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Francesco Brancati - One of the best experts on this subject based on the ideXlab platform.
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Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders
European Journal of Human Genetics, 2013Co-Authors: Lorena Travaglini, Nadia Elkhartoufi, Francesco Brancati, Miriam Iannicelli, Jennifer Silhavy, Elizabeth Nickerson, Eric Scott, Emily Spencer, Stacey Gabriel, Sophie ThomasAbstract:Joubert Syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain–hindbrain malformation known as the ‘molar tooth sign’. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel Syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert Syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS fetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus.
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mutations in tmem216 perturb ciliogenesis and cause joubert Meckel and related Syndromes
Nature Genetics, 2010Co-Authors: Enza Maria Valente, Francesco Brancati, Miriam Iannicelli, Lorena Travaglini, Clare V Logan, Soumaya Mougouzerelli, Jeong Ho Lee, Jennifer L Silhavy, Sveva RomaniAbstract:Joubert Syndrome (JBTS), related disorders (JSRDs) and Meckel Syndrome (MKS) are ciliopathies. We now report that MKS2 and CORS2 (JBTS2) loci are allelic and caused by mutations in TMEM216, which encodes an uncharacterized tetraspan transmembrane protein. Individuals with CORS2 frequently had nephronophthisis and polydactyly, and two affected individuals conformed to the oro-facio-digital type VI phenotype, whereas skeletal dysplasia was common in fetuses affected by MKS. A single G218T mutation (R73L in the protein) was identified in all cases of Ashkenazi Jewish descent (n = 10). TMEM216 localized to the base of primary cilia, and loss of TMEM216 in mutant fibroblasts or after knockdown caused defective ciliogenesis and centrosomal docking, with concomitant hyperactivation of RhoA and Dishevelled. TMEM216 formed a complex with Meckelin, which is encoded by a gene also mutated in JSRDs and MKS. Disruption of tmem216 expression in zebrafish caused gastrulation defects similar to those in other ciliary morphants. These data implicate a new family of proteins in the ciliopathies and further support allelism between ciliopathy disorders.
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expanding cep290 mutational spectrum in ciliopathies
American Journal of Medical Genetics Part A, 2009Co-Authors: Sophie Audollent, Francesco Brancati, Lorena Travaglini, Enrico Bertini, Isabelle Perrault, Tania Attiebitach, Josseline Kaplan, Miriam IannicelliAbstract:Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert Syndrome and related disorders (JSRD), Meckel Syndrome (MKS), Senior-Loken Syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C-terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.
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mks3 tmem67 mutations are a major cause of coach Syndrome a joubert Syndrome related disorder with liver involvement
Human Mutation, 2009Co-Authors: Francesco Brancati, Eugen Boltshauser, Miriam Iannicelli, Annalisa Mazzotta, Lorena Travaglini, Enrico Bertini, Stefano Darrigo, Elisa Fazzi, Romina GallizziAbstract:The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the "molar tooth sign", a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel Syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs.
Lorena Travaglini - One of the best experts on this subject based on the ideXlab platform.
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Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders
European Journal of Human Genetics, 2013Co-Authors: Lorena Travaglini, Nadia Elkhartoufi, Francesco Brancati, Miriam Iannicelli, Jennifer Silhavy, Elizabeth Nickerson, Eric Scott, Emily Spencer, Stacey Gabriel, Sophie ThomasAbstract:Joubert Syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain–hindbrain malformation known as the ‘molar tooth sign’. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel Syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert Syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS fetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus.
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mutations in tmem216 perturb ciliogenesis and cause joubert Meckel and related Syndromes
Nature Genetics, 2010Co-Authors: Enza Maria Valente, Francesco Brancati, Miriam Iannicelli, Lorena Travaglini, Clare V Logan, Soumaya Mougouzerelli, Jeong Ho Lee, Jennifer L Silhavy, Sveva RomaniAbstract:Joubert Syndrome (JBTS), related disorders (JSRDs) and Meckel Syndrome (MKS) are ciliopathies. We now report that MKS2 and CORS2 (JBTS2) loci are allelic and caused by mutations in TMEM216, which encodes an uncharacterized tetraspan transmembrane protein. Individuals with CORS2 frequently had nephronophthisis and polydactyly, and two affected individuals conformed to the oro-facio-digital type VI phenotype, whereas skeletal dysplasia was common in fetuses affected by MKS. A single G218T mutation (R73L in the protein) was identified in all cases of Ashkenazi Jewish descent (n = 10). TMEM216 localized to the base of primary cilia, and loss of TMEM216 in mutant fibroblasts or after knockdown caused defective ciliogenesis and centrosomal docking, with concomitant hyperactivation of RhoA and Dishevelled. TMEM216 formed a complex with Meckelin, which is encoded by a gene also mutated in JSRDs and MKS. Disruption of tmem216 expression in zebrafish caused gastrulation defects similar to those in other ciliary morphants. These data implicate a new family of proteins in the ciliopathies and further support allelism between ciliopathy disorders.
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expanding cep290 mutational spectrum in ciliopathies
American Journal of Medical Genetics Part A, 2009Co-Authors: Sophie Audollent, Francesco Brancati, Lorena Travaglini, Enrico Bertini, Isabelle Perrault, Tania Attiebitach, Josseline Kaplan, Miriam IannicelliAbstract:Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert Syndrome and related disorders (JSRD), Meckel Syndrome (MKS), Senior-Loken Syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C-terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.
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mks3 tmem67 mutations are a major cause of coach Syndrome a joubert Syndrome related disorder with liver involvement
Human Mutation, 2009Co-Authors: Francesco Brancati, Eugen Boltshauser, Miriam Iannicelli, Annalisa Mazzotta, Lorena Travaglini, Enrico Bertini, Stefano Darrigo, Elisa Fazzi, Romina GallizziAbstract:The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the "molar tooth sign", a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel Syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs.
Enrico Bertini - One of the best experts on this subject based on the ideXlab platform.
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joubert Syndrome and related disorders
Handbook of Clinical Neurology, 2013Co-Authors: Enza Maria Valente, Bruno Dallapiccola, Enrico BertiniAbstract:Joubert Syndrome (JS) is a rare autosomal recessive condition characterized by a peculiar midbrain-hindbrain malformation, known as the molar tooth sign (MTS). The neurological presentation of JS includes hypotonia that evolves into 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 Joubert Syndrome and related disorders (JSRDs), that share the MTS. To date, 16 causative genes have been identified, all encoding for proteins expressed in the primary cilium or its apparatus. Indeed, JSRD present clinical and genetic overlap with a growing field of disorders due to mutations in ciliary proteins, that are collectively known as "ciliopathies." These include isolated nephronophthisis, Senior-Loken Syndrome, Bardet-Biedl Syndrome and, in particular, Meckel Syndrome, which is allelic at JSRD at seven distinct loci. Significant genotype-phenotype correlates are emerging between specific clinical presentations and mutations in JSRD genes, with relevant implications in terms of molecular diagnosis, clinical follow-up, and management of mutated patients. Moreover, the identification of mutations allows early prenatal diagnosis in couples at risk, while fetal neuroimaging may remain uninformative until the late second trimester of pregnancy.
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expanding cep290 mutational spectrum in ciliopathies
American Journal of Medical Genetics Part A, 2009Co-Authors: Sophie Audollent, Francesco Brancati, Lorena Travaglini, Enrico Bertini, Isabelle Perrault, Tania Attiebitach, Josseline Kaplan, Miriam IannicelliAbstract:Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert Syndrome and related disorders (JSRD), Meckel Syndrome (MKS), Senior-Loken Syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C-terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.
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mks3 tmem67 mutations are a major cause of coach Syndrome a joubert Syndrome related disorder with liver involvement
Human Mutation, 2009Co-Authors: Francesco Brancati, Eugen Boltshauser, Miriam Iannicelli, Annalisa Mazzotta, Lorena Travaglini, Enrico Bertini, Stefano Darrigo, Elisa Fazzi, Romina GallizziAbstract:The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the "molar tooth sign", a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel Syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs.
Miriam Iannicelli - One of the best experts on this subject based on the ideXlab platform.
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Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders
European Journal of Human Genetics, 2013Co-Authors: Lorena Travaglini, Nadia Elkhartoufi, Francesco Brancati, Miriam Iannicelli, Jennifer Silhavy, Elizabeth Nickerson, Eric Scott, Emily Spencer, Stacey Gabriel, Sophie ThomasAbstract:Joubert Syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain–hindbrain malformation known as the ‘molar tooth sign’. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel Syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert Syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS fetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus.
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mutations in tmem216 perturb ciliogenesis and cause joubert Meckel and related Syndromes
Nature Genetics, 2010Co-Authors: Enza Maria Valente, Francesco Brancati, Miriam Iannicelli, Lorena Travaglini, Clare V Logan, Soumaya Mougouzerelli, Jeong Ho Lee, Jennifer L Silhavy, Sveva RomaniAbstract:Joubert Syndrome (JBTS), related disorders (JSRDs) and Meckel Syndrome (MKS) are ciliopathies. We now report that MKS2 and CORS2 (JBTS2) loci are allelic and caused by mutations in TMEM216, which encodes an uncharacterized tetraspan transmembrane protein. Individuals with CORS2 frequently had nephronophthisis and polydactyly, and two affected individuals conformed to the oro-facio-digital type VI phenotype, whereas skeletal dysplasia was common in fetuses affected by MKS. A single G218T mutation (R73L in the protein) was identified in all cases of Ashkenazi Jewish descent (n = 10). TMEM216 localized to the base of primary cilia, and loss of TMEM216 in mutant fibroblasts or after knockdown caused defective ciliogenesis and centrosomal docking, with concomitant hyperactivation of RhoA and Dishevelled. TMEM216 formed a complex with Meckelin, which is encoded by a gene also mutated in JSRDs and MKS. Disruption of tmem216 expression in zebrafish caused gastrulation defects similar to those in other ciliary morphants. These data implicate a new family of proteins in the ciliopathies and further support allelism between ciliopathy disorders.
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expanding cep290 mutational spectrum in ciliopathies
American Journal of Medical Genetics Part A, 2009Co-Authors: Sophie Audollent, Francesco Brancati, Lorena Travaglini, Enrico Bertini, Isabelle Perrault, Tania Attiebitach, Josseline Kaplan, Miriam IannicelliAbstract:Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert Syndrome and related disorders (JSRD), Meckel Syndrome (MKS), Senior-Loken Syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C-terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.
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mks3 tmem67 mutations are a major cause of coach Syndrome a joubert Syndrome related disorder with liver involvement
Human Mutation, 2009Co-Authors: Francesco Brancati, Eugen Boltshauser, Miriam Iannicelli, Annalisa Mazzotta, Lorena Travaglini, Enrico Bertini, Stefano Darrigo, Elisa Fazzi, Romina GallizziAbstract:The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the "molar tooth sign", a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel Syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs.
Melissa A Parisi - One of the best experts on this subject based on the ideXlab platform.
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clinical and molecular features of joubert Syndrome and related disorders
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2009Co-Authors: Melissa A ParisiAbstract:Joubert Syndrome (JBTS; OMIM 213300) is a rare, autosomal recessive disorder characterized by a specific congenital malformation of the hindbrain and a broad spectrum of other phenotypic findings that is now known to be caused by defects in the structure and/or function of the primary cilium. The complex hindbrain malformation that is characteristic of JBTS can be identified on axial magnetic resonance imaging and is known as the molar tooth sign (MTS); other diagnostic criteria include intellectual disability, hypotonia, and often, abnormal respiratory pattern and/or abnormal eye movements. In addition, a broad spectrum of other anomalies characterize Joubert Syndrome and related disorders (JSRD), and may include retinal dystrophy, ocular coloboma, oral frenulae and tongue tumors, polydactyly, cystic renal disease (including cystic dysplasia or juvenile nephronophthisis), and congenital hepatic fibrosis. The clinical course can be variable, but most children with this condition survive infancy to reach adulthood. At least eight genes cause JSRD, with some genotype-phenotype correlations emerging, including the association between mutations in the MKS3 gene and hepatic fibrosis characteristic of the JSRD subtype known as COACH Syndrome. Several of the causative genes for JSRD are implicated in other ciliary disorders, such as juvenile nephronophthisis and Meckel Syndrome, illustrating the close association between these conditions and their overlapping clinical features that reflect a shared etiology involving the primary cilium.
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mks3 related ciliopathy with features of autosomal recessive polycystic kidney disease nephronophthisis and joubert Syndrome
The Journal of Pediatrics, 2009Co-Authors: Meral Gunayaygun, Dan Doherty, Melissa A Parisi, Maya Tuchman, Ekaterini Tsilou, David E Kleiner, Marjan Huizing, Baris Turkbey, Peter L Choyke, Lisa M GuaywoodfordAbstract:Objectives To describe 3 children with mutations in a Meckel Syndrome gene ( MKS3 ), with features of autosomal recessive polycystic kidney disease (ARPKD), nephronophthisis, and Joubert Syndrome (JS). Studydesign Biochemical evaluations, magnetic resonance and ultrasound imaging, electroretinograms, IQ testing, and sequence analysis of the PKHD1 and MKS3 genes were performed. Functional consequences of the MKS3 mutations were evaluated by cDNA sequencing and transfection studies with constructs of Meckelin, the protein product of MKS3. Results These 3 children with MKS3 mutations had features typical of ARPKD, that is, enlarged, diffusely microcystic kidneys and early-onset severe hypertension. They also exhibited early-onset chronic anemia, a feature of nephronophthisis, and speech and oculomotor apraxia, suggestive of JS. Magnetic resonance imaging of the brain, originally interpreted as normal, revealed midbrain and cerebellar abnormalities in the spectrum of the "molar tooth sign" that characterizes JS. Conclusions These findings expand the phenotypes associated with MKS3 mutations. MKS3 -related ciliopathies should be considered in patients with an ARPKD-like phenotype, especially in the presence of speech and oculomotor apraxia. In such patients, careful expert evaluation of the brain images can be beneficial because the brain malformations can be subtle.