Syndromic ciliopathy: a taiwanese single-center study.

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_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.

Dual and opposing roles for the kinesin-2 motor, KIF17, in Hedgehog-dependent cerebellar development.

While the kinesin-2 motors KIF3A and KIF3B have essential roles in ciliogenesis and Hedgehog (HH) signal transduction, potential role(s) for another kinesin-2 motor, KIF17, in HH signaling have yet to be explored. Here, we investigated the contribution of KIF17 to HH-dependent cerebellar development, where Kif17 is expressed in both HH-producing Purkinje cells and HH-responding cerebellar granule neuron progenitors (CGNPs). Germline Kif17 deletion in mice results in cerebellar hypoplasia due to reduced CGNP proliferation, a consequence of decreased HH pathway activity mediated through decreased Sonic HH (SHH) protein. Notably, Purkinje cell-specific Kif17 deletion partially phenocopies Kif17 germline mutants. Unexpectedly, CGNP-specific Kif17 deletion results in the opposite phenotype-increased CGNP proliferation and HH target gene expression due to altered GLI transcription factor processing. Together, these data identify KIF17 as a key regulator of HH-dependent cerebellar development, with dual and opposing roles in HH-producing Purkinje cells and HH-responding CGNPs.

Joubert syndrome presenting bilateral peroneal neuropathies: A case report.

RATIONALE: Joubert syndrome (JS) is a rare genetic disorder that presents with various neurological symptoms, primarily involving central nervous system dysfunction. Considering the etiology of JS, peripheral nervous system abnormalities cannot be excluded; however, cases of JS accompanied by peripheral nervous system abnormalities have not yet been reported. Distinct radiological findings on brain magnetic resonance imaging were considered essential for the diagnosis of JS. However, recently, cases of JS with normal or nearly normal brain morphology have been reported. To date, there is no consensus on the most appropriate diagnostic method for JS when imaging-based diagnostic approach is challenging. This report describes the case of an adult patient who exhibited bilateral peroneal neuropathies and was finally diagnosed with JS through genetic testing. PATIENT CONCERNS AND DIAGNOSIS: A 27-year-old man visited our outpatient clinic due to a gait disturbance that started at a very young age. The patient exhibited difficulty maintaining balance, especially when walking slowly. Oculomotor apraxia was observed on ophthalmic evaluation. During diagnostic workups, including brain imaging and direct DNA sequencing, no conclusive findings were detected. Only nerve conduction studies revealed profound bilateral peroneal neuropathies. We performed whole genome sequencing to obtain a proper diagnosis and identify the gene mutation responsible for JS. LESSONS: This case represents the first instance of peripheral nerve dysfunction in JS. Further research is needed to explore the association between JS and peripheral nervous system abnormalities. Detailed genetic testing may serve as a valuable tool for diagnosing JS when no prominent abnormalities are detected in brain imaging studies.

Joubert syndrome-derived induced pluripotent stem cells show altered neuronal differentiation in vitro.

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.

High Incidence of CPLANE1-Related Joubert Syndrome in the Products of Conceptions from Early Pregnancy Losses

Background: The fetal monogenic causes of early pregnancy losses (EPLs) are mainly unknown, with only a few articles on the subject published. In our previous study of EPLs using whole-exome sequencing analysis, we confirmed a genetic diagnosis of CPLANE1-related Joubert syndrome (JS) in three EPLs from two couples and identified a relatively common CPLANE1 allele among our population (NM_001384732.1:c.1819delT;c.7817T>A, further after referred as "complex allele"). Pathogenic variants in the CPLANE1 (C5orf42) gene are reported to cause JS type 17, a primary ciliopathy with various system defects. Aims: To examine the hypothesis that the CPLANE1 "complex allele," whether homozygous or compound heterozygous, is a common cause of EPLs in our population. Study Design: Cohort study/case-control study.ontrol study. Methods: In this study, we used polymerase chain reaction-based methods to screen for CPLANE1 "complex allele" presence among 246 euploid EPLs (< 12 gestational weeks) from families in North Macedonia. We also investigated the impact of this allele in 650 women with EPLs versus 646 women with no history of pregnancy loss and at least one livebirth, matched by ethnic origin. Results: We found a high incidence of JS in the total study group of EPLs (2.03%), with a considerably higher incidence among Albanian families (6.25%). Although not statistically significant, women with EPLs had a higher allele frequency of the CPLANE1 "complex allele" (AF = 1.38%) than the controls (AF = 0.85%; p = 0.2). Albanian women had significantly higher frequency of the "complex allele" than the Macedonians (AF = 1.65% and 0.39%, respectively; p = 0.003). Conclusion: To the best of our knowledge, this is the highest reported incidence of fetal monogenic disease that might cause EPLs. Targeted screening for the CPLANE1 "complex allele" would be warranted in Albanian ethnic couples because it would detect one JS in every 16 euploid EPLs. Our findings have a larger impact on the pathogenesis of pregnancy loss and contribute to a better understanding of the pathogenicity of the variants in the CPLANE1 gene.

Joubert syndrome causing mutation in C2 domain of CC2D2A affects structural integrity of cilia and cellular signaling molecules.

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.

Novel compound heterozygous variants in ARL13B lead to Joubert syndrome.

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.

A genetic variant in the MAST1 gene is associated with mega-corpus-callosum syndrome with hypoplastic cerebellar vermis, in a fetus.

BACKGROUND: Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations is a rare neurological disorder that is associated with typical clinical and imaging features. The syndrome is caused by pathogenic variants in the MAST1 gene, which encodes a microtubule-associated protein that is predominantly expressed in postmitotic neurons in the developing nervous system. METHODS: Fetal DNA from umbilical cord blood samples and genomic DNA from peripheral blood lymphocytes were subjected to whole-exome sequencing. The potential causative variants were verified by Sanger sequencing. RESULTS: A 26-year-old primigravid woman was referred to our prenatal center at 25 weeks of gestation due to abnormal ultrasound findings in the brain of the fetus. The brain abnormalities included wide cavum septum pellucidum, shallow and incomplete bilateral lateral fissure cistern, bilateral dilated lateral ventricles, hyperplastic corpus callosum, lissencephaly, and cortical dysplasia. No obvious abnormalities were observed in the brainstem or cerebellum hemispheres, but the cerebellum vermis was small. Whole-exome sequencing identified a de novo, heterozygous missense variant, c.695T>C(p.Leu232Pro), in the MAST1 gene and a genetic diagnosis of mega-corpus-callosum syndrome was considered. CONCLUSION: This study is the first prenatal case of MAST1-related disorder reported in the Chinese population and has expanded the mutation spectrum of the MAST1 gene.

Suspected Autosomal Recessive Polycystic Kidney Disease but Cerebellar Vermis Hypoplasia, Oligophrenia Ataxia, Coloboma, and Hepatic Fibrosis (COACH) Syndrome in Retrospect, A Delayed Diagnosis Aided by Genotyping and Reverse Phenotyping: A Case Report and A Review of the Literature.

The clinical features of cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis (COACH) characterize the rare autosomal recessive multisystem disorder called COACH syndrome. COACH syndrome belongs to the spectrum of Joubert syndrome and related disorders (JSRDs) and liver involvement distinguishes COACH syndrome from the rest of the JSRD spectrum. Developmental delay and oculomotor apraxia occur early but with time, these can improve and may not be readily apparent or no longer need active medical management. Congenital hepatic fibrosis and renal disease, on the other hand, may develop late, and the temporal incongruity in organ system involvement may delay the recognition of COACH syndrome. We present a case of a young adult presenting late to a Renal Genetics Clinic for evaluation of renal cystic disease with congenital hepatic fibrosis, clinically suspected to have autosomal recessive polycystic kidney disease. Following genetic testing, a reevaluation of his medical records from infancy, together with reverse phenotyping and genetic phasing, led to a diagnosis of COACH syndrome.

The role of liver transplantation in COACH syndrome (Joubert syndrome with congenital hepatic fibrosis): A review of the literature.

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.

Nanopore long-read sequencing analysis reveals ZIC1 dysregulation caused by a de novo 3q inversion with a breakpoint located 7 kb downstream of ZIC1.

Zic family member 1 (ZIC1), a gene located on chromosome 3q24, encodes a transcription factor with zinc finger domains that is essential for the normal development of the cerebellum. Heterozygous loss-of-function of ZIC1 causes Dandy-Walker malformation, while heterozygous gain-of-function leads to a multiple congenital anomaly syndrome characterized by craniosynostosis, brain abnormalities, facial features, and learning disability. In this study, we present the results of genetic analysis of a male patient with clinically suspected Gomez-Lopez-Hernandez syndrome. The patient displayed multiple congenital abnormalities, including bicoronal craniosynostosis, characteristic facial features, cerebellar malformation with rhombencephalosynapsis, and temporal alopecia, and a de novo inversion of chromosome 3q. Breakpoint analysis using a Nanopore long-read sequencer revealed a breakpoint in the distal centromere of 3q24 located 7 kb downstream of the 3' untranslated region of ZIC1. On the basis of the clinical similarities, we concluded that the abnormalities in this patient were caused by the transcriptional dysregulation of ZIC1. We hypothesize the underlying molecular mechanisms of transcriptional dysregulation of ZIC1 such as the abnormalities in topologically associated domains encompassing ZIC1. This study highlights the usefulness of long-read sequencing in the analysis of de novo balanced chromosomal abnormalities.

New Insights into the Neuropsychological Profile and Intellectual Quotient Variability in Joubert Syndrome Compared to Other Congenital Cerebellar Malformations.

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.

Undifferentiated psychosis or schizophrenia associated with vermis-predominant cerebellar hypoplasia.

Schizophrenia (SCZ) is a well-studied neuropsychiatric condition that has been shown to have a high degree of genetic heritability. Still, little data on the specific genetic risk variants associated with the disease exists. Classification of the SCZ phenotype into SCZ-related endophenotypes is a promising methodology to parse out and elucidate the specific genetic risk variants for each. Here, we present a series of 17 previously reported individuals and a new proband with similar SCZ-related neuropsychiatric characteristics and shared brain imaging findings. Unsurprisingly, these individuals shared classic psychiatric features of SCZ. Interestingly, we also identified shared neuropsychiatric features in this series of individuals that had not been highlighted previously. A consistently decreased IQ, memory impairment, sleep and speech disturbances, and attention deficits were commonly reported findings. The brain imaging findings among these individuals also consistently showed posterior vermis predominant cerebellar hypoplasia (CBLH-V). Most individuals' diagnoses were initially described as Dandy-Walker malformation; however, our independent review of imaging suggests a more consistent pattern of posterior vermis predominant cerebellar hypoplasia rather than true Dandy-Walker malformation. While the specific genetic risk variants for this endophenotype are yet to be described, the aim of this paper is to present the shared neuropsychiatric features and consistent, symmetrical brain image findings which suggest that this subset of individuals comprises an endophenotype of SCZ with a high genetic solve rate.

Phenotypic variability in Joubert syndrome is partially explained by ciliary pathophysiology.

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.

Pontine tegmental cap dysplasia: the role of diffusion tensor imaging.

Pontine tegmental cap dysplasia (PTCD) is a rare hindbrain malformation syndrome. Recurrent aspiration pneumonia is a major cause of death during a first year of life. We report the case of month-old child with an inability to suck milk since birth and multiple convulsions. PTCD was identified using tractography and MRI. This case report describes the imaging findings, the role of diffusion tensor imaging in PTCD and its differentiating features from Joubert syndrome and related disorders (JSRDs). The constellation of imaging features in PTCD includes a midbrain appearance resembling a molar tooth, a flattened anterior pontine belly, hypoplastic middle cerebellar peduncles and dorsal pontine tegmental cap. 'Tegmental cap' is a transversely oriented abnormal bundle of fibres with absent superior cerebellar peduncle decussation. Accurate diagnosis with MRI and tractography and differentiating PTCD from JSRD would help the clinician for appropriate genetic counselling and prognosis.

A novel mutation of the RPGRIP1L gene in a Chinese boy with Joubert syndrome with oculorenal involvement.

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.

Novel association of Dandy-Walker malformation with CAPN15 variants expands the phenotype of oculogastrointestinal neurodevelopmental syndrome.

Oculogastrointestinal neurodevelopmental syndrome has been described in seven previously published individuals who harbor biallelic pathogenic variants in the CAPN15 gene. Biallelic missense variants have been reported to demonstrate a phenotype of eye abnormalities and developmental delay, while biallelic loss of function variants exhibit phenotypes including microcephaly and craniofacial abnormalities, cardiac and genitourinary malformations, and abnormal neurologic activity. We report six individuals from three unrelated families harboring biallelic deleterious variants in CAPN15 with phenotypes overlapping those previously described for this disorder. Of the individuals affected, four demonstrate radiographic evidence of the classical triad of Dandy-Walker malformation including hypoplastic vermis, fourth ventricle enlargement, and torcular elevation. Cerebellar anomalies have not been previously reported in association with CAPN15-related disease. Here, we present three unrelated families with findings consistent with oculogastrointestinal neurodevelopmental syndrome and cerebellar pathology including Dandy-Walker malformation. To corroborate these novel clinical findings, we present supporting data from the mouse model suggesting an important role for this protein in normal cerebellar development. Our findings add six molecularly confirmed cases to the literature and additionally establish a new association of Dandy-Walker malformation with biallelic CAPN15 variants, thereby expanding the neurologic spectrum among patients affected by CAPN15-related disease.

Joubert syndrome: a case report of neonatal presentation and early diagnosis.

BACKGROUND: Joubert syndrome is a rare genetic condition with a prevalence of 1:80,000-1:100,000. In most cases, it shows an autosomal autosomal recessive hereditary pattern, although X-linked and autosomal dominant cases have been described. The distinctive characteristic of this syndrome is the malformation at cerebral and cerebellar levels, known as the "molar tooth sign," hypotonia, and delayed neurodevelopment. CASE REPORT: We describe the case of a newborn with transient tachypnea. However, during hospital stay, he showed other clinical signs not corresponding to the admission diagnosis, such as bradycardia, apneas, hypotonia, and alteration in swallowing mechanics. To rule out etiologies of central origin, we conducted a magnetic resonance of the brain and identified the "molar tooth sign," where the pathognomonic sign of Joubert syndrome. CONCLUSIONS: Rare genetic diseases may manifest as early as the neonatal period with non-specific signs. The early diagnosis of Joubert syndrome is reflected in better pediatric follow-up, which impacts its prognosis and the possibility of improving the patient's quality of life with a multidisciplinary management and genetic counseling.

INTRODUCCIÓN: El síndrome de Joubert es una rara condición genética con una prevalencia de 1:80,000 a 1:100,000. En la mayoría de los casos se presenta con un patrón de herencia autosómica recesiva, aunque se han reporatdo casos ligados al cromosoma X y autosómicos dominantes. La característica distintiva de este síndrome es la malformación a nivel cerebral y del cerebelo conocido como el "signo del molar", hipotonía y retraso en el neurodesarrollo. CASO CLÍNICO: Se describe el caso de un recién nacido con taquipnea transitoria del recién nacido; sin embargo, durante su estancia manifestó otros signos que no correspondían con el diagnóstico de ingreso, como bradicardia, apneas, hipotonía y alteración en la mecánica de la deglución. Para descartar etiologías de origen central, se realizó una resonancia magnética cerebral en la que se detectó el "signo del molar", patognomónico del síndrome de Joubert. CONCLUSIONES: Las enfermedades genéticas raras pueden manifestarse desde el periodo neonatal con signos muy inespecíficos. El diagnóstico precoz del Síndrome de Joubert permite un mejor seguimiento pediátrico que impacta en su pronóstico y en la posibilidad de mejorar la calidad de vida del paciente con un manejo multidisciplinario, así como brindar asesoramiento genético.