Joubert Syndrome-related Disorders Research Articles

An Overview of Genes Involved in the Pure Joubert Syndrome and in Joubert Syndrome-Related Disorders (JSRD)

AbstractJoubert syndrome (JS) is a rare autosomal recessive disease characterized by a peculiar brain malformation, hypotonia, ataxia, developmental delay, abnormal eye movements, and neonatal breathing abnormalities. This picture is often associated with variable multiorgan involvement, mainly of the retina, kidneys and liver, defining a group of conditions termed syndrome and Joubert syndrome-related disorders (JSRD). Currently, more than 30 causative genes have been identified, involved in the development and stability of the primary cilium. Correlations genotype–phenotype are emerging between clinical presentations and mutations in JSRD genes, with implications in terms of molecular diagnosis, prenatal diagnosis, follow-up, and management of mutated patients.

Adolesan bir Erkek Çocukta Poliüri; Tanısal Güçlük

Polyuria in children may become a diagnostic challenge since it may be seen as presenting symptom of an underlying renal or systemic disease. An adolescent boy, who did not have any known illness, was presented with polyuria. The detailed history revealed the findings of learning difficulty, speech impairment, unsteady gait and an operation of polydactyly. He had consanguineous parents and a brother who had abruptly diagnosed with the end-stage renal disease at the age of 21. These clues pointed to genetic background. On physical examination, he had pectus excavatum, atypical facial appearance, dysarthria, hypotonia, rotatory nystagmus, impaired tandem walk, hyperpigmented retinal irregularities. Laboratory examinations showed Stage-4 chronic kidney disease accompanied by tubulopathy. Ultrasonography detected cystic lesions on the corticomedullary junction. Thus, the patient had diagnosed Juvenile-Nephronophthisis. During further examinations, Molar Tooth Sign was detected in cranial MRI imaging. All these clinical and radiological findings indicate the spectrum of Joubert-Syndrome-Related-Disorders (JSRD). Genetic analysis of the patient and his brother revealed homozygous NPHP1 deletion. Distinctly from literature, they both had hematological involvement in the form of persistent thrombocytopenia. Genetic heterogeneity and phenotypic variability of nephronophthisis are major challenges. Although NPHP1 deletions are mostly identified in isolated nephronophthisis, they have also been described in complex ciliopathy syndromes such as JSRD. This case is also specific due to haematological involvement additional to kidney, retina, skeleton, neurological. We think, this case may shed light on future genotype-phenotype studies.

Clinical and Molecular Diagnosis of Joubert Syndrome and Related Disorders

BackgroundJoubert syndrome and related disorders are a group of ciliopathies characterized by mid-hindbrain malformation, developmental delay, hypotonia, oculomotor apraxia, and breathing abnormalities. Molar tooth sign in brain imaging is the hallmark for diagnosis. Joubert syndrome is a clinically and genetically heterogeneous disorder involving mutations in 35 ciliopathy-related genes. We present a large cohort of 59 patients with Joubert syndrome from 55 families. Molecular analysis was performed in 35 families (trio). MethodsClinical exome analysis was performed to identify causal mutations, and genotype-phenotype correlations were evaluated. ResultsAll of the cases were stratified into pure Joubert syndrome (62.7%), Joubert syndrome with retinal disease (22.0%), polydactyly (8.5%), and liver (1.7%) and kidney (1.7%) involvement. Joubert syndrome-related disorders include Meckel-Gruber syndrome in 5.1% cases and Leber congenital amaurosis (1.7%). Of the 35 Joubert syndrome-related genes, 11 were identified in these patients, i.e., CEP290, C5ORF, TCTN1, CC2D2A, RPGRP1L, TCTN3, AHI1, INPP5E, TCTN2, NPHP1, and TMEM237. For the first time, we identified a ciliopathy gene, CCDC28B, as a causal gene in Joubert syndrome in one family. CEP290 accounted for 37.8% cases of pure Joubert syndrome, Joubert syndrome with retinal and renal disease, and Meckel-Gruber syndrome. The p.G1890∗ allele in CEP290 is highly recurrent. Of the six families with Joubert syndrome who had a prenatal diagnosis, one fetus was normal, two were carriers, and three were affected. ConclusionsThis is the largest study of Joubert syndrome from India. Although a high degree of locus and allelic heterogeneity was observed, CEP290 variants were the most common among these patients.

Joubert syndrome-related disorders associated with Blake's pouch cyst

Joubert syndrome (OMIM 213300) is an uncommon autosomal recessive disorder that is characterised by distinct mid-hindbrain abnormalities, hypotonia and developmental delay. The molar tooth sign is a distinctive radiological feature of Joubert Syndrome that is best seen on a magnetic resonance imaging (MRI) or axial computed tomography (CT) scan. Here, we present a case of Joubert syndrome with mutation of the TMEM67 gene associated with Blake's pouch cyst. Blake's pouch cyst is a rare finding that is considered a part of the Dandy–Walker spectrum. In more than 90% of the surviving neonates with Blake's pouch cyst diagnosed by ultrasound prenatally, there were no associated abnormalities and a normal developmental progress was assessed at 1–5 years. Rarely, however, trisomy 21, cardiac anomalies and Beckwith–Wiedemann syndrome have been found to be associated with Blake's pouch cyst.

Primary Cilia Signaling Promotes Axonal Tract Development and Is Disrupted in Joubert Syndrome-Related Disorders Models.

Appropriate axonal growth and connectivity are essential for functional wiring of the brain. Joubert syndrome-related disorders (JSRD), a group of ciliopathies in which mutations disrupt primary cilia function, are characterized by axonal tract malformations. However, little is known about how cilia-driven signaling regulates axonal growth and connectivity. We demonstrate that the deletion of related JSRD genes, Arl13b and Inpp5e, in projection neurons leads to de-fasciculated and misoriented axonal tracts. Arl13b deletion disrupts the function of itsdownstream effector, Inpp5e, and deregulates ciliary-PI3K/AKT signaling. Chemogenetic activation of ciliary GPCR signaling and cilia-specific optogenetic modulation of downstream second messenger cascades (PI3K, AKT, and AC3) commonly regulated by ciliary signaling receptors induce rapid changes in axonal dynamics. Further, Arl13b deletion leads to changes in transcriptional landscape associated with dysregulated PI3K/AKT signaling. These data suggest that ciliary signaling acts to modulate axonal connectivity and that impaired primary cilia signaling underlies axonal tract defects in JSRD.

Whole Exome Sequencing in a Korean Child with Joubert Syndrome-related Disorders

Whole Exome Sequencing in a Korean Child with Joubert Syndrome-related Disorders

KIAA0556 is a novel ciliary basal body component mutated in Joubert syndrome.

BackgroundJoubert syndrome (JBTS) and related disorders are defined by cerebellar malformation (molar tooth sign), together with neurological symptoms of variable expressivity. The ciliary basis of Joubert syndrome related disorders frequently extends the phenotype to tissues such as the eye, kidney, skeleton and craniofacial structures.ResultsUsing autozygome and exome analyses, we identified a null mutation in KIAA0556 in a multiplex consanguineous family with hallmark features of mild Joubert syndrome. Patient-derived fibroblasts displayed reduced ciliogenesis potential and abnormally elongated cilia. Investigation of disease pathophysiology revealed that Kiaa0556-/- null mice possess a Joubert syndrome-associated brain-restricted phenotype. Functional studies in Caenorhabditis elegans nematodes and cultured human cells support a conserved ciliary role for KIAA0556 linked to microtubule regulation. First, nematode KIAA0556 is expressed almost exclusively in ciliated cells, and the worm and human KIAA0556 proteins are enriched at the ciliary base. Second, C. elegans KIAA0056 regulates ciliary A-tubule number and genetically interacts with an ARL13B (JBTS8) orthologue to control cilium integrity. Third, human KIAA0556 binds to microtubules in vitro and appears to stabilise microtubule networks when overexpressed. Finally, human KIAA0556 biochemically interacts with ciliary proteins and p60/p80 katanins. The latter form a microtubule-severing enzyme complex that regulates microtubule dynamics as well as ciliary functions.ConclusionsWe have identified KIAA0556 as a novel microtubule-associated ciliary base protein mutated in Joubert syndrome. Consistent with the mild patient phenotype, our nematode, mice and human cell data support the notion that KIAA0556 has a relatively subtle and variable cilia-related function, which we propose is related to microtubule regulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0858-z) contains supplementary material, which is available to authorized users.

Joubert syndrome and related disorders: Report of five Tunisian cases

Joubert syndrome and Joubert syndrome related disorders are rare autosomal recessive disorders, clinically and genetically heterogeneous characterized by cerebellar vermis hypoplasia and a peculiar midbrain-hindbrain malformation the “molar tooth sign”. Clinical picture is characterized by hypotonia, ataxia, developmental delay, abnormal eye movements and occasionally by abnormal respiratory pattern in the neonatal period. Combination of additional features, such as polydactyly, ocular coloboma, retinal dystrophy, renal disease, hepatic fibrosis, encephalocele, and other brain malformations define various clinical subtypes. We report five cases (belonging to four families) with associated elastopathy in one family. We discuss clinical heterogeneity in particular the unusual association to elastopathy in one family and absence of abnormal neonatal respiratory pattern in all five cases.

Response to Heller and Bolz

Response to Heller and Bolz

Neuro-Ophthalmological Findings in Children and Adolescents with Chronic Ataxia

Chronic ataxia is a challenging problem in paediatric neurology. It is caused by a multitude of disorders that at least initially have similar or non-specific phenotype. Some of these disorders have associated neuro-ophthalmological signs (N-OS). The aims of this study are to describe the N-OS and their frequencies in general and by disease aetiology in paediatric patients with chronic ataxia. The authors identified 184 patients under age 17 years with chronic ataxia (>2 months duration or recurrent) during 1991–2008 from multiple sources. Diagnoses and N-OS were ascertained following charts review. Mean age (SD) was 15 (7.7) years. Median duration of follow-up was 6.4 years. There were 214 N-OS in 115 patients (median = 2, range = 1–5 N-OS/patient). Strabismus was present in 29.3% of patients, nystagmus 27.7%, impaired smooth pursuit 23.4%, hypometric saccades 10.3%, decreased visual acuity 9.2%, abnormal optic discs 8.7%, abnormal pupillary examination 2.7%, hypermetric saccades 2.2%, impaired ductions 1.6%, and abnormal visual fields in 1.1% of patients. N-OS were reported most commonly among patients with the following disorders (commonest N-OS): hypoxic-ischaemic encephalopathy following birth (strabismus), episodic ataxia (nystagmus), neuronal ceroid lipofuscinosis (abnormal optic discs), neuronal migration disorder (strabismus), ischaemic stroke (nystagmus), Joubert syndrome–related disorders (strabismus), leukodystrophy (nystagmus), Friedreich ataxia (hypometric saccades, impaired smooth pursuit, nystagmus), mitochondrial disease (strabismus, nystagmus), ataxia telangiectasia (impaired smooth pursuit), and Angelman syndrome (strabismus). N-OS occur commonly in children with chronic ataxia. Although non-specific, they vary with disease aetiology, potentially aiding in the assessment of these patients.

Intrafamilial Variability and Clinical Heterogeneity in Two Siblings with NPHP4 loss of Function Mutations

Joubert syndrome–related disorders (JSRDs) are a group of clinically and genetically pleiotropic conditions that share a midbrain-hindbrain malformation, the pathognomonic molar tooth sign (MTS) visible on brain imaging, with variable involvement of other organs and systems mainly the eyes and the kidneys. Nevertheless, the definition of JSRDs remained problematical due to the extreme phenotypic heterogeneity, often with intrafamilial variability, and the significant clinical overlap among distinct forms. Here we describe two siblings with nephronophthisis (NPHP), the elder is best categorized as JSRD. Nevertheless, his younger sibling lacked the characteristic molar tooth sign; hence best categorized as NPHP- related ciliopathy. Both siblings had NPHP as the common renal phenotype, yet with variable neurological and ocular involvement. Genetic linkage and mutation analysis revealed a novel homozygous, potential loss of function mutation (c.2618dupA, pH is 873Glnfs*14) in the gene NPHP4 in both siblings. This finding extends the phenotypic spectrum associated with NPHP4 mutations, with discernible clinical heterogeneity and intrafamilial variability.

C5orf42 is the major gene responsible for OFD syndrome type VI

Oral-facial-digital syndrome type VI (OFD VI) is a recessive ciliopathy defined by two diagnostic criteria: molar tooth sign (MTS) and one or more of the following: (1) tongue hamartoma (s) and/or additional frenula and/or upper lip notch; (2) mesoaxial polydactyly of one or more hands or feet; (3) hypothalamic hamartoma. Because of the MTS, OFD VI belongs to the "Joubert syndrome related disorders". Its genetic aetiology remains largely unknown although mutations in the TMEM216 gene, responsible for Joubert (JBS2) and Meckel-Gruber (MKS2) syndromes, have been reported in two OFD VI patients. To explore the molecular cause(s) of OFD VI syndrome, we used an exome sequencing strategy in six unrelated families followed by Sanger sequencing. We identified a total of 14 novel mutations in the C5orf42 gene in 9/11 families with positive OFD VI diagnostic criteria including a severe fetal case with microphthalmia, cerebellar hypoplasia, corpus callosum agenesis, polydactyly and skeletal dysplasia. C5orf42 mutations have already been reported in Joubert syndrome confirming that OFD VI and JBS are allelic disorders, thus enhancing our knowledge of the complex, highly heterogeneous nature of ciliopathies.

Molar Tooth Sign Is Not Pathognomonic for Joubert Syndrome

A 12-year-old girl was admitted for the evaluation of epilepsy and psychomotor retardation. She was born at term after an uneventful pregnancy. There was no consanguinity. Developmental milestones were delayed and she had been treated for epilepsy since 3 months of age. She was walking with support and was able to say a few words like “mama” and “dada.” She had dysmorphologic findings including broad nasal tip, frontal bossing, hypertelorism, tongue hamartomas, notching of the teeth (Fig 1), high arched palate, low set ears, and bilateral preaxial poly-syndactyly of bilateral feet with bifid hallux. Deep tendon reflexes were hyperactive. Echocardiography, abdominopelvic ultrasonography, and ophthalmologic examinations were normal. Brain magnetic resonance imaging revealed molar tooth sign and vermian agenesis (Fig 2). A diagnosis of Varadi-Papp syndrome (orofaciodigital syndrome type VI) was made based on her clinical and radiologic findings. Genetic analysis of INPP5 E and TMEM216 genes revealed no mutation. Figure 2T1-weighted axial scan showing “molar tooth sign.” View Large Image Figure Viewer Download Hi-res image The Molar Tooth Sign Is Pathognomonic for Joubert Syndrome!Pediatric NeurologyVol. 50Issue 6PreviewAs researchers deeply involved in clinical, neuroimaging, and genetic studies on Joubert syndrome (JS), we read with great interest the article by Dirik et al.1 The authors report on a 12-year-old girl with intellectual disability, tongue hamartomas, preaxial poly-syndactyly of both feet, and notching of the teeth. Brain magnetic resonance imaging showed a molar tooth sign (MTS). The authors correctly made the diagnosis of oral-facial-digital syndrome type VI (OFDVI), and based on this they concluded that the MTS is not pathognomonic for JS, but may be seen in other disorders including OFDVI. Full-Text PDF Clinical Syndromes or Ciliopathies Associated With Molar Tooth SignPediatric NeurologyVol. 50Issue 6PreviewWe have read with interest the letter to the Editor by Poretti et al.1 regarding our publication “Molar tooth sign is not pathognomonic for Joubert syndrome.”2 We agree with the authors that a distinction between Joubert syndrome, Joubert syndrome-related disorders, and individual syndromes included in the Joubert syndrome-related disorders does not appear to contribute to the diagnostic definition of patients and may be confusing. The authors suggested a less confusing and clinically more relevant nomenclature, which uses only the term Joubert syndrome and adopt a descriptive classification based on the extent of involvement. Full-Text PDF

Detailed clinical, genetic and neuroimaging characterization of OFD VI syndrome

Oral-facial-digital syndrome type VI (OFD VI) is characterized by the association of malformations of the face, oral cavity and extremities, distinguished from the 12 other OFD syndromes by cerebellar and metacarpal abnormalities. Cerebellar malformations in OFD VI have been described as a molar tooth sign (MTS), thus, including OFD VI among the “Joubert syndrome related disorders” (JSRD). OFD VI diagnostic criteria have recently been suggested: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of hands or feet; 3) hypothalamic hamartoma. In order to further delineate this rare entity, we present the neurological and radiological data of 6 additional OFD VI patients. All patients presented oral malformations, facial dysmorphism and distal abnormalities including frequent polydactyly (66%), as well as neurological symptoms with moderate to severe mental retardation. Contrary to historically reported patients, mesoaxial polydactyly did not appear to be a predominant clinical feature in OFD VI. Sequencing analyzes of the 14 genes implicated in JSRD up to 2011 revealed only an OFD1 frameshift mutation in one female OFD VI patient, strengthening the link between these two oral-facial-digital syndromes and JSRD.

Clinical characterization and NPHP1 mutations in nephronophthisis and associated ciliopathies: A single center experience

Nephronophthisis (NPHP) is a recessive disorder of the kidney that is the leading genetic cause of end-stage renal failure in children. Egypt is a country with a high rate of consanguineous marriages; yet, only a few studies have investigated the clinical and molecular characteristics of NPHP and related ciliopathies in the Egyptian population. We studied 20 children, from 17 independent families, fulfilling the clinical and the ultrasonographic criteria of NPHP. Analysis for a homozygous deletion of the NPHP1 gene was performed by polymerase chain reaction on the genomic DNA of all patients. Patients were best categorized as 75% juvenile NPHP, 5% infantile NPHP, and 20% Joubert syndrome-related disorders (JSRD). The mean age at diagnosis was 87.5 + 45.4 months, which was significantly late as compared with the age at onset of symptoms, 43.8 ± 29.7 months (P <0.01). Homozygous NPHP1 deletions were detected in six patients from five of 17 (29.4%) studied families. Our study demonstrates the clinical phenotype of NPHP and related disorders in Egyptian children. Also, we report that homozygous NPHP1 deletions account for 29.4% of NPHP in the studied families in this cohort, thereby confirming the diagnosis of type-1 NPHP. Moreover, our findings confirm that NPHP1 deletions can indeed be responsible for JSRD.

TMEM237 Is Mutated in Individuals with a Joubert Syndrome Related Disorder and Expands the Role of the TMEM Family at the Ciliary Transition Zone

Joubert syndrome related disorders (JSRDs) have broad but variable phenotypic overlap with other ciliopathies. The molecular etiology of this overlap is unclear but probably arises from disrupting common functional module components within primary cilia. To identify additional module elements associated with JSRDs, we performed homozygosity mapping followed by next-generation sequencing (NGS) and uncovered mutations in TMEM237 (previously known as ALS2CR4). We show that loss of the mammalian TMEM237, which localizes to the ciliary transition zone (TZ), results in defective ciliogenesis and deregulation of Wnt signaling. Furthermore, disruption of Danio rerio (zebrafish) tmem237 expression produces gastrulation defects consistent with ciliary dysfunction, and Caenorhabditis elegans jbts-14 genetically interacts with nphp-4, encoding another TZ protein, to control basal body-TZ anchoring to the membrane and ciliogenesis. Both mammalian and C.elegans TMEM237/JBTS-14 require RPGRIP1L/MKS5 for proper TZ localization, and we demonstrate additional functional interactions between C.elegans JBTS-14 and MKS-2/TMEM216, MKSR-1/B9D1, and MKSR-2/B9D2. Collectively, our findings integrate TMEM237/JBTS-14 in a complex interaction network of TZ-associated proteins and reveal a growing contribution of a TZ functional module to the spectrum of ciliopathy phenotypes.

Clinical utility gene card for: Joubert syndrome

Joubert-Boltshauser syndrome; Joubertsyndrome related disorders (JSRD), including: Cerebellar vermishypoplasia/aplasia, oligophrenia, congenital ataxia, ocular coloboma,and hepatic fibrosis (COACH) syndrome; Cerebellooculorenal orcerebello-oculo-renal (COR) syndrome; Dekaban–Arima syndrome;Va´radi–Papp syndrome or orofaciodigital type VI (OFDVI) syndrome;Malta syndrome.1.2 OMIM# of the disease213300, 243910, 216360, and 277170.1.3 Name of the analysed genes or DNA/chromosome segmentsJBTS1/INPP5E, JBTS2/TMEM216, JBTS3/AHI1, JBTS4/NPHP1,JBTS5/CEP290, JBTS6/TMEM67, JBTS7/RPGRIP1L, JBTS8/ARL13B,JBTS9/CC2D2A, and JBTS10/OFD1.1.4 OMIM# of the gene(s)613037, 613277, 608894, 607100, 610142, 609884, 610937, 608922,612013, and 300170.1.5 Mutational spectrumMissense and nonsense mutations, splice site mutations, deletions,and insertions. Genomic rearrangements so far reported onlyfor NPHP1 (homozygous deletions represent 495% mutations)and CEP290 (heterozygous multiexon deletion reported in asingle patient). Marked allelic heterogeneity, with a large numberof mutations, was reported in each of the 10 genes. Gene–phenotype correlations are known for selected genes (about 50%patients with COR phenotype and about 75% patients withCOACH phenotype have mutations in CEP290 and TMEM67 genes,respectively).1.6 Analytical methodsDirect sequencing of coding genomic regions and splice site junctions;multiplex microsatellite analysis for detection of NPHP1 homozygousdeletion. Possibly, qPCR or targeted array-CGH for detection ofgenomic rearrangements in other genes.1.7 Analytical validationDirect sequencing of both DNA strands; verification of sequence andqPCR results in an independent experiment.1.8 Estimated frequency of the disease(incidence at birth (‘birth prevalence’) or population prevalence)No good population-based data on JSRD prevalence have beenpublished. A likely underestimated frequency between 1/80000 and1/100000 live births is based on unpublished data.1.9 If applicable, prevalence in the ethnic group of investigatedpersonIn Ashkenazi Jews, the estimated carrier frequency of the foundermutation p.R73L in the TMEM216 gene is about 1%.1.10 Diagnostic settingComment: The early detection of breathing abnormalities and/oroculomotor apraxia is suggestive of JS and related disorders. Definitediagnosis is made based on the identification of the characteristichindbrain malformation on brain imaging, that is, the ‘molar toothsign’ or its component features.2. TEST CHARACTERISTICS2.1 Analytical sensitivity(proportion of positive tests if the genotype is present)Nearly 100%. A test for large deletions/duplications in genes otherthan NPHP1 should be considered, especially in patients in whom asingle heterozygous mutation has been detected with conventionalsequencing. The presence of deep intronic mutations is not exploredwith current screening methods.

Then and now: Past Opitz winners discuss the influence of the award on their careers

Then and now: Past Opitz winners discuss the influence of the award on their careers

Joubert Syndrome Associated with Severe Central Sleep Apnea

We report on a patient with mental retardation and chronic hypercapnic respiratory failure who was found to have severe central apnea and periodic breathing while undergoing an evaluation of low oxygen saturation during wakefulness at rest. Magnetic resonance imaging of the brain, which was performed to uncover potential causes for the central sleep apnea, revealed a "molar tooth sign" consistent with the diagnosis of Joubert syndrome. Joubert syndrome-related disorders are autosomal-recessive disorders characterized by diffuse hypotonia, developmental delay, abnormal respiratory patterns, and the pathognomonic neuroradiologic finding of a molar tooth sign. Adaptive servoventilation failed to correct the central apneas or the periodic breathing. Treatment with bilevel positive airway pressure in S/T mode led to resolution of the central events, improvement in sleep quality, and normalization of the oxygen saturation during wakefulness.

CEP290, a gene with many faces: mutation overview and presentation of CEP290base

Ciliopathies are an emerging group of disorders, caused by mutations in ciliary genes. One of the most intriguing disease genes associated with ciliopathies is CEP290, in which mutations cause a wide variety of distinct phenotypes, ranging from isolated blindness over Senior-Loken syndrome (SLS), nephronophthisis (NPHP), Joubert syndrome (related disorders) (JS[RD]), Bardet-Biedl syndrome (BBS), to the lethal Meckel-Grüber syndrome (MKS). Despite the identification of over 100 unique CEP290 mutations, no clear genotype-phenotype correlations could yet be established, and consequently the predictive power of a CEP290-related genotype remains limited. One of the challenges is a better understanding of second-site modifiers. In this respect, there is a growing interest in the potential modifying effects of variations in genes encoding other members of the ciliary proteome that interact with CEP290. Here, we provide an overview of all CEP290 mutations identified so far, with their associated phenotypes. To this end, we developed CEP290base, a locus-specific mutation database that links mutations with patients and their phenotypes (medgen.ugent.be/cep290base).