Systematic analysis of physical examination characteristics of 94 individuals with Joubert syndrome: Keys to suspecting the diagnosis.

Joubert syndrome (JS) is a neurodevelopmental disorder characterized by hypotonia and developmental delay, as well as the obligatory molar tooth sign on brain imaging. Since hypotonia and developmental delay are nonspecific features, there must be a high level of clinical suspicion of JS so that the diagnostic brain imaging and/or molecular testing for the >38 genes associated with JS is/are obtained. The goal of this study was to analyze clinical photographs of a cohort of patients with JS to define a list of physical examination features that should prompt investigation for JS. Analysis of photographs from 94 individuals with JS revealed that there is a recognizable pattern of facial features in JS that changes over time as individuals age. Macrocephaly, head tilting even when looking straight ahead, eye movement abnormalities (oculomotor apraxia, nystagmus, strabismus), and ptosis are common in those with JS. Distinctive features in younger children include triangular-shaped open mouth with tongue protrusion; in older children and adults, mandibular prognathia and prominent nasal bridge are common.

Growth in Joubert syndrome: Growth curves and physical measurements with correlation to genotype and hepatorenal disease in 170 individuals.

Joubert syndrome (JS) is a genetically heterogenous disorder of nonmotile cilia with a characteristic "molar tooth sign" on axial brain imaging. Clinical features can include developmental delay, kidney failure, liver disease, and retinal dystrophy. Prospective growth and measurement data on 170 individuals with JS were collected, including parental measurements, birth measurements, and serial measures when available. Analysis of growth parameters in the context of hepatorenal disease, genotype, and other features was performed on 100 individuals assessed at the National Institutes of Health Clinical Center. Individuals with JS had shorter stature despite normal growth velocity and were shorter than predicted for mid-parental height. Individuals were lighter in weight, resulting in a normal body mass index (BMI). Head circumference was larger, averaging 1.9 Z-scores above height. At birth, head circumference was proportional to length. Individuals with variants in CPLANE1 had a larger head circumference compared to other genotypes; individuals with evidence of liver disease had lower weight and BMI; and individuals with polydactyly had shorter height. Here we present growth curves and physical measurements for Joubert syndrome based on the largest collection of individuals with this disorder to aid in clinical management and diagnosis.

Healthcare recommendations for Joubert syndrome.

Joubert syndrome (JS) is a recessive neurodevelopmental disorder defined by a characteristic cerebellar and brainstem malformation recognizable on axial brain magnetic resonance imaging as the "Molar Tooth Sign". Although defined by the neurological features, JS is associated with clinical features affecting many other organ systems, particularly progressive involvement of the retina, kidney, and liver. JS is a rare condition; therefore, many affected individuals may not have easy access to subspecialty providers familiar with JS (e.g., geneticists, neurologists, developmental pediatricians, ophthalmologists, nephrologists, hepatologists, psychiatrists, therapists, and educators). Expert recommendations can enable practitioners of all types to provide quality care to individuals with JS and know when to refer for subspecialty care. This need will only increase as precision treatments targeting specific genetic causes of JS emerge. The goal of these recommendations is to provide a resource for general practitioners, subspecialists, and families to maximize the health of individuals with JS throughout the lifespan.

Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency.

Joubert syndrome and related disorders (JSRD) are a heterogeneous group of ciliopathies defined based on the mid-hindbrain abnormalities that result in the characteristic "molar tooth sign" on brain imaging. The core clinical findings of JSRD are hypotonia, developmental delay, abnormal eye movements and breathing abnormalities. To date, more than 30 JSRD genes that encode proteins important for structure and/or function of cilia have been identified. Here, we present 2 siblings with Joubert syndrome associated with growth hormone deficiency. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C). The intronic mutation alters normal splicing by activating a cryptic acceptor splice site in exon 16. The novel acceptor site skips nine nucleotides, deleting three amino acids from the protein coding frame. KIAA0753 (OFIP) is a centrosome and pericentriolar satellite protein, previously not known to cause Joubert syndrome. We present comprehensive clinical descriptions of the Joubert syndrome patients as well as the cellular phenotype of defective ciliogenesis in the patients' fibroblasts.

Molecular genetic findings and clinical correlations in 100 patients with Joubert syndrome and related disorders prospectively evaluated at a single center.

PURPOSE: Joubert syndrome (JS) is a genetically and clinically heterogeneous ciliopathy characterized by distinct cerebellar and brainstem malformations resulting in the diagnostic "molar tooth sign" on brain imaging. To date, more than 30 JS genes have been identified, but these do not account for all patients. METHODS: In our cohort of 100 patients with JS from 86 families, we prospectively performed extensive clinical evaluation and provided molecular diagnosis using a targeted 27-gene Molecular Inversion Probes panel followed by whole-exome sequencing (WES). RESULTS: We identified the causative gene in 94% of the families; 126 (27 novel) unique potentially pathogenic variants were found in 20 genes, including KIAA0753 and CELSR2, which had not previously been associated with JS. Genotype-phenotype correlation revealed the absence of retinal degeneration in patients with TMEM67, C5orf52, or KIAA0586 variants. Chorioretinal coloboma was associated with a decreased risk for retinal degeneration and increased risk for liver disease. TMEM67 was frequently associated with kidney disease. CONCLUSION: In JS, WES significantly increases the yield for molecular diagnosis, which is essential for reproductive counseling and the option of preimplantation and prenatal diagnosis as well as medical management and prognostic counseling for the age-dependent and progressive organ-specific manifestations, including retinal, liver, and kidney disease.Genet Med advance online publication 26 January 2017.

Neuropsychological phenotypes of 76 individuals with Joubert syndrome evaluated at a single center.

Joubert syndrome (JS) is a genetically heterogeneous ciliopathy characterized by hypo-dysplasia of the cerebellar vermis, a distinct hindbrain/midbrain malformation (molar tooth sign), and intellectual disability. We evaluated the neuropsychological profiles of 76 participants with JS in the context of molecular genetics and clinical covariates. Evaluations included neuropsychological testing, structured parental interviews, DNA sequencing, brain magnetic resonance imaging (MRI), electroencephalography (EEG), ophthalmologic examination, and assessment for renal and hepatic disease. On average, participants manifested Full Scale Intelligence Quotients (FSIQ) in the moderately to profoundly low range (M = 64.3 ± 15.3). Of the Wechsler index scores, verbal comprehension was least affected and processing speed was most affected. Receptive language was rated as better than expressive language on the Vineland Adaptive Behavior Scales-Second Edition. Those with abnormal EEG had a significantly lower FSIQ (n = 15; M = 50.7 ± 12.9) compared to participants with normal EEG (n = 39; M = 64.7 ± 16.3; p = .004). Participants taking psychiatric medications manifested a lower FSIQ (n = 20; M = 54.8 ± 13.2) than those not taking them (n = 42; M = 65.0 ± 17.2; p = .022). These correlations were also present in the TMEM67-related JS sub-cohort (n = 14). Based on parental assessment, psychiatric and behavioral problems were significantly more common than in the general population for all measures (p < .004 for all). The majority (65%) of individuals with JS have some degree of intellectual disability. Abnormal EEG is associated with lower neuropsychological function. Processing speed is a weakness, while verbal comprehension and receptive language are relative strengths. These findings may guide parents, teachers, therapists, and doctors to determine appropriate therapies, accommodations, and academic goals for individuals with JS.

CELSR2, encoding a planar cell polarity protein, is a putative gene in Joubert syndrome with cortical heterotopia, microophthalmia, and growth hormone deficiency.

Joubert syndrome is a ciliopathy characterized by a specific constellation of central nervous system malformations that result in the pathognomonic "molar tooth sign" on imaging. More than 27 genes are associated with Joubert syndrome, but some patients do not have mutations in any of these genes. Celsr1, Celsr2, and Celsr3 are the mammalian orthologues of the drosophila planar cell polarity protein, flamingo; they play important roles in neural development, including axon guidance, neuronal migration, and cilium polarity. Here, we report bi-allelic mutations in CELSR2 in a Joubert patient with cortical heterotopia, microophthalmia, and growth hormone deficiency. © 2017 Wiley Periodicals, Inc.

Defective ciliogenesis in INPP5E-related Joubert syndrome.

Joubert syndrome is a neurodevelopmental disorder, characterized by malformation of the mid and hindbrain leading to the pathognomonic molar tooth appearance of the brainstem and cerebellum on axial MRI. Core clinical manifestations include hypotonia, tachypnea/apnea, ataxia, ocular motor apraxia, and developmental delay of varying degrees. In addition, a subset of patients has retinal dystrophy, chorioretinal colobomas, hepatorenal fibrocystic disease, and polydactyly. Joubert syndrome exhibits genetic heterogeneity, with mutations identified in more than 30 genes, including INPP5E, a gene encoding inositol polyphosphate 5-phosphatase E, which is important in the development and stability of the primary cilium. Here, we report the detailed clinical phenotypes of two sisters with a novel homozygous variant in INPP5E (NM_019892.4: c.1565G>C, NP_063945.2: p.Gly552Ala), expanding the phenotype associated with Joubert syndrome type 1. Expression studies using patient-derived fibroblasts showed changes in mRNA and protein levels. Analysis of fibroblasts from patients revealed that a significant number of cells had shorter or no cilia, indicating defects in ciliogenesis, and cilia maintenance.

TMEM231 Gene Conversion Associated with Joubert and Meckel-Gruber Syndromes in the Same Family.

Joubert and Meckel-Gruber syndromes (JS and MGS) are ciliopathies with overlapping features. JS patients manifest the "molar tooth sign" on brain imaging and variable eye, kidney, and liver disease. MGS presents with polycystic kidneys, occipital encephalocele, and polydactyly; it is typically perinatally fatal. Both syndromes are genetically heterogeneous; some genes cause either syndrome. Here, we report two brothers married to unrelated women. The first brother had three daughters with JS and a son with polycystic kidneys who died at birth. The second brother's wife had a fetal demise due to MGS. Whole exome sequencing identified TMEM231 NM_001077416.2: c.784G>A; p.(Asp262Asn) in all children and the wife of the first brother; the second brother's wife had a c.406T>G;p.(Trp136Gly) change. In-depth analysis uncovered a rare gene conversion event in TMEM231, leading to loss of exon 4, in all the affected children of first brother. We believe that the combination of this gene conversion with different missense mutations led to a spectrum of phenotypes that span JS and MGS.

Genotype-phenotype correlation in CC2D2A-related Joubert syndrome reveals an association with ventriculomegaly and seizures.

BACKGROUND: Joubert syndrome (JS) is a ciliopathy characterised by a distinctive brain malformation (the 'molar tooth sign'), developmental delay, abnormal eye movements and abnormal breathing pattern. Retinal dystrophy, cystic kidney disease, liver fibrosis and polydactyly are variably present, resulting in significant phenotypic heterogeneity and overlap with other ciliopathies. JS is also genetically heterogeneous, resulting from mutations in 13 genes. These factors render clinical/molecular diagnosis and management challenging. CC2D2A mutations are a relatively common cause of JS and also cause Meckel syndrome. The clinical consequences of CC2D2A mutations in patients with JS have been incompletely reported. METHODS: Subjects with JS from 209 families were evaluated to identify mutations in CC2D2A. Clinical and imaging features in subjects with CC2D2A mutations were compared with those in subjects without CC2D2A mutations and reports in the literature. RESULTS: 10 novel CC2D2A mutations in 20 subjects were identified; a summary is provided of all published CC2D2A mutations. Subjects with CC2D2A-related JS were more likely to have ventriculomegaly (p<0.0001) and seizures (p=0.024) than subjects without CC2D2A mutations. No mutation-specific genotype-phenotype correlations could be identified, but the findings confirm the observation that mutations that cause CC2D2A-related JS are predicted to be less deleterious than mutations that cause CC2D2A-related Meckel syndrome. Missense variants in the coiled-coil and C2 domains, as well as the C-terminal region, identify these regions as important for the biological mechanisms underlying JS. CONCLUSIONS: CC2D2A testing should be prioritised in patients with JS and ventriculomegaly and/or seizures. Patients with CC2D2A-related JS should be monitored for hydrocephalus and seizures.

MKS3-related ciliopathy with features of autosomal recessive polycystic kidney disease, nephronophthisis, and Joubert Syndrome.

OBJECTIVES: To describe 3 children with mutations in a Meckel syndrome gene (MKS3), with features of autosomal recessive polycystic kidney disease (ARPKD), nephronophthisis, and Joubert syndrome (JS). STUDY DESIGN: Biochemical evaluations, magnetic resonance and ultrasound imaging, electroretinograms, IQ testing, and sequence analysis of the PKHD1 and MKS3 genes were performed. Functional consequences of the MKS3 mutations were evaluated by cDNA sequencing and transfection studies with constructs of meckelin, the protein product of MKS3. RESULTS: These 3 children with MKS3 mutations had features typical of ARPKD, that is, enlarged, diffusely microcystic kidneys and early-onset severe hypertension. They also exhibited early-onset chronic anemia, a feature of nephronophthisis, and speech and oculomotor apraxia, suggestive of JS. Magnetic resonance imaging of the brain, originally interpreted as normal, revealed midbrain and cerebellar abnormalities in the spectrum of the "molar tooth sign" that characterizes JS. CONCLUSIONS: These findings expand the phenotypes associated with MKS3 mutations. MKS3-related ciliopathies should be considered in patients with an ARPKD-like phenotype, especially in the presence of speech and oculomotor apraxia. In such patients, careful expert evaluation of the brain images can be beneficial because the brain malformations can be subtle.