Abstract Introduction Joubert Syndrome and Related Disorders (JSRD) are a group of rare neurodevelopmental conditions characterized by congenital cerebellar and brainstem malformations, most notably the “molar tooth sign” on neuroimaging. Sleep disordered breathing (SDB) has been described in JSRD, but little data exist on non-respiratory disorders, despite frequent descriptions of restless sleep, insomnia, and altered sleep-wake cycles. The aim of this study was to use validated sleep questionnaires to start characterizing the full breadth of sleep disorders in individuals with JSRD and their caregivers. Methods Caregivers and/or participants with JSRD filled out on-line questionnaires including the Obstructive Sleep Apnea -18 (OSA-18), Childrens Sleep Habits Questionnaire (CSHQ), Pediatric Sleep Questionnaire (PSQ), PROMIS Sleep-Related Impairment, Morning-Eveningness Chronotype Questionnaire (MECQ), and provided demographic information, comorbidity profiles, and sleep study histories. SPSS was used to perform preliminary descriptive statistical analyses. Human subjects approval was obtained through the University of Washington. Results To date, 94 participants have completed the survey (mean age 14.5 ± 10.6, 40% Female). Fifty percent of participants reported having undergone a sleep study, and 33% reported a diagnosis of SDB. In contrast, 89%, 86% and 42% of respondents reported scores above clinical cutoffs for the OSA-18, PSQ , and CSHQ respectively, suggesting much higher rates of SDB. PROMIS scores showed sleep-related impairment in 62% of parents and 51% of participants (via parent proxy questionnaire). Beyond SDB disturbances, restless sleep (reported by 56% of participants), insomnia symptoms (67% of participants/caregivers reported trouble sleeping), and circadian dysregulation emerged as common contributors to elevated scores. Caregivers consistently reported significant negative impact on daytime behavior, attention, mood, and overall family functioning. Conclusion Individuals with JSRD exhibit high rates of sleep disturbance across multiple domains, with subjective measures identifying far more impairment than reflected in reported diagnostic rates of SDB. Restless sleep, insomnia, and circadian misalignment may be under-recognized contributors to morbidity. These findings highlight the need for improved clinical screening, targeted evaluation, and JSRD-specific treatment strategies, as well as continued enrollment in ongoing research efforts to better characterize sleep phenotypes in this population. Support (if any) MC: HRSAAT2T2MC007; WP: K08HL179396; DD: 5R01HD100730

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

Objective:This study evaluates contusion volume and location as predictors of PTE while considering mortality as a competing risk using automated segmentation of acute CT images. Methods:Adult TBI patients who visited our center (2014-2025) were identified and categorized into three outcome groups: PTE, post-TBI mortality, and event-free. Clinical covariates were extracted from health records, and CT scans were processed using the BLAST-CT algorithm to segment intraparenchymal hemorrhage (IPH), edema, intraventricular (IVH), and extra-axial hemorrhage (EAH). Five-fold nested cross-validation was performed, with L1-regularized regression used for feature selection within each training fold and model performance evaluated in the corresponding test fold. Within each fold, the selected features were then used to fit separate cause-specific multivariable Cox models for PTE and mortality. Contusion location associations were assessed using both multivariable Cox and sparse canonical correlation analysis. Results:Of 1017 identified patients, 6.1% developed PTE, 10.5% died, and 83.4% had no event. In multivariable analysis, total contusion volumes (p<0.001) were independently predicted both PTE and mortality, meanwhile and EAH volume (p<0.01) predicted mortality only. When regionalized, frontal (p<0.01) and temporal (p<0.01) contusions independently predicted PTE, whereas frontal (p=0.04) contusions also independently predicted mortality. Sparse canonical correlation analysis identified an association of frontotemporal and insular contusions with PTE but not mortality. Interpretation:Automatically measured contusion segmentation from acute CT imaging could help predict post-traumatic epilepsy. A competing risk framework highlighted that contusion volume is associated with both PTE and mortality risk, whereas unique contusion location patterns may aid in post-traumatic epilepsy assessment in a broad TBI population.

Access to a precise genetic diagnosis (PrGD) in critically ill newborns is limited and inequitable because the complex inclusion criteria used to prioritize testing eligibility omit many patients at high risk for a genetic condition. SeqFirst-neo is a program to test whether a genotype-driven workflow using simple, broad exclusion criteria to assess eligibility for rapid genome sequencing (rGS) increases access to a PrGD in critically ill newborns. All 408 newborns admitted to a neonatal intensive care unit between January 2021 and February 2022 were assessed, and of 240 eligible infants, 126 were offered rGS (i.e., intervention group [IG]) and compared to 114 infants who received conventional care in parallel (i.e., conventional care group [CCG]). A PrGD was made in 62/126 (49.2%) IG neonates compared to 11/114 (9.7%) CCG infants. The odds of receiving a PrGD were ∼9 times greater in the IG vs. the CCG, and this difference was maintained at 12 months follow-up. Access to a PrGD in the IG vs. CCG differed significantly between infants identified as non-White (34/74, 45.9% vs. 6/29, 20.7%; p = 0.024) and Black (8/10, 80.0% vs. 0/4; p = 0.015). Neonatologists were significantly less successful at predicting a PrGD in non-White than non-Hispanic White infants. The use of a standard workflow in the IG with a PrGD revealed that a PrGD would have been missed in 26/62 (42%) infants. The use of simple, broad exclusion criteria that increase access to genetic testing significantly increases access to a PrGD, improves access equity, and results in fewer missed diagnoses.

Validate whether simple quantitative measures of CT-based lobar contusion volumes associate with post-traumatic epilepsy (PTE).

The Seq First Developmental Differences (DDi) project aims to improve early and equitable access to a precise genetic diagnosis (PrGD) in children with atypical development by offering whole genome sequencing (WGS) upon presentation rather than after a conventional staged evaluation and testing. We hypothesized that a simplified clinical workflow and early access to WGS would lead to increased access to a PrGD, for more participants than those who received conventional care.

Objectives:Transcript sequencing of patient-derived samples has been shown to improve the diagnostic yield for solving cases of suspected Mendelian conditions, yet the added benefit of full-length long-read transcript sequencing is largely unexplored. Methods:We applied short-read and full-length transcript sequencing and mitochondrial functional studies to a patient-derived fibroblast cell line from an individual with neuropathy that previously lacked a molecular diagnosis. Results:We identified an intronic homozygous MFN2 c.600-31T>G variant that disrupts the branch point critical for intron 6 splicing. Full-length long-read isoform complementary DNA (cDNA) sequencing after treatment with a nonsense-mediated mRNA decay (NMD) inhibitor revealed that this variant creates 5 distinct altered splicing transcripts. All 5 altered splicing transcripts have disrupted open reading frames and are subject to NMD. Furthermore, a patient-derived fibroblast line demonstrated abnormal lipid droplet formation, consistent with MFN2 dysfunction. Although correctly spliced full-length MFN2 transcripts are still produced, this branch point variant results in deficient MFN2 levels and autosomal recessive Charcot-Marie-Tooth disease, axonal, type 2A (CMT2A). Discussion:This case highlights the utility of full-length isoform sequencing for characterizing the molecular mechanism of undiagnosed rare diseases and expands our understanding of the genetic basis for CMT2A.

SLC1A4 is a trimeric neutral amino acid transporter essential for shuttling L-serine from astrocytes into neurons. Individuals with biallelic variants in SLC1A4 are known to have spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) syndrome, but individuals with heterozygous variants are not thought to have disease. We identify an 8-year-old patient with global developmental delay, spasticity, epilepsy, and microcephaly who has a de novo heterozygous three amino acid duplication in SLC1A4 (L86_M88dup). We demonstrate that L86_M88dup causes a dominant-negative N-glycosylation defect of SLC1A4, which in turn reduces the plasma membrane localization of SLC1A4 and the transport rate of SLC1A4 for L-serine.

Background Post-traumatic epilepsy (PTE) is a severe complication of traumatic brain injury (TBI). Electroencephalography aids early post-traumatic seizure diagnosis, but its optimal utility for PTE prediction remains unknown. We aim to evaluate the contribution of quantitative electroencephalograms to predict first-year PTE (PTE1). Methods We performed a multicentre, retrospective case–control study of patients with TBI. 63 PTE1 patients were matched with 63 non-PTE1 patients by admission Glasgow Coma Scale score, age and sex. We evaluated the association of quantitative electroencephalography features with PTE1 using logistic regressions and examined their predictive value relative to TBI mechanism and CT abnormalities. Results In the matched cohort (n=126), greater epileptiform burden, suppression burden and beta variability were associated with 4.6 times higher PTE1 risk based on multivariable logistic regression analysis (area under the receiver operating characteristic curve, AUC (95% CI) 0.69 (0.60 to 0.78)). Among 116 (92%) patients with available CT reports, adding quantitative electroencephalography features to a combined mechanism and CT model improved performance (AUC (95% CI), 0.71 (0.61 to 0.80) vs 0.61 (0.51 to 0.72)). Conclusions Epileptiform and spectral characteristics enhance covariates identified on TBI admission and CT abnormalities in PTE1 prediction. Future trials should incorporate quantitative electroencephalography features to validate this enhancement of PTE risk stratification models.

Targeted sequencing remains a valuable technique for clinical and research applications. However, many existing technologies suffer from pervasive guanine-cytosine (GC) sequence content bias, high input DNA requirements, and high cost for custom panels. We have developed Cas12a-Capture, a low-cost and highly scalable method for targeted sequencing. The method utilizes preprogrammed guide RNAs to direct CRISPR-Cas12a cleavage of double-stranded DNA in vitro and then takes advantage of the resulting four to five nucleotide overhangs for selective ligation with a custom sequencing adapter. Addition of a second sequencing adapter and enrichment for ligation products generates a targeted sequence library. We first performed a pilot experiment with 7176 guides targeting 3.5 Mb of DNA. Using these data, we modeled the sequence determinants of Cas12a-Capture efficiency, then designed an optimized set of 11,438 guides targeting 3.0 Mb. The optimized guide set achieves an average 64-fold enrichment of targeted regions with minimal GC bias. Cas12a-Capture variant calls had strong concordance with Illumina Platinum Genome calls, especially for single nucleotide variants, which could be improved by applying basic variant quality heuristics. We believe Cas12a-Capture has a wide variety of potential clinical and research applications and is amendable for selective enrichment for any double-stranded DNA template or genome.

Background and Objective To identify clinical, ECG, and blood-based biomarkers associated with atrial fibrillation (AF) detection after ischaemic stroke or TIA that could help inform patient selection for cardiac monitoring. Methods We performed a systematic review and meta-analysis and searched electronic databases for cohort studies from January 15, 2000, to January 15, 2020. The outcome was AF >= 30 seconds within 1 year after ischemic stroke/TIA. We used random effects models to create summary estimates of risk. Risk of bias was assessed using the Quality in Prognostic Studies tool. Results We identified 8,503 studies, selected 34 studies, and assessed 69 variables (42 clinical, 20 ECG, and 7 blood-based biomarkers). The studies included 11,569 participants and AF was detected in 1,478 (12.8%). Overall, risk of bias was moderate. Variables associated with increased likelihood of AF detection are older age (odds ratio [OR] 3.26, 95% confidence interval [CI] 2.35-4.54), female sex (OR 1.47, 95% CI 1.23-1.77), a history of heart failure (OR 2.56, 95% CI 1.87-3.49), hypertension (OR 1.42, 95% CI 1.15-1.75) or ischemic heart disease (OR 1.80, 95% CI 1.34-2.42), higher modified Rankin Scale (OR 6.13, 95% CI 2.93-12.84) or National Institutes of Health Stroke Scale score (OR 2.50, 95% CI 1.64-3.81), no significant carotid/intracranial artery stenosis (OR 3.23, 95% CI 1.14-9.11), no tobacco use (OR 1.93, 95% CI 1.48-2.51), statin therapy (OR 2.07, 95% CI 1.14-3.73), stroke as index diagnosis (OR 1.59, 95% CI 1.17-2.18), systolic blood pressure (OR 1.61, 95% CI 1.16-2.22), IV thrombolysis treatment (OR 2.40, 95% CI 1.83-3.16), atrioventricular block (OR 2.12, 95% CI 1.08-4.17), left ventricular hypertrophy (OR 2.21, 95% CI 1.03-4.74), premature atrial contraction (OR 3.90, 95% CI 1.74-8.74), maximum P-wave duration (OR 3.19, 95% CI 1.40-7.25), PR interval (OR 2.32, 95% CI 1.11-4.83), P-wave dispersion (OR 7.79, 95% CI 4.16-14.61), P-wave index (OR 3.44, 95% CI 1.87-6.32), QTc interval (OR 3.68, 95% CI 1.63-8.28), brain natriuretic peptide (OR 13.73, 95% CI 3.31-57.07), and high-density lipoprotein cholesterol (OR 1.49, 95% CI 1.17-1.88) concentrations. Variables associated with reduced likelihood are minimum P-wave duration (OR 0.53, 95% CI 0.29-0.98), low-density lipoprotein cholesterol (OR 0.73, 95% CI 0.57-0.93), and triglyceride (OR 0.51, 95% CI 0.41-0.64) concentrations. Discussion We identified multimodal biomarkers that could help guide patient selection for cardiac monitoring after ischaemic stroke/TIA. Their prognostic utility should be prospectively assessed with AF detection and recurrent stroke as outcomes.

Introduction: Cardiac monitoring is performed to detect atrial fibrillation (AF) after stroke. Identifying patients at high or low risk of AF may allow cardiac monitoring approaches to be tailored on a more personalised basis. We performed a systematic review and meta-analysis to identify variables associated with AF detection after ischaemic stroke. Methods: We followed the Cochrane Collaboration Guidelines and retrieved 8503 studies. After screening, 35 studies were selected and 68 variables were assessed. We assessed 41 clinical variables, 20 ECG parameters and 7 blood biomarkers associated with AF detection >30 seconds duration in the first year after stroke. Comprehensive Meta-analysis software was used to generate an odds ratio and Forest plot for each variable. Studies were assessed for quality using the Quality in Prognostic Studies (QUIPS) tool. Results: The 35 studies included 12010 patients and AF was detected in 1551 patients (13%). Of the 68 variables assessed, 20 were associated with increased odds of AF, 5 were associated with reduced odds of AF and 43 were not associated with AF (Figure 1). The variables most strongly associated with AF detection (odds ratio >3.00) were older age, patients who received IV thrombolytic therapy, maximum P-wave duration, premature atrial complexes, P-wave dispersion, P-wave index, QTc interval and brain natriuretic peptide. Risk of bias was low in 3 studies, moderate in 24 studies and high in 8 studies. Conclusions: We have identified clinically applicable variables that can stratify the probability of AF detection after stroke. Our results will help guide more personalised approaches to cardiac monitoring for AF detection after stroke.

Background: The ‘impact’ of a scientific paper is a measure of influence in its field. In recent years, traditional, citation-based measures of impact have been complemented by Altmetrics, which quantify outputs including social media footprint. As authors and research institutions seek to increase their visibility both within and beyond the academic community, it is important to identify and compare the determinants of traditional and alternative metrics. We explored this using Stroke – a leading journal in its field. Methods: We described the impact of original research papers published in Stroke (2015-2016) using citation count and Altmetric Attention Score (Altmetrics). Using these two metrics as our outcomes, we assessed univariable and multivariable associations with 21 plausibly relevant publication features. We set the significance threshold at p<0.01. Results: Across 911 papers published in Stroke, there was an average citation count of 21.60 (±17.40) and Altmetric score of 17.99 (±47.37). The two impact measures were weakly correlated (r=0.15, p<0.001). Citations were independently associated with five publication features at a significance level of p<0.01: Time Since Publication (beta=0.87), Number of Authors (beta=0.22), Publication Type (beta=6.76), Number of Previous Publications (beta=0.01) and Editorial (beta=9.45). For Altmetrics, we observed a trend for independent associations with: Time Since Publication (beta=-0.25, p=0.02), Number of References (beta=0.32, p=0.02) and Country of Affiliation (beta=8.59, p=0.01). Our models explained 21% and 3% of variance in citations and Altmetrics, respectively. Conclusion: Papers published in Stroke have impact. Certain aspects of content and format may contribute to impact, but these differ for traditional measures and Altmetrics, and explain only a very modest proportion of variance in the latter. Citation counts and Altmetrics seem to represent different constructs and, therefore, should be used in conjunction to allow a more comprehensive assessment of publication impact.

Progress in addressing the origins of intellectual and developmental disabilities accelerated with the establishment 50 years ago of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health and associated Intellectual and Developmental Disabilities Research Centers. Investigators at these Centers have made seminal contributions to understanding human brain and behavioral development and defining mechanisms and treatments of disorders of the developing brain. ANN NEUROL 2019;86:332–343

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.

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.

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

Common polymorphisms in the first intron of FTO are associated with increased body weight in adults. Previous studies have suggested that a CUX1-regulatory element within the implicated FTO region controls expression of FTO and the nearby ciliary gene, RPGRIP1L. Given the role of ciliary genes in energy homeostasis, we hypothesized that mice hypomorphic for Rpgrip1l would display increased adiposity. We find that Rpgrip1l(+/-) mice are hyperphagic and fatter, and display diminished suppression of food intake in response to leptin administration. In the hypothalamus of Rpgrip1l(+/-) mice, and in human fibroblasts with hypomorphic mutations in RPGRIP1L, the number of AcIII-positive cilia is diminished, accompanied by impaired convening of the leptin receptor to the vicinity of the cilium, and diminished pStat3 in response to leptin. These findings suggest that RPGRIP1L may be partly or exclusively responsible for the obesity susceptibility signal at the FTO locus.