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Ciliopathies encompass a broad spectrum of diseases stemming from dysfunction of the primary (non-motile) cilia, present on almost all cells in the human body. These disorders include autosomal dominant and recessive polycystic kidney diseases, nephronophthisis, and multisystem ciliopathies such as Joubert, Meckel, Bardet-Biedl, Alström, oral-facial-digital syndromes, and skeletal ciliopathies. The majority of these ciliopathies are associated with fibrocystic kidney disease resulting in progressive kidney dysfunction. In addition, many ciliopathies are associated with extra-renal manifestations including congenital hepatic fibrosis, retinal dystrophy, obesity, and brain and skeletal anomalies. The diagnoses may be challenging due to their overlapping clinical features and molecular heterogeneity. To date, over 190 genes encoding proteins that localize to the primary cilia have been identified as disease-causing. This review will discuss the clinical features of the most frequently encountered disorders of primary cilia., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Introduction: Chediak-Higashi syndrome (CHS) is rare autosomal recessive disorder caused by bi-allelic variants in the Lysosomal Trafficking Regulator ( LYST ) gene. Diagnosis is established by the detection of pathogenic variants in LYST in combination with clinical evidence of disease. Conventional molecular genetic testing of LYST by genomic DNA (gDNA) Sanger sequencing detects the majority of pathogenic variants, but some remain undetected for several individuals clinically diagnosed with CHS. In this study, cDNA Sanger sequencing was pursued as a complementary method to identify variant alleles that are undetected by gDNA Sanger sequencing and to increase molecular diagnostic yield. Methods: Six unrelated individuals with CHS were clinically evaluated and included in this study. gDNA Sanger sequencing and cDNA Sanger sequencing were performed to identify pathogenic LYST variants. Results: Ten novel LYST alleles were identified, including eight nonsense or frameshift variants and two in-frame deletions. Six of these were identified by conventional gDNA Sanger sequencing; cDNA Sanger sequencing was required to identify the remaining variant alleles. Conclusion: By utilizing cDNA sequencing as a complementary technique to identify LYST variants, a complete molecular diagnosis was obtained for all six CHS patients. In this small CHS cohort, the molecular diagnostic yield was increased, and canonical splice site variants identified from gDNA Sanger sequencing were validated by cDNA sequencing. The identification of novel LYST alleles will aid in diagnosing patients and these molecular diagnoses will also lead to genetic counseling, access to services and treatments and clinical trials in the future., 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 Kuptanon, Morimoto, Nicoli, Stephen, Yarnell, Dorward, Owen, Parikh, Ozbek, Malbora, Ciccone, Gunay-Aygun, Gahl, Introne and Malicdan.)

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., (© 2022 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

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., (© 2021 Wiley Periodicals LLC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Purpose: Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency., Methods: Three individuals with intellectual disability and iris anomalies and truncating de novo PRR12 variants were described previously. We add 21 individuals with similar PRR12 variants identified via matchmaking platforms, bringing the total number to 24., Results: We observed 12 frameshift, 6 nonsense, 1 splice-site, and 2 missense variants and one patient with a gross deletion involving PRR12. Three individuals had additional genetic findings, possibly confounding the phenotype. All patients had developmental impairment. Variable structural eye defects were observed in 12/24 individuals (50%) including anophthalmia, microphthalmia, colobomas, optic nerve and iris abnormalities. Additional common features included hypotonia (61%), heart defects (52%), growth failure (54%), and kidney anomalies (35%). PrediXcan analysis showed that phecodes most strongly associated with reduced predicted PRR12 expression were enriched for eye- (7/30) and kidney- (4/30) phenotypes, such as wet macular degeneration and chronic kidney disease., Conclusion: These findings support PRR12 haploinsufficiency as a cause for a novel disorder with a wide clinical spectrum marked chiefly by neurodevelopmental and eye abnormalities.

Alström Syndrome (ALMS) is an ultra-rare multisystem genetic disorder caused by autosomal recessive variants in the ALMS1 gene, which is located on chromosome 2p13. ALMS is a multisystem, progressive disease characterised by visual disturbance, hearing impairment, cardiomyopathy, childhood obesity, extreme insulin resistance, accelerated non-alcoholic fatty liver disease (NAFLD), renal dysfunction, respiratory disease, endocrine and urologic disorders. Clinical symptoms first appear in infancy with great variability in age of onset and severity. ALMS has an estimated incidence of 1 case per 1,000,000 live births and ethnically or geographically isolated populations have a higher-than-average frequency. The rarity and complexity of the syndrome and the lack of expertise can lead to delayed diagnosis, misdiagnosis and inadequate care. Multidisciplinary and multiprofessional teams of experts are essential for the management of patients with ALMS, as early diagnosis and intervention can slow the progression of multi-organ dysfunctions and improve patient quality of life.These guidelines are intended to define standard of care for patients suspected or diagnosed with ALMS of any age. All information contained in this document has originated from a systematic review of the literature and the experiences of the authors in their care of patients with ALMS. The Appraisal of Guidelines for Research & Evaluation (AGREE II) system was adopted for the development of the guidelines and for defining the related levels of evidence and strengths of recommendations.These guidelines are addressed to: a) specialist centres, other hospital-based medical teams and staffs involved with the care of ALMS patients, b) family physicians and other primary caregivers and c) patients and their families.

Background and Objectives: We have previously published the characteristics of kidney and liver disease in a cohort of 73 individuals with molecularly confirmed autosomal recessive polycystic kidney disease-congenital hepatic fibrosis, based upon cross-sectional data. Here, we present prospective data on the same cohort., Design, Setting, Participants, and Measurements: Comprehensive biochemical and imaging data on progression of kidney and liver disease in 60 of the 73 patients were prospectively collected at the NIH Clinical Center on multiple visits between 2003 and 2019., Results and Conclusions: Of the 73 patients, 23 received a renal allograft at an average age of 17.5 years and 10 underwent liver transplantation at an average age of 20.3 years. Patients who presented perinatally and those who had corticomedullary disease required kidney transplantation significantly earlier. The mean eGFR slope in patients with corticomedullary disease was -1.6 ml/min/1.73 m 2 /y, in comparison to -0.6 ml/min/1.73 m 2 /y in those with medullary disease. Kidney size remained the same over time and normalized to the upper limit of normal by 20-25 years of age. The extent of renal disease on ultrasound remained largely unchanged; no patient progressed from the "medullary" to the "corticomedullary" group. There was no correlation between eGFR slope and kidney size. The synthetic function of the liver remained largely intact even in patients with advanced portal hypertension. Based on spleen length/height ratio, two thirds of patients had portal hypertension which remained stable in 39% and worsened in 61%. Patients with portal hypertension had lower platelet counts and relatively higher levels of AST, GGT, direct bilirubin and ammonia. The progression rates of kidney and liver disease were independent of each other. Patients with bi-allelic non-truncating PKHD1 variants had similar progression of kidney and liver disease in comparison to those who were compound heterozygous for a non-truncating and a truncating variant., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Establishing the diagnosis of hereditary fructose intolerance (HFI) remains difficult despite the availability of specific molecular genetic testing of the ALDOB gene. This is attributable, at least in part, to the lack of a specific and practical biomarker. We report the incidental diagnosis of HFI as a consequence of nontargeted genetic testing ordered for alternative indications in 5 patients, including 3 children and 2 adults. Two of the children were diagnosed with HFI after extensive evaluations that ultimately involved clinical or research exome sequencing. The third child was diagnosed with HFI during subsequent genetic testing of at-risk family members. Both adults learned to avoid fructose and remained asymptomatic of HFI before diagnosis. One was diagnosed with HFI during preconception, nontargeted expanded carrier screening. For the other, concern for HFI was initially raised by indeterminate direct-to-consumer genetic testing results. None of these patients presented with infantile acute liver failure or other acute decompensation. Our findings suggest that the emphasis of classic teaching on infantile liver failure after first exposure to fructose may be inadvertently increasing the likelihood of missing cases of HFI characterized by other manifestations. HFI is likely underdiagnosed and should be considered for patients with nonspecific findings as well as for individuals with significant aversion to sweets., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients' primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.

Genetic and phenotypic heterogeneity and the lack of sufficiently large patient cohorts pose a significant challenge to understanding genetic associations in rare disease. Here we identify Bsnd (alias Barttin ) as a genetic modifier of cystic kidney disease in Joubert syndrome, using a Cep290 -deficient mouse model to recapitulate the phenotypic variability observed in patients by mixing genetic backgrounds in a controlled manner and performing genome-wide analysis of these mice. Experimental down-regulation of Bsnd in the parental mouse strain phenocopied the severe cystic kidney phenotype. A common polymorphism within human BSND significantly associates with kidney disease severity in a patient cohort with CEP290 mutations. The striking phenotypic modifications we describe are a timely reminder of the value of mouse models and highlight the significant contribution of genetic background. Furthermore, if appropriately managed, this can be exploited as a powerful tool to elucidate mechanisms underlying human disease heterogeneity., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

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., (© 2019 Wiley Periodicals, Inc.)

Joubert syndrome (JBTS) is an incurable multisystem ciliopathy syndrome. The most commonly mutated gene in JBTS patients with a cerebello-retinal-renal phenotype is CEP290 (alias JBTS5). The encoded CEP290 protein localises to the proximal end of the primary cilium, in the transition zone, where it controls ciliary protein composition and signalling. We examined primary cilium structure and composition in fibroblast cells derived from homozygous and compound heterozygous JBTS5 patients with nonsense mutations in CEP290 and show that elongation of cilia, impaired ciliogenesis and ciliary composition defects are typical features in JBTS5 cells. Targeted skipping of the mutated exon c.5668 G > T using antisense oligonucleotide (ASO) therapy leads to restoration of CEP290 protein expression and functions at the transition zone in homozygous and compound heterozygous JBTS5 cells, allowing a rescue of both cilia morphology and ciliary composition. This study, by demonstrating that targeted exon skipping is able to rescue ciliary protein composition defects, provides functional evidence for the efficacy of this approach in the treatment of JBTS.

Non-motile ciliopathies (disorders of the primary cilia) include autosomal dominant and recessive polycystic kidney diseases, nephronophthisis, as well as multisystem disorders Joubert, Bardet-Biedl, Alström, Meckel-Gruber, oral-facial-digital syndromes, and Jeune chondrodysplasia and other skeletal ciliopathies. Chronic progressive disease of the kidneys, liver, and retina are common features in non-motile ciliopathies. Some ciliopathies also manifest neurological, skeletal, olfactory and auditory defects. Obesity and type 2 diabetes mellitus are characteristic features of Bardet-Biedl and Alström syndromes. Overlapping clinical features and molecular heterogeneity of these ciliopathies render their diagnoses challenging. In this review, we describe the clinical characteristics of individual organ disease for each ciliopathy and provide natural history data on kidney, liver, retinal disease progression and central nervous system function., (© 2019 – IOS Press and the authors. All rights reserved.)

Lysine-specific demethylase 6B (KDM6B) demethylates trimethylated lysine-27 on histone H3. The methylation and demethylation of histone proteins affects gene expression during development. Pathogenic alterations in histone lysine methylation and demethylation genes have been associated with multiple neurodevelopmental disorders. We have identified a number of de novo alterations in the KDM6B gene via whole exome sequencing (WES) in a cohort of 12 unrelated patients with developmental delay, intellectual disability, dysmorphic facial features, and other clinical findings. Our findings will allow for further investigation in to the role of the KDM6B gene in human neurodevelopmental disorders., (© 2019 Wiley Periodicals, Inc.)

A 55-yr-old male with severe intellectual disability, behavioral problems, kyphoscoliosis, and dysmorphic features was referred for a genetic evaluation. Chromosomal microarray, RASopathy gene panel, mitochondrial sequencing, and fragile X testing were all negative. Subsequent whole-exome sequencing revealed a heterozygous, truncating variant in the AHDC1 gene, consistent with a diagnosis of Xia-Gibbs syndrome (XGS). Review of his clinical history showed many classic dysmorphic and clinical features of XGS, but no major health issues in adulthood other than intellectual disability. This individual is the oldest published XGS case to date, demonstrates the wide phenotypic spectrum of the disorder, and provides information on the condition's natural history. As more adults undergo genomic studies, we will continue to learn about the adult phenotypes of genetic conditions typically diagnosed in the pediatric setting., (© 2019 Murdock et al.; Published by Cold Spring Harbor Laboratory Press.)

We report three patients with Feingold 2 syndrome with the novel features of growth hormone deficiency associated with adenohypophyseal compression, aortic dilation, phalangeal joint contractures, memory, and sleep problems in addition to the typical features of microcephaly, brachymesophalangy, toe syndactyly, short stature, and cardiac anomalies. Microdeletions of chromosome 13q that include the MIR17HG gene were found in all three. One of the patients was treated successfully with growth hormone. In addition to expanding the phenotype of Feingold 2 syndrome, we suggest management of patients with Feingold 2 syndrome include echocardiography at the time of diagnosis in all patients and consideration of evaluation for growth hormone deficiency in patients with short stature., (© 2019 Wiley Periodicals, Inc.)

Purpose: Joubert syndrome (JS) is caused by mutations in >34 genes that encode proteins involved with primary (nonmotile) cilia and the cilium basal body. This study describes the varying ocular phenotypes in JS patients, with correlation to systemic findings and genotype., Design: Patients were systematically and prospectively examined at the National Institutes of Health (NIH) Clinical Center in the setting of a dedicated natural history clinical trial., Participants: Ninety-nine patients with JS examined at a single center., Methods: All patients underwent genotyping for JS, followed by complete age-appropriate ophthalmic examinations at the NIH Clinical Center, including visual acuity (VA), fixation behavior, lid position, motility assessment, slit-lamp biomicroscopy, dilated fundus examination with an indirect ophthalmoscope, and retinoscopy. Color and fundus autofluorescence imaging, Optos wide-field photography (Dunfermline, Scotland, UK), and electroretinography (ERG) were performed when possible., Main Outcome Measures: The VA (with longitudinal follow-up where possible), ptosis, extraocular muscle function, retinal and optic nerve status, and retinal function as measured by ERG., Results: Among patients with JS with quantifiable VA (68/99), values ranged from 0 logarithm of the minimum angle of resolution (logMAR) (Snellen 20/20) to 1.5 logMAR (Snellen 20/632). Strabismus (71/98), nystagmus (66/99), oculomotor apraxia (60/77), ptosis (30/98), coloboma (28/99), retinal degeneration (20/83), and optic nerve atrophy (8/86) were identified., Conclusions: We recommend regular monitoring for ophthalmological manifestations of JS beginning soon after birth or diagnosis. We demonstrate delayed visual development and note that the amblyogenic time frame may last significantly longer in JS than is typical. In general, patients with coloboma were less likely to display retinal degeneration, and those with retinal degeneration did not have coloboma. Severe retinal degeneration that is early and aggressive is seen in disease caused by specific genes, such as CEP290- and AHI1-associated JS. Retinal degeneration in INPP5E-, MKS1-, and NPHP1-associated JS was generally milder. Finally, ptosis surgery can be helpful in a subset of patients with JS; decisions as to timing and benefit/risk ratio need to be made on an individual basis according to expert consultation., (Published by Elsevier Inc.)

Alström Syndrome is a ciliopathy associated with obesity, insulin resistance/type 2 diabetes mellitus, cardiomyopathy, retinal degeneration, hearing loss, progressive liver and kidney disease, and normal cognitive function. ALMS1, the protein defective in this disorder, localizes to the cytoskeleton, microtubule organizing center, as well as the centrosomes and ciliary basal bodies and plays roles in formation and maintenance of cilia, cell cycle regulation, and endosomal trafficking. Kidney disease in this disorder has not been well characterized. We performed comprehensive multisystem evaluations on 38 patients. Kidney function decreased progressively; eGFR varied inversely with age (p = 0.002). Eighteen percent met the definition for chronic kidney disease (eGFR < 60 mL/min/1.73 m 2 and proteinuria); all were adults with median age of 32.8 (20.6-37.9) years. After adjusting for age, there were no significant associations of kidney dysfunction with type 2 diabetes mellitus, dyslipidemia, hypertension, cardiomyopathy or portal hypertension suggesting that kidney disease in AS is a primary manifestation of the syndrome due to lack of ALMS1 protein. Approximately one-third of patients had hyperechogenicity of the renal parenchyma on imaging. While strict control of type 2 diabetes mellitus may decrease kidney-related morbidity and mortality in Alström syndrome, identification of novel targeted therapies is needed., (Copyright © 2018. Published by Elsevier Inc.)

Noncirrhotic portal hypertension (NCPH) is a rare disease that may lead to serious clinical consequences. Currently, noninvasive tools for the assessment of NCPH are absent. We investigated the utility of spleen and liver volumetrics as a marker of the presence and severity of portal hypertension in this population. A cohort of NCPH patients evaluated between 2003 and 2015 was retrospectively studied. The association of spleen and liver volumes with the hepatic venous pressure gradient (HVPG) level was evaluated using locally weighted scatterplot smoothing curves. A cohort of patients with viral hepatitis-related liver disease was used as controls. Of the 86 patients with NCPH evaluated during the study period, 75 (mean age, 35 ± 17; 73% males) were included in the final analysis. Patients with portal hypertension had significantly higher spleen and liver to body mass index (BMI) ratios compared to patients with HVPG <5 mm Hg (39.5 ± 27.9 versus 22.8 ± 10.6 cm 3 /kg/m 2 , P = 0.003; 91.1 ± 40.1 versus 71.4 ± 16.7 cm 3 /kg/m 2 , P = 0.014, for spleen/BMI and liver/BMI, respectively). In contrast to the patients with viral hepatitis, a positive linear correlation was observed in the NCPH cohort between spleen/BMI and liver/BMI (above a cutoff of 25 and 80 cm 3 /kg/m 2 , respectively) and HVPG level. Additionally, only in the NCPH cohort was an increase in spleen/BMI range quartile predictive of a higher prevalence of portal hypertension and clinically significant portal hypertension (trend, P = 0.014 and 0.031, respectively). Conclusion: Spleen and liver volumetrics may have utility in the assessment of NCPH as a noninvasive biomarker that can be performed using routine radiologic examinations. Further studies are needed to validate these findings. ( Hepatology Communications 2018; 00:000-000).

Background: Alström syndrome (AS), a monogenic form of obesity, is caused by recessive mutations in the centrosome- and basal body-associated gene ALMS1. AS is characterized by retinal dystrophy, sensory hearing loss, cardiomyopathy, childhood obesity, and metabolic derangements., Objective: We sought to characterize the endocrine and metabolic features of AS while accounting for obesity as a confounder by comparing patients with AS to body mass index (BMI)-matched controls., Methods: We evaluated 38 patients with AS (age 2 to 38 years) who were matched with 76 controls (age 2 to 48 years) by age, sex, race, and BMI. Fasting biochemistries, mixed meal test (MMT), indirect calorimetry, dual-energy X-ray absorptiometry, and MRI/magnetic resonance spectroscopy were performed., Results: Frequent abnormalities in AS included 76% obesity, 37% type 2 diabetes mellitus (T2DM), 29% hypothyroidism (one-third central, two-thirds primary), 3% central adrenal insufficiency, 57% adult hypogonadism (one-third central, two-thirds primary), and 25% female hyperandrogenism. Patients with AS and controls had similar BMI z scores, body fat, waist circumference, abdominal visceral fat, muscle fat, resting energy expenditure (adjusted for lean mass), free fatty acids, glucagon, prolactin, ACTH, and cortisol. Compared with controls, patients with AS were shorter and had lower IGF-1 concentrations (Ps ≤ 0.001). Patients with AS had significantly greater fasting and MMT insulin resistance indices, higher MMT glucose, insulin, and C-peptide values, higher HbA1c, and higher prevalence of T2DM (Ps < 0.001). Patients with AS had significantly higher triglycerides, lower high-density lipoprotein cholesterol, and a 10-fold greater prevalence of metabolic syndrome (Ps < 0.001). Patients with AS demonstrated significantly greater liver triglyceride accumulation and higher transaminases (P < 0.001)., Conclusion: Severe insulin resistance and T2DM are the hallmarks of AS. However, patients with AS may present with multiple other endocrinopathies affecting growth and development.

Background and Aims: Joubert Syndrome (JS) is a rare, inherited, ciliopathy defined by cerebellar and brainstem malformations and is variably associated with liver, kidney, and ocular dysfunction. This study characterizes the hepatic findings in JS and identifies factors associated with probable portal hypertension., Methods: Hundred individuals with JS were prospectively evaluated at the National Institutes of Health Clinical Center. Laboratory tests, imaging, and DNA sequencing were performed. Patients were stratified based on the spleen length/patient height ratio as a marker of splenomegaly, used as a surrogate for probable portal hypertension., Results: Forty-three patients (43%) had liver involvement based on elevated liver enzymes and/or liver hyperechogenicity and/or splenomegaly. None of the patients had macroscopic liver cysts or bile duct dilatation. Based on the spleen length/patient height ratio, 13 patients were stratified into a probable portal hypertension group. We observed significant elevations in alkaline phosphatase (269 vs 169 U/L, P ≤ 0.001), alanine aminotransferase (92 vs 42 U/L, P = 0.004), aspartate aminotransferase (77 vs 40 U/L, P = 0.002), and gamma-glutamyl transferase (226 vs 51 U/L, P ≤ 0.001) in the probable portal hypertension group. Platelets were lower in the probable portal hypertension cohort (229 vs 299 × 10 cells/μL, P = 0.008), whereas synthetic function was intact in both groups. Probable portal hypertension was also more prevalent in patients with kidney disease (P = 0.001) and colobomas (P = 0.02), as well as mutations in the TMEM67 gene (P = 0.001)., Conclusions: In JS, probable portal hypertension is associated with abnormal hepatic enzymes, as well as presence of kidney disease, coloboma, and/or mutation in TMEM67. These findings may allow early identification of JS patients who have or are more likely to develop liver disease.

Primary cilia are sensory organelles that protrude from the cell membrane. Defects in the primary cilium cause ciliopathy disorders, with retinal degeneration as a prominent phenotype. Here, we demonstrate that the retinal pigment epithelium (RPE), essential for photoreceptor development and function, requires a functional primary cilium for complete maturation and that RPE maturation defects in ciliopathies precede photoreceptor degeneration. Pharmacologically enhanced ciliogenesis in wild-type induced pluripotent stem cells (iPSC)-RPE leads to fully mature and functional cells. In contrast, ciliopathy patient-derived iPSC-RPE and iPSC-RPE with a knockdown of ciliary-trafficking protein remain immature, with defective apical processes, reduced functionality, and reduced adult-specific gene expression. Proteins of the primary cilium regulate RPE maturation by simultaneously suppressing canonical WNT and activating PKCδ pathways. A similar cilium-dependent maturation pathway exists in lung epithelium. Our results provide insights into ciliopathy-induced retinal degeneration, demonstrate a developmental role for primary cilia in epithelial maturation, and provide a method to mature iPSC epithelial cells for clinical applications., (Published by Elsevier Inc.)

Background and Objectives: Joubert syndrome is a genetically heterogeneous ciliopathy associated with >30 genes. The characteristics of kidney disease and genotype-phenotype correlations have not been evaluated in a large cohort at a single center., Design, Setting, Participants, & Measurements: We evaluated 97 individuals with Joubert syndrome at the National Institutes of Health Clinical Center using abdominal ultrasonography, blood and urine chemistries, and DNA sequencing., Results: Patients were ages 0.6-36 years old (mean of 9.0±7.6 years old); 41 were female. Mutations were identified in 19 genes in 92 patients; two thirds of the mutations resided in six genes: TMEM67 , C5orf42 , CC2D2A , CEP290 , AHI1 , and KIAA0586 . Kidney disease was detected in 30%, most commonly in association with the following genes: CEP290 (six of six), TMEM67 (11 of 22), and AHI1 (three of six). No kidney disease was identified in patients with mutations in C5orf42 (zero of 15) or KIAA0586 (zero of six). Prenatal ultrasonography of kidneys was normal in 72% of patients with kidney disease. Specific types of kidney disease included nephronophthisis (31%), an overlap phenotype of autosomal recessive polycystic kidney disease/nephronophthisis (35%), unilateral multicystic dysplastic kidney (10%), and indeterminate-type cystic kidney disease (24%). Early-onset hypertension occurred in 24% of patients with kidney disease. Age at ESRD ( n =13) ranged from 6 to 24 years old (mean of 11.3±4.8 years old)., Conclusions: Kidney disease occurs in up to one third of patients with Joubert syndrome, most commonly in those with mutations in CEP290 , TMEM67 , and AHI1 . Patients with mutations in C5orf42 or KIAA0586 are less likely to develop kidney disease. Prenatal ultrasonography is a poor predictor of kidney involvement in Joubert syndrome. Unilateral multicystic dysplastic kidney and autosomal recessive polycystic kidney disease-like enlarged kidneys with early-onset hypertension can be part of the Joubert syndrome kidney phenotype., (Copyright © 2017 by the American Society of Nephrology.)

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&#95;019892.4: c.1565G>C, NP&#95;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., (© 2017 Wiley Periodicals, Inc.)

The cover image, by Isabel Hardee et al., is based on the Clinical Report Defective ciliogenesis in INPP5E-related Joubert syndrome, DOI: 10.1002/ajmg.a.38376. Design Credit: Darryl Leja., (© 2017 Wiley Periodicals, Inc.)

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.

Background: Alström syndrome (AS) is a rare monogenetic disorder with multi-organ involvement. Complex metabolic disturbances are common and cardiomyopathy is a well-recognized feature in infants as well as in older children and adults. Although the mechanism of cardiomyopathy is not known, previous reports suggest that individuals with infantile-onset cardiac disease recover completely., Methods: In this single center prospective series of 38 children and adults (age range 1.7 to 37.9years; 20 females) with AS, we evaluated cardiac manifestations in detail, in the context of specific ALMS1 mutations and multisystem involvement. All patients underwent ALMS1 sequencing, biochemical testing, electrocardiogram, and echocardiographic imaging with speckle tracking to evaluate systolic strain; 21 patients underwent cardiac magnetic resonance imaging with T1 mapping., Results: Approximately half of patients (17/38) had a previous diagnosis of cardiomyopathy. Global longitudinal strain, a measure of systolic contractile function, was abnormal in 94% of patients and correlated with body mass index (r=0.602, p=0.002) and C-reactive protein level (r=0.56, p=0.004), but only in children. Electrocardiographic abnormalities were seen in two-thirds of patients, and left ventricular dilatation and/or dysfunction was present in 4 adults and 4 children., Conclusion: AS patients with a history of resolved infantile cardiomyopathy continue to have residual impairment in cardiac function. For patients with a normal ejection fraction and no prior cardiac history, strain can be abnormal, suggesting subclinical cardiac involvement. Close cardiac screening and aggressive modification of other manifestations of AS that are risk factors for cardiac disease, including obesity, inflammation, diabetes and dyslipidemia, are essential in caring for patients with AS., (Published by Elsevier Inc.)

Background: Joubert syndrome is a clinically and genetically heterogeneous ciliopathy. Neuroimaging findings have not been systematically evaluated in a large cohort of patients with Joubert syndrome in correlation with molecular genetic cause and cognitive function., Methods: Brain MRI of 110 patients with Joubert syndrome was included in this study. A comprehensive evaluation of brain MRI studies for infratentorial and supratentorial morphological abnormalities was performed. Genetic cause was identified by whole-exome sequencing, and cognitive functions were assessed with age-appropriate neurocognitive tests in a subset of patients., Results: The cerebellar hemispheres were enlarged in 18% of the patients, mimicking macrocerebellum. The posterior fossa was enlarged in 42% of the patients, resembling Dandy-Walker malformation. Abnormalities of the brainstem, such as protuberance at the ventral contour of the midbrain, were present in 66% of the patients. Abnormalities of the supratentorial brain were present in approximately one-third of the patients, most commonly malrotation of the hippocampi. Mild ventriculomegaly, which typically did not require shunting, was present in 23% of the patients. No correlation between neuroimaging findings and molecular genetic cause was apparent. A novel predictor of outcome was identified; the more severe the degree of vermis hypoplasia, the worse the neurodevelopmental outcome was., Conclusions: The spectrum of neuroimaging findings in Joubert syndrome is wide. Neuroimaging does not predict the genetic cause, but may predict the neurodevelopmental outcome. A high degree of vermis hypoplasia correlates with worse neurodevelopmental outcome. This finding is important for prognostic counselling in Joubert syndrome., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Alström syndrome (AS) is a rare autosomal recessive ciliopathy caused by mutations in the ALMS1 gene. Hallmark characteristics include childhood onset of severe retinal degeneration, sensorineural hearing loss, obesity, insulin-resistant diabetes, and cardiomyopathy. Here we comprehensively characterize the auditory and otologic manifestations in a prospective case series of 38 individuals, aged 1.7-37.9 years, with genetically confirmed AS. Hearing loss was preceded by retinal dystrophy in all cases, and had an average age of detection of 7.45 years (range 1.5-15). Audiometric assessments showed mean pure tone averages (0.5, 1, 2, 4 kHz) of 48.6 and 47.5 dB HL in the right and left ears, respectively. Hearing was within normal limits for only 8/74 ears (11%). For the 66 ears with hearing loss, the degree was mild (12%), moderate (54%), or severe (8%). Type of hearing loss was predominantly sensorineural (77%), while three ears had mixed loss, no ears had conductive loss, and type of hearing loss was indeterminate for the remaining 12 ears. Serial audiograms available for 33 patients showed hearing loss progression of approximately 10-15 dB/decade. Our data show that hearing loss associated with AS begins in childhood and is a predominantly symmetric, sensory hearing loss that may progress to a severe degree. Absent otoacoustic emissions, intact speech discrimination, and disproportionately normal auditory brainstem responses suggest an outer hair cell site of lesion. These findings indicate that individuals with AS would benefit from sound amplification and if necessary, cochlear implantation., (© 2017 Wiley Periodicals, Inc.)

Mutations in CEP290, a transition zone protein in primary cilia, cause diverse ciliopathies, including Leber congenital amaurosis (LCA) and Joubert-syndrome and related disorders (JSRD). We examined cilia biogenesis and function in cells derived from CEP290-LCA and CEP290-JSRD patients. CEP290 protein was reduced in LCA fibroblasts with no detectable impact on cilia; however, optic cups derived from induced pluripotent stem cells (iPSCs) of CEP290-LCA patients displayed less developed photoreceptor cilia. Lack of CEP290 in JSRD fibroblasts resulted in abnormal cilia and decreased ciliogenesis. We observed selectively reduced localization of ADCY3 and ARL13B. Notably, Hedgehog signaling was augmented in CEP290-JSRD because of enhanced ciliary transport of Smoothened and GPR161. These results demonstrate a direct correlation between the extent of ciliogenesis defects in fibroblasts and photoreceptors with phenotypic severity in JSRD and LCA, respectively, and strengthen the role of CEP290 as a selective ciliary gatekeeper for transport of signaling molecules in and out of the cilium., (Published by Elsevier Inc.)

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., (© 2017 Wiley Periodicals, Inc.)

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.