnaire (PSQ) and the Children's Sleep Habits Questionnaire (CSHQ) along with general medical health information focused on respiratory and sleep problems were mailed to all patients and families. Caregivers were asked to complete the survey for both children with JS and unaffected siblings, if any. Baseline diagnostic PSG was retrospectively reviewed for those with available studies, and the sleep parameters were compared to a referent cohort., Results: Study participants with JS were older than their unaffected siblings ( p  = 0.02). Genetic mutations were available for 41 out of 118 individuals, with the most common mutation being MKS3 (31.4%). Patients with JS had higher scores in the PSQ compared to their unaffected siblings ( p  < 0.001). PSG data showed severe SDB with apnea-hypopnea index (AHI) of 23 ± 15 events/h in patients with JS. Events were primarily obstructive (obstructive AHI 18 ± 15 events/h vs central AHI 4 ± 4 events/h). Abnormal sleep architecture with increased arousal indices, decreased efficiency, and more time awake and in light sleep or wakefulness when compared to the referent data., Conclusion: SDB is common and severe in patients with JS, and the significantly greater obstructive component reported in this cohort makes it necessary to perform complete PSG studies to address or prevent clinical manifestations in this at-risk population. PSQ could represent a viable method to screen for SDB in JS.

Background: Prenatal whole exome sequencing (WES) is becoming an increasingly used diagnostic tool for fetuses with structural anomalies. However, the identification of variants of uncertain significance (VUS) in clinically relevant genes can significantly complicate prenatal diagnosis and genetic counseling., Case Presentation: A fetus conceived through in vitro fertilization at the third attempt presented with polydactyly and molar tooth sign at 24 + 6 weeks of gestation. Trio-based WES was performed on both parents and the affected fetus, revealing a pair of compound heterozygous CPLANE1 variants (c.4646 A > T/p.Glu1549Val and c.1233 C > A/p.Tyr411*) potentially associated with Joubert syndrome. According to the ACMG guidelines, one of the biallelic variants was classified as VUS, and the other as pathogenic. However, these variants had no allele frequencies in the general population. The p.Tyr411* variant was classified as deleterious, while the p.Glu1549Val variant was located in highly conserved residues, was predicted to be damaging by in silico tools, and altered hydrogen bonding. Furthermore, CPLANE1 expression was highest in the brain during the embryonic and fetal stages. These findings provide additional support for the association between CPLANE1 variants in this fetus and Joubert syndrome. Thus, the most likely diagnosis was Joubert syndrome, and after careful consideration, the couple decided to terminate the pregnancy., Conclusion: The expression patterns of CPLANE1 and the molecular effects of the variants may provide further evidence supporting the potential for prenatal diagnosis of Joubert syndrome in the case of biallelic VUS and pathogenic variant. This study suggests that molecular insights may play a role in interpreting VUS in clinically relevant prenatal genes for prenatal diagnosis., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the ethics committee of the Chengdu Women’s and Children’s Central Hospital, approval ethics number 2024(3). Consent for publication: Written informed consent was obtained from the family regarding the publication of the case. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Joubert syndrome is a rare autosomal recessive disorder characterized by the presence of the molar tooth sign on imaging. We report the case of a 5-year-old girl diagnosed with Joubert syndrome during the investigation of chronic vomiting. The patient presented with neuropsychomotor delay, a history of neonatal respiratory disorders, and hydrocephalus treated with a ventriculoperitoneal shunt. Brain magnetic resonance imaging revealed a deepened interpeduncular fossa, thickening and horizontalization of the upper cerebellar peduncles, and vermian hypoplasia, resulting in the characteristic "molar tooth" appearance. The neuropsychomotor delay was attributed to Joubert syndrome, while the chronic vomiting was linked to hyperdrainage. This case underscores the potential for clinical signs of Joubert syndrome to confuse clinicians and highlights the importance of recognizing the pathognomonic molar tooth sign in imaging, which all radiologists should be familiar with., (© 2024 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Joubert Syndrome (JBTS) is a neurodevelopmental ciliopathy defined by a highly specific midbrain-hindbrain malformation, variably associated with additional neurological features. JBTS displays prominent genetic heterogeneity with >40 causative genes that encode proteins localising to the primary cilium, a sensory organelle that is essential for transduction of signalling pathways during neurodevelopment, among other vital functions. JBTS proteins localise to distinct ciliary subcompartments, suggesting diverse functions in cilium biology. Currently, there is no unifying pathomechanism to explain how dysfunction of such diverse primary cilia-related proteins results in such a highly specific brain abnormality. To identify the shared consequence of JBTS gene dysfunction, we carried out transcriptomic analysis using zebrafish mutants for the JBTS-causative genes cc2d2aw38, cep290fh297, inpp5ezh506, talpid3i264 and togaram1zh510 and the Bardet-Biedl syndrome-causative gene bbs1k742. We identified no commonly dysregulated signalling pathways in these mutants and yet all mutants displayed an enrichment of altered gene sets related to central nervous system function. We found that JBTS mutants have altered primary cilia throughout the brain but do not display abnormal brain morphology. Nonetheless, behavioural analyses revealed reduced locomotion and loss of postural control which, together with the transcriptomic results, hint at underlying abnormalities in neuronal activity and/or neuronal circuit function. These zebrafish models therefore offer the unique opportunity to study the role of primary cilia in neuronal function beyond early patterning, proliferation and differentiation., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Background: Biallelic SUFU variants have originally been linked to Joubert syndrome, comprising cerebellar abnormalities, dysmorphism, and polydactyly. In contrast, heterozygous truncating variants have recently been associated with developmental delay and ocular motor apraxia, but only a limited number of patients have been reported. Here, we aim to delineate further the mild end of the phenotypic spectrum related to SUFU haploinsufficiency., Methods: Nine individuals (from three unrelated families) harboring truncating SUFU variants were investigated, including two previously reported individuals (from one family). We provide results from a comprehensive assessment comprising neuroimaging, neuropsychology, video-oculography, and genetic testing., Results: We identified three inherited or de novo truncating variants in SUFU (NM&#95;016169.4): c.895C>T p.(Arg299∗), c.71dup p.(Ala25Glyfs∗23), and c.71del p.(Pro24Argfs∗72). The phenotypic expression showed high variability both between and within families. Clinical features include motor developmental delay (seven of nine), axial hypotonia (five of nine), ocular motor apraxia (three of nine), and cerebellar signs (three of nine). Four of the six reported children had macrocephaly. Neuropsychological and developmental assessments revealed mildly delayed language development in the youngest children, whereas general cognition was normal in all variant carriers. Subtle but characteristic SUFU-related neuroimaging abnormalities (including superior cerebellar dysplasia, abnormalities of the superior cerebellar peduncles, rostrally displaced fastigium, and vermis hypoplasia) were observed in seven of nine individuals., Conclusions: Our data shed further light on the mild but recognizable features of SUFU haploinsufficiency and underline its marked phenotypic variability, even within families. Notably, neurodevelopmental and behavioral abnormalities are mild compared with Joubert syndrome and seem to be well compensated over time., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Pathogenic variants in the CEP290 gene may result in a broad spectrum of diseases, ranging from lethal neonatal syndromes to isolated retinopathy. A detailed review of the clinical spectrum with the incidence of affected extraocular systems has not yet been published. A review of published papers was carried out to provide a comprehensive report on systemic signs and symptoms associated with CEP290 ciliopathies and to explore the genotype-phenotype correlation. Genetic and clinical data were collected on patients with biallelic variants in the CEP290 gene and the extraocular tissues affected. Genotype-phenotype analysis was performed. Two hundred thirty-five patients were included in the analysis. The most frequently reported organs affected, after the eye, were the central nervous system (82.6%, 194/235), followed by the kidney (53.2%, 125/235), skeletal system (15.3% 36/235), and a large spectrum of other, less frequently reported clinical manifestations. Patients with two variants that together predictably resulted in a low amount of CEP290 protein showed a significant association with having two or more extraocular organ systems affected. This is the most extensive report to date on patients with CEP290-ciliopathy and affected extraocular tissues. Based on these findings and previous publications, systemic screening is proposed, together with a clinical pathway for patients with CEP290-related ciliopathy., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

We report a case of severe central sleep apnea incidentally diagnosed during polysomnography for suspected obstructive sleep apnea. Characteristic clinical features included episodic hyperventilation followed by apnea from hypocapnia, which did not follow a Cheyne-Stokes pattern. Combined with the identification of cerebellar and brainstem malformations known as the "molar tooth sign" on a brain magnetic resonance imaging, developmental delay, and motor coordination problems, Joubert syndrome (a congenital disease) was first diagnosed at the age of 50 years. Central apneas were also observed during wakefulness, although not continuously. During sleep, continuous positive airway pressure and adaptive servo-ventilation were ineffective at the referring clinic and at our hospital. Supplemental oxygen decreased the frequency of central apneas and significantly shortened the duration of each central sleep apnea compared with room air. In contrast, the opposite response was observed with acetazolamide administration., Citation: Murashima R, Shiota S, Sugiyama A, et al. A case of middle-aged central sleep apnea due to Joubert syndrome with different treatment effects of oxygen and acetazolamide. J Clin Sleep Med . 2024;20(10):1705-1710., (© 2024 American Academy of Sleep Medicine.)

Joubert syndrome and related disorders (JSRD) present diagnostic challenges due to their varied clinical features. Neuroimaging, particularly MRI and CT, is critical for identifying the distinctive "molar tooth sign" and other neuroanatomical abnormalities. This case report and literature review emphasize the role of neuroimaging in diagnosing JSRD. Our search targeted pediatric cases with terms like "Joubert anomaly" and "diagnostic imaging." Key findings include cerebellar vermal agenesis, ataxia, developmental delay, and oculomotor apraxia. Cognitive impairment ranges widely, complicating assessment. CT scans reveal dysplastic or absent cerebellar vermis, while MRI shows the characteristic "molar tooth" sign and additional abnormalities such as malformed cerebellar peduncles and enlarged posterior fossa. Accurate diagnosis of JSRD depends on correlating clinical symptoms with specific radiological findings. A multidisciplinary approach is vital for managing this complex disorder., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Alhashimi et al.)

Joubert syndrome (JS) is a rare autosomal recessive disorder with brain stem and cerebellar malformations. Early diagnosis through Magnetic Resonance Imaging (MRI) and ultrasonography (US) is crucial for managing this condition. This report presents a JS case diagnosed at 24 weeks of pregnancy. A 25-year-old gravida 2, para 1 woman was referred at 24 weeks' gestation for suspected posterior fossa abnormalities. Ultrasound revealed normal cerebellar hemispheres but significant abnormalities in the cerebellar vermis, including the molar tooth sign and polydactyly, suggesting JS. The fetal MRI confirmed these findings. Following specialist consultations, the patient opted to terminate the pregnancy. A stillborn female infant was delivered, and genomic DNA sequencing identified a frameshift deletion in the AHI1 gene. Early prenatal diagnosis of JS is crucial for informed pregnancy management. The combination of ultrasonography, MRI, and genomic DNA sequencing proved effective for diagnosis., (© 2024 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Joubert Syndrome, manifests in a spectrum of neurological symptoms. This case describes a 7-year-old girl with perinatal complications, and subsequent neurodevelopmental challenges. An MRI confirmed the diagnosis of Joubert syndrome, with the distinctive "molar tooth sign" being a key imaging characteristic. Approximately 25% of cases exhibit nephronophthisis, impacting kidney function, further complicating the clinical picture. Diagnosis relies on imaging and management necessitates a multidisciplinary approach, addressing symptoms and complications, with prognosis linked to the presence of organic disease. The case emphasizes the significance of a multidisciplinary strategy, including genetic counseling, and underscores the diverse manifestations of this syndrome. Prenatal identification through ultrasound and MRI plays a crucial role in diagnosing and treating this rare condition., (© 2024 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Introduction: Joubert syndrome a rare genetic disorder, is characterized by abnormalities in the development of the central nervous system with "molar signs" on magnetic resonance imaging of the brain and accompanied by cerebellar vermis hypoplasia, ataxia, hypotonia, and developmental delay. Keratoconus (KC) is a kind of genetically predisposed eye disease that causes blindness characterized by a dilated thinning of the central or paracentral cornea conically projected forward, highly irregular astigmatism, and severe visual impairment. Klinefelter syndrome is caused by an extra X chromosome in the cells of male patients, and the main phenotype is tall stature and dysplasia with secondary sex characteristics. This study was intended to identify the genetic etiology and determine the clinical diagnosis of one Han Chinese family with specific clinical manifestations of keratoconus and multiorgan involvement., Methods: A comprehensive ocular and related general examination was performed on one patient and his asymptomatic parents and brother. Pathogenic genes were tested by exome sequencing. CNV-seq was used to verify the copy number variation, and peripheral blood was cultured for karyotype analysis. The pathogenicity of the identified variant was determined subject to ACMG guidelines. The Gene Expression Omnibus (GEO) dataset of keratoconus-related genes in the NCBI database was obtained to analyze the differentially expressed genes in corneal tissues of the keratoconus group and the normal control group, and analysis of protein-protein interaction networks (PPI) was performed., Results: Proband, a 25-year-old male, had sudden loss of vision in the left eye for 1 week. Best corrected visual acuity (BCVA): 0.5 (-1.00DS/-5.00DC*29°) in the right eye, counting fingers/40 cm in the left eye. Slit-lamp microscopy of the right eye showed mild anterior protrusion of the cornea and thinning of the cone-topped cornea. The left eye showed marked thinning of the central region of the cornea, rounded edema in the form of a cone-like bulge, epithelial bullae, edema and turbidity of the stroma, and bulging of the Descemet's membrane. Cranial magnetic resonance imaging (MRI) revealed changes in the midbrain and cerebellum, with a "molar sign" and a "bat-winged" ventriculus quartus cerebri. General check-up: 168 cm in height, decreased muscle tone in all four limbs, knee jerk elicited, negative Babinski sign, abdominal reflexes elicited, finger-to-nose test positive, intentional tremor evident in both hands, positive Romberg's sign, instability of gait, level I intellectual disability, poor adaptive behavior, communication disorders, teeth all dentures, a peculiar face with blepharophimosis, wide inner canthus distance, mild ptosis, severe positive epicanthus, high palatal arches, exotropia, hypotrichosis of beard and face, inconspicuous prominentia laryngea, and short upper and lower limbs. Exome sequencing detected compound heterozygous frameshift variants M1:c.9279dup: p .His3094Thrfs*18 and M2:c.6515&#95;6522del: p .Lys2172Thrfs*37 in the patient's CPLANE1 gene and the presence of duplication-type CNV on the X chromosome. Sanger sequencing showed that the mother and father carried the M1 and M2 variants, respectively, and the younger brother carried the M2 variant, which was a novel variant. CNV-seq analysis showed the presence of a duplication-type CNV Xp22.33-Xq28 (2757837-156030895) of approximately 155 Mb on the X chromosome of the proband, which was a de novo variant and carried by neither of the parents. The two heterozygous frameshift variants and duplication-type CNV were pathogenic according to the ACMG guidelines. Differential expression analysis of keratoconus-related genes showed that CPLANE1 was upregulated in the corneal tissues of keratoconus patients compared with normal controls, and such a difference was statistically significant ( p = 0.000515, <0.05). PPI analysis showed that the CPLANE1-NPHP3 complex protein acted as a bridge between cilia and extracellular matrix tissue. According to the genetic test results and clinical phenotype analysis, the family was finally diagnosed with Joubert syndrome combined with Keratoconus and Klinefelter syndrome., Discussion: In this study, we report a proband in a Han Chinese family with both Joubert syndrome and X-linked Klinefelter syndrome as well as keratoconus, and the phenotype spectrum of CPLANE1 -Joubert syndrome may be expanded accordingly. Meanwhile, the significance of exome sequencing was emphasized in aiding the clinical diagnosis of complex cases, which is difficult to make., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fang, Ma, Rong, Lian, Wu, Gao, Li and Sheng.)

A hamartoma is a benign proliferation of typical mature cells specific to a particular anatomical site. In the oral cavity, they may occur as isolated cases or be associated with genetic syndromes. Oral-facial-digital syndrome type VI is a rare genetic disorder with an estimated incidence of one in 50,000-250,000 newborns. Here, we report a case of a 2-year-old boy diagnosed with oral-facial-digital syndrome type VI who was referred for evaluation of a bilateral and normochromic to slightly pinkish nodule on the lateral surface of the tongue. Clinically, the child presented hypotonia, low visual acuity, absence of oculocephalic reflex, delay in neuropsychomotor development, and polydactyly in the feet. Excisional biopsies of both sides of the tongue were performed using a 1.5 W high-power diode laser (wavelength of 980 nm), and histopathological analysis revealed abundant mature adipocytes predominantly arranged in lobules that mainly surrounded the minor salivary gland parenchyma. The surgical sites healed with no complications and the patient remains under follow-up for 10 months. Due to the limited literature on this syndrome and the frequent presence of tongue hamartomas in children, dentists need to be familiar with them., (© 2024 Special Care Dentistry Association and Wiley Periodicals LLC.)

Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and is one of the most frequent genetic causes for kidney failure (KF) in children and adolescents. Over 20 genes cause NPHP and over 90 genes contribute to renal ciliopathies often involving multiple organs. About 15-20% of NPHP patients have additional extrarenal symptoms affecting other organs than the kidneys. The involvement of additional organ systems in syndromic forms of NPHP is explained by shared expression of most NPHP gene products in centrosomes and primary cilia, a sensory organelle present in most mammalian cells. This finding resulted in the classification of NPHP as a ciliopathy. If extrarenal symptoms are present in addition to NPHP, these disorders are defined as NPHP-related ciliopathies (NPHP-RC) and can involve the retina (e.g., with Senior-Løken syndrome), CNS (central nervous system) (e.g., with Joubert syndrome), liver (e.g., Boichis and Arima syndromes), or bone (e.g., Mainzer-Saldino and Sensenbrenner syndromes). This review focuses on the pathological findings and the recent genetic advances in NPHP and NPHP-RC. Different mechanisms and signaling pathways are involved in NPHP ranging from planar cell polarity, sonic hedgehog signaling (Shh), DNA damage response pathway, Hippo, mTOR, and cAMP signaling. A number of therapeutic interventions appear to be promising, ranging from vasopressin receptor 2 antagonists such as tolvaptan, cyclin-dependent kinase inhibitors such as roscovitine, Hh agonists such as purmorphamine, and mTOR inhibitors such as rapamycin., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Autism (or autism spectrum disorder) was initially defined as a psychiatric disorder, with the likely cause maternal behavior (the very destructive "refrigerator mother" theory). It took several decades for research into brain mechanisms to become established. Both neuropathological and imaging studies found differences in the cerebellum in autism spectrum disorder, the most widely documented being a decreased density of Purkinje cells in the cerebellar cortex. The popular interpretation of these results is that cerebellar neuropathology is a critical cause of autism spectrum disorder. We challenge that view by arguing that if fewer Purkinje cells are critical for autism spectrum disorder, then any condition that causes the loss of Purkinje cells should also cause autism spectrum disorder. We will review data on damage to the cerebellum from cerebellar lesions, tumors, and several syndromes (Joubert syndrome, Fragile X, and tuberous sclerosis). Collectively, these studies raise the question of whether the cerebellum really has a role in autism spectrum disorder. Autism spectrum disorder is now recognized as a genetically caused developmental disorder. A better understanding of the genes that underlie the differences in brain development that result in autism spectrum disorder is likely to show that these genes affect the development of the cerebellum in parallel with the development of the structures that do underlie autism spectrum disorder., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Joubert syndrome (JS) is a recessively inherited congenital ataxia characterized by hypotonia, psychomotor delay, abnormal ocular movements, intellectual disability, and a peculiar cerebellar and brainstem malformation, the "molar tooth sign." Over 40 causative genes have been reported, all encoding for proteins implicated in the structure or functioning of the primary cilium, a subcellular organelle widely present in embryonic and adult tissues. In this paper, we developed an in vitro neuronal differentiation model using patient-derived induced pluripotent stem cells (iPSCs), to evaluate possible neurodevelopmental defects in JS. To this end, iPSCs from four JS patients harboring mutations in distinct JS genes (AHI1, CPLANE1, TMEM67, and CC2D2A) were differentiated alongside healthy control cells to obtain mid-hindbrain precursors and cerebellar granule cells. Differentiation was monitored over 31 days through the detection of lineage-specific marker expression by qRT-PCR, immunofluorescence, and transcriptomics analysis. All JS patient-derived iPSCs, regardless of the mutant gene, showed a similar impairment to differentiate into mid-hindbrain and cerebellar granule cells when compared to healthy controls. In addition, analysis of primary cilium count and morphology showed notable ciliary defects in all differentiating JS patient-derived iPSCs compared to controls. These results confirm that patient-derived iPSCs are an accessible and relevant in vitro model to analyze cellular phenotypes connected to the presence of JS gene mutations in a neuronal context., (© 2024. The Author(s).)

Background: Syndromic ciliopathies are a group of congenital disorders characterized by broad clinical and genetic overlap, including obesity, visual problems, skeletal anomalies, mental retardation, and renal diseases. The hallmark of the pathophysiology among these disorders is defective ciliary functions or formation. Many different genes have been implicated in the pathogenesis of these diseases, but some patients still remain unclear about their genotypes., Methods: The aim of this study was to identify the genetic causes in patients with syndromic ciliopathy. Patients suspected of or meeting clinical diagnostic criteria for any type of syndromic ciliopathy were recruited at a single diagnostic medical center in Southern Taiwan. Whole exome sequencing (WES) was employed to identify their genotypes and elucidate the mutation spectrum in Taiwanese patients with syndromic ciliopathy. Clinical information was collected at the time of patient enrollment., Results: A total of 14 cases were molecularly diagnosed with syndromic ciliopathy. Among these cases, 10 had Bardet-Biedl syndrome (BBS), comprising eight BBS2 patients and two BBS7 patients. Additionally, two cases were diagnosed with Alström syndrome, one with Oral-facial-digital syndrome type 14, and another with Joubert syndrome type 10. A total of 4 novel variants were identified. A recurrent splice site mutation, BBS2: c.534 + 1G > T, was present in all eight BBS2 patients, suggesting a founder effect. One BBS2 patient with homozygous c.534 + 1G > T mutations carried a third ciliopathic allele, TTC21B: c.264&#95;267dupTAGA, a nonsense mutation resulting in a premature stop codon and protein truncation., Conclusions: Whole exome sequencing (WES) assists in identifying molecular pathogenic variants in ciliopathic patients, as well as the genetic hotspot mutations in specific populations. It should be considered as the first-line genetic testing for heterogeneous disorders characterized by the involvement of multiple genes and diverse clinical manifestations., (© 2024. The Author(s).)

Joubert syndrome (JBTS) is a systematic developmental disorder mainly characterized by a pathognomonic mid-hindbrain malformation. All known JBTS-associated genes encode proteins involved in the function of antenna-like cellular organelle, primary cilium, which plays essential roles in cellular signal transduction and development. Here, we identified four unreported variants in ARL13B in two patients with the classical features of JBTS. ARL13B is a member of the Ras GTPase family and functions in ciliogenesis and cilia-related signaling. The two missense variants in ARL13B harbored the substitutions of amino acids at evolutionarily conserved positions. Using model cell lines, we found that the accumulations of the missense variants in cilia were impaired and the variants showed attenuated functions in ciliogenesis or the trafficking of INPP5E. Overall, these findings expanded the ARL13B pathogenetic variant spectrum of JBTS., (© 2024 Wiley Periodicals LLC.)

The neuropsychological characteristics of the cerebellar cognitive affective syndrome (CCAS) in congenital, non-progressive malformations of the cerebellum have been scarcely investigated, and even less is known for Joubert syndrome (JS), an inherited, non-progressive cerebellar ataxia characterized by the so-called molar tooth sign. The few studies on this topic reported inconsistent results about intellectual functioning and specific neuropsychological impairments. The aim of this research is to examine the neuropsychological profile of JS compared to other congenital cerebellar malformations (CM), considering individual variability of intellectual quotient (IQ) in the two groups. Fourteen patients with JS and 15 patients with CM aged 6-25 years were tested through a comprehensive, standardized neuropsychological battery. Their scores in the neuropsychological domains were inspected through descriptive analysis and compared by mean of MANOVA and ANOVA models, then replicated inserting IQ as covariate. The two groups showed a largely overlapping neuropsychological profile, consistent with CCAS. However, the JS group showed worse performance in visual-spatial memory compared to CM patients, although this difference was mitigated when considering IQ. These findings highlight a divergence between JS and other CM in visual-spatial memory, which might suggest a critical role of the cerebellum in recalling task-relevant memories and might inform rehabilitative interventions., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Pediatric cystic kidney disease (CyKD) includes conditions characterized by renal cysts. Despite extensive research in this field, there are no reliable genetics or other biomarkers to estimate the phenotypic consequences. Therefore, CyKD in children heavily relies on clinical and diagnostic testing to predict the long-term outcomes., Aim: A retrospective study aimed to provide a concise overview of this condition and analyze real-life data from a single-center pediatric CyKD cohort followed during a 12-year period., Methods and Materials: Medical records were reviewed for extensive clinical, laboratory, and radiological data, treatment approaches, and long-term outcomes., Results: During the study period, 112 patients received a diagnosis of pediatric CyKD. Male patients were more involved than female (1:0.93). Fifty-six patients had a multicystic dysplastic kidney; twenty-one of them had an autosomal dominant disorder; fifteen had an isolated renal cyst; ten had been diagnosed with autosomal recessive polycystic kidney disease; three had the tuberous sclerosis complex; two patients each had Bardet-Biedl, Joubert syndrome, and nephronophthisis; and one had been diagnosed with the trisomy 13 condition. Genetic testing was performed in 17.9% of the patients, revealing disease-causing mutations in three-quarters (75.0%) of the tested patients. The most commonly presenting symptoms were abdominal distension (21.4%), abdominal pain (15.2%), and oligohydramnios (12.5%). Recurrent urinary tract infections (UTI) were documented in one-quarter of the patients, while 20.5% of them developed hypertension during the long-term follow-up. Antibiotic prophylaxis and antihypertensive treatment were the most employed therapeutic modalities. Seventeen patients progressed to chronic kidney disease (CKD), with thirteen of them eventually reaching end-stage renal disease (ESRD). The time from the initial detection of cysts on an ultrasound (US) to the onset of CKD across the entire cohort was 59.0 (7.0-31124.0) months, whereas the duration from the detection of cysts on an US to the onset of ESRD across the whole cohort was 127.0 (33.0-141.0) months. The median follow-up duration in the cohort was 3.0 (1.0-7.0) years. The patients who progressed to ESRD had clinical symptoms at the time of initial clinical presentation., Conclusion: This study is the first large cohort of patients reported from Croatia. The most common CyKD was the multicystic dysplastic kidney disease. The most common clinical presentation was abdominal distention, abdominal pain, and oliguria. The most common long-term complications were recurrent UTIs, hypertension, CKD, and ESRD.

Joubert syndrome (JS) is a rare autosomal recessive neurodevelopmental condition characterized by congenital mid-hindbrain abnormalities and a variety of clinical manifestations. This article describes a case of Joubert syndrome type 21 with microcephaly, seizures, developmental delay and language regression, caused by a CSPP1 gene variant and examines the contributing variables. This paper advances the understanding of JS by summarizing the literature and offering detection patterns for practitioners with clinical suspicions of JS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Wei, Zhang, Fu, Ye and Yao.)

Cilia are organelles extend from cells to sense external signals for tuning intracellular signaling for optimal cellular functioning. They have evolved sensory and motor roles in various cells for tissue organization and homeostasis in development and post-development. More than a thousand genes are required for cilia function. Mutations in them cause multisystem disorders termed ciliopathies. The null mutations in CC2D2A result in Meckel syndrome (MKS), which is embryonic lethal, whereas patients who have missense mutations in the C2 domain of CC2D2A display Joubert syndrome (JBTS). They survive with blindness and mental retardation. How C2 domain defects cause disease conditions is not understood. To answer this question, C2 domain of Cc2d2a (mice gene) was knocked down (KD) in IMCD-3 cells by shRNA. This resulted in defective cilia morphology observed by immunofluorescence analysis. To further probe the cellular signaling alteration in affected cells, gene expression profiling was done by RNAseq and compared with the controls. Bioinformatics analysis revealed that the differentially expressed genes (DEGs) have functions in cilia. Among the 61 cilia DEGs identified, 50 genes were downregulated and 11 genes were upregulated. These cilia genes are involved in cilium assembly, protein trafficking to the cilium, intraflagellar transport (IFT), cellular signaling like polarity patterning, and Hedgehog signaling pathway. This suggests that the C2 domain of CC2D2A plays a critical role in cilia assembly and molecular signaling hosted in cilia for cellular homeostasis. Taken together, the missense mutations in the C2 domain of CC2D2A seen in JBTS might have affected cilia-mediated signaling in neurons of the retina and brain., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: COACH syndrome is a rare autosomal recessive genetic disease characterized by liver fibrosis, which leads to severe complications related to portal hypertension. However, only a few patients with COACH syndrome undergoing liver transplantation (LT) have been reported., Materials and Methods: We herein report the outcomes of four children who underwent LT for COACH syndrome at our institute and review three previously reported cases to elucidate the role of LT in COACH syndrome., Results: All four patients in our institute were female, and three received living donors LT. All patients were diagnosed with COACH syndrome by genetic testing. LT was performed in these patients at 3, 7, 9, and 14 years old. The indication for LT was varices related to portal hypertension in all patients. One showed an intrapulmonary shunt. Blood tests revealed renal impairment due to nephronophthisis in three patients, and one developed renal insufficiency after LT. The liver function was maintained in all patients. A literature review revealed detailed information for three more patients. The indication for LT in these three cases was portal hypertension, such as bleeding from esophageal varices. One patient had chronic renal failure on hemodialysis at LT and underwent combined liver and kidney transplantation. Of these three previous patients, one died from hepatic failure due to de novo HCV infection 3 years after LT., Conclusions: LT should be considered an effective treatment for COACH syndrome in patients with severe portal hypertension. However, a detailed follow-up of the renal function is necessary., (© 2023 Wiley Periodicals LLC.)

Introduction: Joubert syndrome (JS) arises from defects of primary cilia resulting in potential malformations of the brain, kidneys, eyes, liver, and limbs. Several of the 35+ genes associated with JS have recognized genotype/phenotype correlations, but most genes have not had enough reported individuals to draw meaningful conclusions., Methods: A PubMed literature review identified 688 individuals with JS across 32 genes and 112 publications to bolster known genotype/phenotype relationships and identify new correlations. All included patients had the "molar tooth sign" and a confirmed genetic diagnosis. Individuals were categorized by age, ethnicity, sex and the presence of developmental disability/intellectual disability, hypotonia, abnormal eye movements, ataxia, visual impairment, renal impairment, polydactyly, and liver abnormalities., Results: Most genes demonstrated unique phenotypic profiles. Grouping proteins based on physiologic interactions established stronger phenotypic relationships that reflect known ciliary pathophysiology. Age-stratified data demonstrated that end-organ disease is progressive in JS. Most genes demonstrated a significant skew towards having variants with either residual protein function or no residual protein function., Conclusion: This cohort demonstrates that clinically meaningful genotype/phenotype relationships exist within most JS-related genes and can be referenced to allow for more personalized clinical care., (© 2023 University College London (UCL) and John Wiley & Sons Ltd.)

Formation of the vertebrate heart with its complex arterial and venous connections is critically dependent on patterning of the left-right axis during early embryonic development. Abnormalities in left-right patterning can lead to a variety of complex life-threatening congenital heart defects. A highly conserved pathway responsible for left-right axis specification has been uncovered. This pathway involves initial asymmetric activation of a nodal signaling cascade at the embryonic node, followed by its propagation to the left lateral plate mesoderm and activation of left-sided expression of the Pitx2 transcription factor specifying visceral organ asymmetry. Intriguingly, recent work suggests that cardiac laterality is encoded by intrinsic cell and tissue chirality independent of Nodal signaling. Thus, Nodal signaling may be superimposed on this intrinsic chirality, providing additional instructive cues to pattern cardiac situs. The impact of intrinsic chirality and the perturbation of left-right patterning on myofiber organization and cardiac function warrants further investigation. We summarize recent insights gained from studies in animal models and also some human clinical studies in a brief overview of the complex processes regulating cardiac asymmetry and their impact on cardiac function and the pathogenesis of congenital heart defects., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Background: Joubert syndrome (JS) is a rare genetically heterogeneous primary ciliopathy characterized by a pathognomonic cerebellar and brainstem malformation, the "molar tooth sign", and variable organ involvement (such as eye, kidney, liver, and skeleton). Here, we present a case of JS in a Chinese boy., Case Presentation: An 11-year-old Chinese boy presented with neonatal asphyxiation and hypoxia, strabismus, subsequent developmental delay, ataxia and end-stage kidney disease (ESKD). Routine blood tests showed severe anemia, increasing blood urea nitrogen and creatinine, elevated parathyroid hormone, hypocalcemia, hypokalemia and metabolic acidosis. Urine tests showed mild proteinuria. Ultrasound showed two small kidneys. Brain magnetic resonance imaging (MRI) showed dysplasia of the cerebellar vermis and extension of the upper cerebellar feet with the "molar tooth sign". Genetic analysis showed novel compound heterozygous mutations in the RPGRIP1L gene [p.L447fs*7(p.Leu447fsTer7) and p.G908V (p.Gly908Val)]., Conclusion: In the present study, we identified novel compound heterozygous mutations in the RPGRIP1L gene in a Chinese boy. The clinical and genetic findings of this study will expand the understanding of JS., (© 2023. The Author(s).)

Cholestatic pruritus is a debilitating symptom associated with many liver diseases and is often refractory to medical management. Nasobiliary drainage is a relatively safe and effective method for treating intractable cholestatic pruritus. It should be considered for patients with refractory cholestatic pruritus who have failed or have contraindications to medical therapy as a predictor of response before surgical fistula creation., (© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Joubert syndrome (JS) is a recessive disorder that is characterized by midbrain-hindbrain malformation and shows the "molar tooth sign" on magnetic resonance imaging. Mutations in 40 genes, including Abelson helper integration site 1 ( AHI1 ), inositol polyphosphate-5-phosphatase ( INPP5E ), coiled-coil and c2 domain-containing protein 2A ( CC2D2A ), and ARL2-like protein 1 ( ARL13B ), can cause JS. Classic JS is a part of a group of diseases associated with JS, and its manifestations include various neurological signs such as skeletal abnormalities, ocular coloboma, renal disease, and hepatic fibrosis. Here, we present a proband with the molar tooth sign, ataxia, and developmental and psychomotor delays in a Dagestan family from Russia. Molecular genetic testing revealed two novel heterozygous variants, c.2924G>A (p.Arg975His) in exon 28 and c.1241C>G (p.Pro414Arg) in exon 12 of the transmembrane protein 67 ( TMEM67 ) gene. These TMEM67 gene variants significantly affected the development of JS type 6. This case highlights the importance of whole exome sequencing for a proper clinical diagnosis of children with complex motor and psycho-language delays. This case also expands the clinical phenotype and genotype of TMEM67 -associated diseases., Competing Interests: Declaration of conflicting interestThe authors declare no potential conflict of interest.

Objective: To investigate the computed tomography and magnetic resonance imaging manifestations of Joubert syndrome (JS)., Method: In this retrospective analysis, we investigated the clinical and imaging characteristics of JS in a cohort of twelve pediatric patients with confirmed diagnoses. Specifically, we analyzed both computed tomography (CT) and magnetic resonance imaging (MRI) manifestations in this population. CTs were performed on four patients and MRIs were performed on twelve, respectively., Results: JS is characterized by specific CT and MRI findings, including midline fissure, batwing, or triangular formations of the fourth ventricle between the bilateral cerebellar hemispheres, and molar sign at the midbrain level. All twelve cases in this cohort exhibited these traits, along with other cerebral abnormalities, such as dysplasia of the corpus callosum in two cases, gray matter heterotopia in one case, and occipital meningocele in one case., Conclusion: JS has distinctive CT and MRI characteristics that can be clinically identified., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2023 The Author(s).)

Background: Joubert syndrome (JS) is a group of rare ciliopathies, mainly characterized by cerebellar dysplasia representing the "molar tooth sign (MTS)" on neuroimaging, hypotonia, and developmental delay. Having a complicated genotype-phenotype correlation due to its rich genetic heterogeneity, JS is usually combined with other organic defects affecting the retina, kidney, and liver. This report aimed to present new cases and novel variants of JS., Case Presentation: Five unrelated patients who were diagnosed with JS, with or without typical clinical characteristics, received integrated examinations, including whole-exome sequencing (WES) and Sanger sequencing. We identified nine pathogenic variants in the TCTN2, CPLANE1, INPP5E, NPHP1, and CC2D2A genes., Conclusion: Four novel pathogenic mutations in the TCTN2, CPLANE1, and INPP5E genes were reported. The findings broadened the genotypic spectrum of JS and contributed to a better understanding of genotype-phenotype correlation., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Mutations in CEP290, which encodes a centrosomal protein, cause Joubert syndrome, retinal dystrophy, and several other manifestations. Retinal dystrophy related to CEP290 mutation (Leber's congenital amaurosis type 10) presents with a severe visual impairment from birth, wandering eye movements, and oculodigital reflex. Fundus examination may initially be normal, but varying degrees of retinal pigmentation can be detected over time. This report presents 4 children who were referred to the ophthalmology clinic with a lack of eye contact and the suspicion of low vision. The ophthalmological examination revealed very poor visual function, the vision slightly improved over time, and enophthalmos became evident. There was neuromotor retardation in their history and mutations in the CEP290 gene were revealed in the whole-exome analysis. Both pediatricians and ophthalmologists should be aware of the coincidence between severe vision loss and neuromotor retardation and should refer patients for genetic testing if they suspect it. Genetic diagnosis will enable patients to be followed both neurologically and ophthalmologically and to benefit from rehabilitation opportunities that will contribute to visual and neurological development. It will also allow the family to receive genetic counseling on disease progression and heredity, and to follow ongoing gene therapy studies for mutations in the relevant gene., Competing Interests: Conflict of Interest: None declared., (Copyright: © 2023 by Beyoglu Eye Training and Research Hospital.)

Joubert syndrome (JBTS) is a Mendelian disorder of the primary cilium defined by the clinical triad of hypotonia, developmental delay, and a distinct cerebellar malformation called the molar tooth sign. JBTS is inherited in an autosomal recessive, autosomal dominant, or X-linked recessive manner. Though over 40 genes have been identified as causal for JBTS, molecular diagnosis is not made in 30%-40% of individuals who meet clinical criteria. TOPORS encodes topoisomerase I-binding arginine/serine-rich protein, and homozygosity for a TOPORS missense variant (c.29C > A; p.(Pro10Gln)) was identified in individuals with the ciliopathy oral-facial-digital syndrome in two families of Dominican descent. Here, we report an additional proband of Dominican ancestry with JBTS found by exome sequencing to be homozygous for the identical p.(Pro10Gln) TOPORS missense variant. Query of the Mount Sinai BioMe biobank, which includes 1880 individuals of Dominican ancestry, supports a high carrier frequency of the TOPORS p.(Pro10Gln) variant in individuals of Dominican descent. Our data nominates TOPORS as a novel causal gene for JBTS and suggests that TOPORS variants should be considered in the differential of ciliopathy-spectrum disease in individuals of Dominican ancestry., (© 2023 Wiley Periodicals LLC.)

Background and Aims: Joubert syndrome (JBTS, OMIM # 213300) is a group of ciliopathies characterized by mid-hindbrain malformation, developmental delay, hypotonia, oculomotor apraxia, and breathing abnormalities. Molar tooth sign in brain imaging is the hallmark for diagnosing JBTS. It is a clinically and genetically heterogeneous disorder involving mutations in more than 40 ciliopathy-related genes. However, long-term follow-up data are scarce, and further research is needed to determine the abundant phenotypes and genetics of this disorder. The study aimed to summarize clinical manifestations, particular appearance on cranial imaging, genetic data, and prognostic features of patients with JBTS., Methods: A retrospective case review of 36 cases of JBTS from May 1986 to December 2021 was performed. Clinical data of JBTS patients with development retardation and molar tooth sign on cranial imaging as the main features were analyzed. Genetic testing was performed according to consent obtained from patients and their families. The Gesell Developmental Scale was used to evaluate the intelligence level before and after treatment. The children were divided into a purely neurological JBTS (pure JBTS) group and JBTS with multi-organ system involvement group and then followed up every 3-6 months., Results: We enrolled 18 males and 18 females. Thirty-four (94.44%) cases had developmental delay, one patient (2.78%) had strabismus, and one patient (2.78%) had intermittent dizziness. There was one case co-morbid with Lesch-Nyhan syndrome. Three-quarters of cases had one or more other organ or system involvement, with a greater predilection for vision and hearing impairment. JBTS could also involve the skin. Thirty-one cases (86.11%) showed a typical molar tooth sign, and five cases showed a bat wing sign on cranial imaging. Abnormal video electroencephalogram (VEEG) result was obtained in 7.69% of cases. We found six JBTS-related novel gene loci variants: CPLANE1 : c.4189 + 1G > A, c.3101T > C(p.Ile1034Thr), c.3733T > C (p.Cys1245Arg), c.4080G > A(p.Lys1360=); RPGRIP1l : c.1351-11A > G; CEP120 : c.214 C > T(p.Arg72Cys). The CHD7 gene may be potentially related to the occurrence of JBTS. Analysis showed that the prognosis of pure JBTS was better than that of JBTS with neurological and non-neurological involvement after the formal rehabilitation treatment ( P  < 0.05). Of the three children with seizures, two cases had epilepsy with a poor prognosis, and another case had breath-holding spells., Conclusion: Our findings indicate that early cranial imaging is helpful for the etiological diagnosis of children with unexplained developmental delay and multiple malformations. Patients with JBTS may have coexisting skin abnormalities. The novel gene loci of CPLANE1 , RPGRIP1l , and CEP120 were associated with JBTS in our study and provided significant information to enrich the related genetic data. Future works investigating several aspects of the association between CHD7 gene and JBTS merit further investigation. The prognosis of children with pure JBTS is better than that of children with JBTS with non-neurological involvement., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Dong, Zhang, Yao, Jia, Wang, Zhu, Xu, Cheng, Zhao and Shi.)

Joubert syndrome (JBTS) is a rare autosomal recessive or X-linked congenital brain malformation with strong genetic heterogeneity. Other neurological features of JBTS include hypotonia, ataxia, developmental delay, and cognitive impairment. Hearing loss with JBTS has been reported in the literature. We present the case of a 3.5-year-old boy born to a healthy consanguineous South Indian couple who was presented with ataxic cerebral palsy (CP) and hearing impairment; medical reports confirmed typical brain malformations of JBTS. Hearing impairment was screened by audiological assessment, which confirmed the presence of severe-profound hearing loss with outer hair cell dysfunction. Whole-exome sequencing (WES) was performed to know the molecular aspects of the condition and to detect any novel mutations. The homozygous mutation AHI1 c.2023G > A associated with JBTS type 3 and GJB2 c.71G > A mutation associated with hearing impairment were identified. Sanger sequencing was performed to validate the result and it identified heterozygous AHI1 c.2023G > A and GJB2 c.71G > A in the patient's parents. This study confirms the diagnosis of JBTS by WES helps identify the genetic causes of hereditary disorders that accelerate genetic evaluation and counseling for at-risk families., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Objectives: To study the clinical and genetic features of Joubert syndrome (JS) in children., Methods: A retrospective analysis was performed on the clinical data, genetic data, and follow-up data of 20 children who were diagnosed with JS in the Department of Children's Rehabilitation, the Third Affiliated Hospital of Zhengzhou University, from January 2017 to July 2022., Results: Among the 20 children with JS, there were 11 boys and 9 girls. The common clinical manifestations were developmental delay (20 children, 100%), abnormal eye movement (19 children, 95%), and hypotonia (16 children, 80%), followed by abnormal respiratory rhythm in 5 children (25%) and unusual facies (including prominent forehead, low-set ears, and triangular mouth) in 3 children (15%), and no limb deformity was observed. All 20 children (100%) had the typical "molar tooth sign" and "midline cleft syndrome" on head images, and 6 children (30%) had abnormal eye examination results. Genetic testing was performed on 7 children and revealed 6 pathogenic genes, i.e., the CPLANE1 , RPGRIP1L , MKS1 , CC2D2A , CEP120 , and AHI1 genes., Conclusions: For children with developmental delay, especially those with abnormal eye movement and hypotonia, it is recommended to perform a head imaging examination to determine the presence or absence of "molar tooth sign" and "midline cleft syndrome", so as to screen for JS to avoid missed diagnosis and misdiagnosis. There are many pathogenic genes for JS, and whole-exome sequencing can assist in the diagnosis of JS.

Joubert syndrome and related disorders (JSRD) are rare and intractable diseases characterized by delayed psychomotor development, hypotonia and/or ataxia, and abnormal respiratory and eye movements. Cerebellar vermis agenesis and molar tooth signs are distinct on cerebral magnetic resonance imaging (MRI). Children with JSRD present with delayed psychomotor development, including intellectual disability and emotional or behavioral problems. Rehabilitation treatments are provided to promote psychomotor development. However, limited reports and evidence exist on rehabilitation treatments for children with JSRD. Three children with JSRD received rehabilitation treatment. The children received rehabilitation treatment once a week to once every one to two months at our hospital and/or other facilities. All patients received physical, occupational, and speech-language-hearing therapy, depending on their symptoms and conditions. In children with tracheostomies due to abnormal respiration, respiratory physical therapy and speech-language-hearing therapy, including augmentative and alternative communication, were needed. For hypotonia and ataxia, an orthotic intervention was considered in all three cases, and foot or ankle-foot orthoses were used in two cases. Although there is no specific or established rehabilitation method for children with JSRD, appropriate rehabilitation approaches, including physical, occupational, speech-language-hearing therapies and orthotic intervention, should be considered and provided to improve their function and expand their activity and participation. Orthotic intervention for hypotonia seems reasonable for improving gross motor development and function in children with JSRD., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Mano et al.)

Background: The term congenital ocular motor apraxia (COMA), coined by Cogan in 1952, designates the incapacity to initiate voluntary eye movements performing rapid gaze shift, so called saccades. While regarded as a nosological entity by some authors, there is growing evidence that COMA designates merely a neurological symptom with etiologic heterogeneity. In 2016, we reported an observational study in a cohort of 21 patients diagnosed as having COMA. Thorough re-evaluation of the neuroimaging features of these 21 subjects revealed a previously not recognized molar tooth sign (MTS) in 11 of them, thus leading to a diagnostic reassignment as Joubert syndrome (JBTS). Specific MRI features in two further individuals indicated a Poretti-Boltshauser syndrome (PTBHS) and a tubulinopathy. In eight patients, a more precise diagnosis was not achieved. We pursued this cohort aiming at clarification of the definite genetic basis of COMA in each patient., Results: Using a candidate gene approach, molecular genetic panels or exome sequencing, we detected causative molecular genetic variants in 17 of 21 patients with COMA. In nine of those 11 subjects diagnosed with JBTS due to newly recognized MTS on neuroimaging, we found pathogenic mutations in five different genes known to be associated with JBTS, including KIAA0586, NPHP1, CC2D2A, MKS1, and TMEM67. In two individuals without MTS on MRI, pathogenic variants were detected in NPHP1 and KIAA0586, arriving at a diagnosis of JBTS type 4 and 23, respectively. Three patients carried heterozygous truncating variants in SUFU, representing the first description of a newly identified forme fruste of JBTS. The clinical diagnoses of PTBHS and tubulinopathy were confirmed by detection of causative variants in LAMA1 and TUBA1A, respectively. In one patient with normal MRI, biallelic pathogenic variants in ATM indicated variant ataxia telangiectasia. Exome sequencing failed to reveal causative genetic variants in the remaining four subjects, two of them with clear MTS on MRI., Conclusions: Our findings indicate marked etiologic heterogeneity in COMA with detection of causative mutations in 81% (17/21) in our cohort and nine different genes being affected, mostly genes associated with JBTS. We provide a diagnostic algorithm for COMA., (© 2023. The Author(s).)

Joubert syndrome (JS) is a clinically and genetically heterogeneous genetic disorder. To date, 40 JS-causing genes have been reported and CPLANE1 is one of the most frequently mutated, with biallelic pathogenic missense and truncating variants explaining up to 14% of JS cases. We present a case of JS diagnosed after the identification of a novel biallelic intragenic duplication of exons 20-46 of CPLANE1. The quadruplication was identified by short-read sequencing and copy number variant analysis and confirmed in tandem by long PCR with the breakpoints defined by a nanopore-based long-read sequencing approach. Based on the genetic findings and the clinical presentation of the patient, a brain MRI was ordered, evidencing the molar tooth sign, which confirmed the diagnosis of JS in the patient. This is, to the best of our knowledge, the first report of an intragenic duplication in this gene as the potential molecular mechanism of JS., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background. Joubert syndrome (JS) is a rare autosomal recessive ciliopathy with an estimated prevalence of 1 in 100,000. JS is characterized by hyperpnoea, hypotonia, ataxia, developmental delay and various neuropathological abnormalities in the brain including cerebellar hypoplasia and cerebellar vermis aplasia. JS can also have variable multi-organ involvement, including the retina, kidneys, liver, and musculoskeletal system. Methods and Results . Here we report a clinical description of two-year-old girl presenting with breathing difficulties, hyperechoic kidneys with loss of corticomedullary differentiation. Brain magnetic resonance imaging revealed the typical molar tooth sign consistent with a clinical diagnosis of JS and retinal examination showed severe retinal dystrophy leading to blindness. Molecular genetic analysis using whole exome sequencing and Sanger sequence confirmation demonstrated a homozygous mutation (c.5493delA, p.(A1832fs*19) in CEP290 which segregated from either parent and was consistent with the multisystem ciliopathy phenotype. This precise variant has been described previously in 2 families from the Kosovar-Albanian region suggesting this allele is a recurrent mutation in this population. Conclusions. Mutations in CEP290 lead to multisystem ciliopathy syndromes and molecular genetic diagnostics of such cases allows precise diagnosis, screening of at risk relatives and appropriate management., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Spahiu L et al.)

The CC2D2A gene is essential for primary cilia formation, and its disruption has been associated with Joubert Syndrome-9 (JBTS9), a ciliopathy with typical neurodevelopmental features. Here, we describe an Italian pediatric patient with typical features of Joubert Syndrome (JBTS): "Molar Tooth Sign", global developmental delay, nystagmus, mild hypotonia, and oculomotor apraxia. Whole exome sequencing and segregation analysis identified in our infant patient a novel heterozygous germline missense variant c.3626C > T; p.(Pro1209Leu) inherited from the father and a novel 7.16 kb deletion inherited from the mother. To the best of our knowledge, this is the first report showing a novel missense and deletion variant involving exon 30 of the CC2D2A gene.

Exploration into the causes of hereditary renal cystic diseases demonstrates a deep-rooted connection with the proteomic components of the cellular organelle cilia. Cilia are essential to the signaling cascades, and their dysfunction has been tied to a range of renal cystic diseases initiating with studies on the oak ridge polycystic kidney (ORPK) mouse model. Here, we delve into renal cystic pathologies that have been tied with ciliary proteosome and highlight the genetics associated with each. The pathologies are grouped based on the mode of inheritance, where inherited causes that result in cystic kidney disease phenotypes include autosomal dominant and autosomal recessive polycystic kidney disease, nephronophthisis (Bardet-Biedl syndrome and Joubert Syndrome), and autosomal dominant tubulointerstitial kidney disease. Alternatively, phakomatoses-, also known as neurocutaneous syndromes, associated cystic kidney diseases include tuberous sclerosis (TS) and Von Hippel-Lindau (VHL) disease. Additionally, we group the pathologies by the mode of inheritance to discuss variations in recommendations for genetic testing for biological relatives of a diagnosed individual., Competing Interests: The authors declare that there is no conflicts of interest., (Copyright: © 2023 Indian Journal of Nephrology.)

Background: Short-rib thoracic dysplasia (SRTD) and Joubert syndrome (JS) are rare genetic ciliopathies, and individuals with either syndrome can manifest cerebellar malformation and variable developmental delays. However, neither of these conditions is easily diagnosed during pregnancy due to a limited fetal phenotype. Here, we investigated a fetus that was initially observed to have short limbs and polydactyly and discovered a compound heterozygous pathogenesis through exome sequencing (ES)., Methods: Simultaneous trio-ES and chromosome microarray analysis was provided for the fetus. The presence and effects of these variants on splicing were further validated at the DNA and RNA levels., Results: Only short limbs and post-axial polydactyly of the fetus were detected during the second trimester. Two variants (c.3940+1G>A and c.3303G>A), affecting splicing of KIAA0586, were identified from amniocytes through ES and validated by Sanger sequencing. More intensive fetal monitoring was applied, and the fetus was also found to have deformed cerebellar malformation and a constricted thoracic cage., Conclusions: Herein, we report the genetic pathogenesis of SRTD and/or JS associated with KIAA0586 in a fetus. The novel splicing variants observed expand the spectrum of KIAA0586 in SRTD and/or JS. Based on the genetic data and the distinct corresponding phenotypes discovered by imaging examination, a comprehensive diagnosis was made during pregnancy and more valuable prognostic information was provided for the parents., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Pediatric tracheostomy in COVID-19 patients is a rarity. Joubert syndrome is a rare genetic disease, involving a lack of muscle control. We report the case of a child with Joubert syndrome and a severe form of COVID-19 infection, in whom we performed tracheostomy in order to replace prolonged intubation and mechanical ventilation; successful decannulation was performed after 12 months. Successful decannulation is still possible in a child with severe comorbidities (Joubert syndrome) even if it might take much longer than in patients without comorbidities., Competing Interests: None., (© 2023 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Joubert syndrome (JBTS) is a class of heterogeneous ciliopathy genetically associated with CPLANE1 mutations. The characteristics of clinical phenotypes and CPLANE1 variants were analyzed in a 2-month-old patient. A 2-month-old patient with JBTS was diagnosed after clinical evaluation including family history, physical examination, cerebral MRI, ultrasonography imaging, VEGG, ocular fundus examination, and comprehensive blood and urine testing. Whole exome sequencing (WES) was performed to detect CPLANE1 variants, and Sanger sequencing was used to confirm the variants. This JBTS patient presented with oculomotor apraxia, dysregulation of breathing pattern, and ataxia. MRI revealed poor continuity of cerebelli, batwing appearance, and molar tooth sign. This patient was noted with abnormal hematology, dysregulation of hepatic function, thyroid function, immunity, and renal function, and encephalopathy. CPLANE1 (c.8948dupT (p.P2984Tfs*7) and c.247G > T (p.G83X)) variants were noticed in the patient as a pathogenic variant and caused autosomal recessive inheritance. The JBTS patient with mutations in CPLANE1 (c.8948dupT (p.P2984Tfs*7) and c.247G > T (p.G83X)) developed JBTS phenotypes. The novel CPLANE1 c.8948dupT (p.P2984Tfs*7) variant will assist clinicians and geneticists in reaching a precise diagnosis for JBTS., Competing Interests: Conflict of interest: Authors state no conflict of interest., (© 2023 the author(s), published by De Gruyter.)

Background: KIAA0586, also known as Talpid3, plays critical roles in primary cilia formation and hedgehog signaling in humans. Variants in KIAA0586 could cause some different ciliopathies, including Joubert syndrome (JBTS), which is a clinically and genetically heterogeneous group of autosomal recessive neurological disorders., Methods and Results: A 9-month-old girl was diagnosed as JBTS by the "molar tooth sign" of the mid-brain and global developmental delay. By whole-exome sequencing, we identified a single nucleotide variant c.3303G > A and a 1.38-kb deletion in KIAA0586 in the proband. These two variants of KIAA0586 were consistent with the mode of autosomal recessive inheritance in the family, which was verified using Sanger sequencing., Conclusions: This finding of a compound heterozygote with a 1.38-kb deletion and c.3303G > A gave a precise genetic diagnosis for the patient, and the novel 1.38-kb deletion also expanded the pathogenic variation spectrum of JBTS caused by KIAA0586., (© 2023. The Author(s).)

Background: Joubert syndrome (JBS) is a rare neurodevelopmental disorder associated with progressive renal, liver, and retinal involvement that exhibits heterogeneity in both clinical manifestations and genetic etiology. Therefore, it is difficult to make a definite prenatal diagnosis. Methods: Whole-exome sequencing and Sanger sequencing were performed to screen the causative gene variants in a suspected JBS family. RNA-seq and protein model prediction were performed to clarify the potential pathogenic mechanism. A more comprehensive review of previously reported cases with OFD1 variants is presented and may help to establish a genotype-phenotype. Results: We identified a novel non-sense variant in the OFD1 gene, OFD1 (NM&#95;003611.3): c.2848A>T (p.Lys950Ter). Sanger sequencing confirmed cosegregation among this family. RNA-seq confirmed that partial degradation of mutant transcripts, which was predicted to be caused by the non-sense-mediated mRNA decay (NMD) mechanism, may explain the reduction in the proportion of mutant transcripts. Protein structure prediction of the non-sense variant transcript revealed that this variant may lead to a change in the OFD1 protein structure. Conclusion: The genetic variation spectrum of JBS10 caused by OFD1 was broadened. The novel variants further deepened our insight into the molecular mechanism of the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Wang, Li, Ding, Liu, Xiong, Yang, Zhang, Wu and Yin.)

The cytosolic carboxypeptidase 6 (CCP6) catalyzes the deglutamylation of polyglutamate side chains, a post-translational modification that affects proteins such as tubulins or nucleosome assembly proteins. CCP6 is involved in several cell processes, such as spermatogenesis, antiviral activity, embryonic development, and pathologies like renal adenocarcinoma. In the present work, the cellular role of CCP6 has been assessed by BioID, a proximity labeling approach for mapping physiologically relevant protein-protein interactions (PPIs) and bait proximal proteins by mass spectrometry. We used HEK 293 cells stably expressing CCP6-BirA* to identify 37 putative interactors of this enzyme. This list of CCP6 proximal proteins displayed enrichment of proteins associated with the centrosome and centriolar satellites, indicating that CCP6 could be present in the pericentriolar material. In addition, we identified cilium assembly-related proteins as putative interactors of CCP6. In addition, the CCP6 proximal partner list included five proteins associated with the Joubert syndrome, a ciliopathy linked to defects in polyglutamylation. Using the proximity ligation assay (PLA), we show that PCM1, PIBF1, and NudC are true CCP6 physical interactors. Therefore, the BioID methodology confirms the location and possible functional role of CCP6 in centrosomes and centrioles, as well as in the formation and maintenance of primary cilia.