RESUMEN
Fanconi anaemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink repair resulting in chromosome breakage1-3. The FA repair pathway protects against endogenous and exogenous carcinogenic aldehydes4-7. Individuals with FA are hundreds to thousands fold more likely to develop head and neck (HNSCC), oesophageal and anogenital squamous cell carcinomas8 (SCCs). Molecular studies of SCCs from individuals with FA (FA SCCs) are limited, and it is unclear how FA SCCs relate to sporadic HNSCCs primarily driven by tobacco and alcohol exposure or infection with human papillomavirus9 (HPV). Here, by sequencing genomes and exomes of FA SCCs, we demonstrate that the primary genomic signature of FA repair deficiency is the presence of high numbers of structural variants. Structural variants are enriched for small deletions, unbalanced translocations and fold-back inversions, and are often connected, thereby forming complex rearrangements. They arise in the context of TP53 loss, but not in the context of HPV infection, and lead to somatic copy-number alterations of HNSCC driver genes. We further show that FA pathway deficiency may lead to epithelial-to-mesenchymal transition and enhanced keratinocyte-intrinsic inflammatory signalling, which would contribute to the aggressive nature of FA SCCs. We propose that the genomic instability in sporadic HPV-negative HNSCC may arise as a result of the FA repair pathway being overwhelmed by DNA interstrand crosslink damage caused by alcohol and tobacco-derived aldehydes, making FA SCC a powerful model to study tumorigenesis resulting from DNA-crosslinking damage.
Asunto(s)
Reparación del ADN , Anemia de Fanconi , Genómica , Neoplasias de Cabeza y Cuello , Humanos , Aldehídos/efectos adversos , Aldehídos/metabolismo , Reparación del ADN/genética , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Anemia de Fanconi/patología , Neoplasias de Cabeza y Cuello/inducido químicamente , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Infecciones por Papillomavirus , Carcinoma de Células Escamosas de Cabeza y Cuello/inducido químicamente , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Daño del ADN/efectos de los fármacosRESUMEN
Fanconi anaemia (FA) is a genetic disorder due to mutations in any of the 22 FANC genes (FANCA-FANCW) and has high phenotypic variation. Siblings may have similar clinical outcome because they share the same variants; however, such association has not been reported. We present the detailed phenotype and clinical course of 25 sibling sets with FA from two institutions. Haematological progression significantly correlated between siblings, which was confirmed in an additional 55 sibling pairs from the International Fanconi Anemia Registry. Constitutional abnormalities were not concordant, except for a moderate degree of concordance in kidney abnormalities and microcephaly.
Asunto(s)
Anemia de Fanconi , Riñón , Microcefalia , Sistema de Registros , Hermanos , Anemia de Fanconi/sangre , Anemia de Fanconi/genética , Anemia de Fanconi/inmunología , Femenino , Humanos , Riñón/anomalías , Riñón/inmunología , Riñón/metabolismo , Masculino , Microcefalia/genética , Microcefalia/inmunología , Microcefalia/metabolismo , Estudios RetrospectivosRESUMEN
Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.
Asunto(s)
Aspartato-ARNt Ligasa/genética , Mutación con Ganancia de Función/genética , Mutación con Pérdida de Función/genética , Trastornos del Neurodesarrollo/genética , Aminoacil-ARN de Transferencia/genética , Alelos , Aminoacil-ARNt Sintetasas/genética , Línea Celular , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Linaje , ARN de Transferencia/genética , Células Madre/fisiologíaRESUMEN
Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Here, we identify biallelic missense and frameshift mutations in NARS1 in seven patients from three unrelated families with microcephaly and neurodevelopmental delay. Patient cells show reduced NARS1 protein, impaired NARS1 activity and impaired global protein synthesis. Cortical brain organoid modeling shows reduced proliferation of radial glial cells (RGCs), leading to smaller organoids characteristic of microcephaly. Single-cell analysis reveals altered constituents of both astrocytic and RGC lineages, suggesting a requirement for NARS1 in RGC proliferation. Our findings demonstrate that NARS1 is required to meet protein synthetic needs and to support RGC proliferation in human brain development.
Asunto(s)
Aspartato-ARNt Ligasa/deficiencia , Aspartato-ARNt Ligasa/genética , Corteza Cerebral/patología , Microcefalia/genética , Células-Madre Neurales/patología , Organoides/patología , Aminoacil-ARN de Transferencia/genética , Adolescente , Adulto , Secuencia de Bases , Diferenciación Celular , Proliferación Celular , Tamaño de la Célula , Supervivencia Celular , Niño , Familia , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Células HEK293 , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Mutación/genética , Células-Madre Neurales/metabolismo , Neuroglía/metabolismo , Linaje , Adulto JovenRESUMEN
Neuronal migration defects, including pachygyria, are among the most severe developmental brain defects in humans. Here, we identify biallelic truncating mutations in CTNNA2, encoding αN-catenin, in patients with a distinct recessive form of pachygyria. CTNNA2 was expressed in human cerebral cortex, and its loss in neurons led to defects in neurite stability and migration. The αN-catenin paralog, αE-catenin, acts as a switch regulating the balance between ß-catenin and Arp2/3 actin filament activities1. Loss of αN-catenin did not affect ß-catenin signaling, but recombinant αN-catenin interacted with purified actin and repressed ARP2/3 actin-branching activity. The actin-binding domain of αN-catenin or ARP2/3 inhibitors rescued the neuronal phenotype associated with CTNNA2 loss, suggesting ARP2/3 de-repression as a potential disease mechanism. Our findings identify CTNNA2 as the first catenin family member with biallelic mutations in humans, causing a new pachygyria syndrome linked to actin regulation, and uncover a key factor involved in ARP2/3 repression in neurons.
Asunto(s)
Complejo 2-3 Proteico Relacionado con la Actina/genética , Movimiento Celular/genética , Corteza Cerebral/fisiología , Neuronas/patología , alfa Catenina/genética , Complejo 2-3 Proteico Relacionado con la Actina/metabolismo , Animales , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Embrión de Mamíferos , Genoma Humano , Humanos , Ratones , Ratones Endogámicos C57BL , Mutación , Proteínas del Tejido Nervioso/genética , Neuronas/metabolismo , Linaje , alfa Catenina/metabolismoRESUMEN
BACKGROUND: Transport protein particle (TRAPP) is a multisubunit complex that regulates membrane trafficking through the Golgi apparatus. The clinical phenotype associated with mutations in various TRAPP subunits has allowed elucidation of their functions in specific tissues. The role of some subunits in human disease, however, has not been fully established, and their functions remain uncertain. OBJECTIVE: We aimed to expand the range of neurodevelopmental disorders associated with mutations in TRAPP subunits by exome sequencing of consanguineous families. METHODS: Linkage and homozygosity mapping and candidate gene analysis were used to identify homozygous mutations in families. Patient fibroblasts were used to study splicing defect and zebrafish to model the disease. RESULTS: We identified six individuals from three unrelated families with a founder homozygous splice mutation in TRAPPC6B, encoding a core subunit of the complex TRAPP I. Patients manifested a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features, and showed splicing defect. Zebrafish trappc6b morphants replicated the human phenotype, displaying decreased head size and neuronal hyperexcitability, leading to a lower seizure threshold. CONCLUSION: This study provides clinical and functional evidence of the role of TRAPPC6B in brain development and function.
Asunto(s)
Trastorno Autístico/genética , Epilepsia/genética , Efecto Fundador , Estudios de Asociación Genética , Microcefalia/genética , Mutación/genética , Trastornos del Neurodesarrollo/genética , Proteínas de Transporte Vesicular/genética , Animales , Trastorno Autístico/complicaciones , Epilepsia/complicaciones , Homocigoto , Humanos , Microcefalia/complicaciones , Fenotipo , Pez CebraRESUMEN
The integrity and dynamic properties of the microtubule cytoskeleton are indispensable for the development of the mammalian brain. Consequently, mutations in the genes that encode the structural component (the α/ß-tubulin heterodimer) can give rise to severe, sporadic neurodevelopmental disorders. These are commonly referred to as the tubulinopathies. Here we report the addition of recessive quadrupedalism, also known as Uner Tan syndrome (UTS), to the growing list of diseases caused by tubulin variants. Analysis of a consanguineous UTS family identified a biallelic TUBB2B mutation, resulting in a p.R390Q amino acid substitution. In addition to the identifying quadrupedal locomotion, all three patients showed severe cerebellar hypoplasia. None, however, displayed the basal ganglia malformations typically associated with TUBB2B mutations. Functional analysis of the R390Q substitution revealed that it did not affect the ability of ß-tubulin to fold or become assembled into the α/ß-heterodimer, nor did it influence the incorporation of mutant-containing heterodimers into microtubule polymers. The 390Q mutation in S. cerevisiae TUB2 did not affect growth under basal conditions, but did result in increased sensitivity to microtubule-depolymerizing drugs, indicative of a mild impact of this mutation on microtubule function. The TUBB2B mutation described here represents an unusual recessive mode of inheritance for missense-mediated tubulinopathies and reinforces the sensitivity of the developing cerebellum to microtubule defects.
Asunto(s)
Cerebelo/anomalías , Malformaciones del Desarrollo Cortical/genética , Microtúbulos/genética , Malformaciones del Sistema Nervioso/genética , Tubulina (Proteína)/genética , Adulto , Sustitución de Aminoácidos/genética , Ganglios Basales/patología , Encéfalo/crecimiento & desarrollo , Encéfalo/patología , Cerebelo/fisiopatología , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/fisiopatología , Femenino , Homocigoto , Humanos , Masculino , Malformaciones del Desarrollo Cortical/fisiopatología , Microtúbulos/patología , Mutación , Malformaciones del Sistema Nervioso/fisiopatología , Fenotipo , Saccharomyces cerevisiae/genéticaRESUMEN
The risk of epilepsy among individuals with intellectual disability (ID) is approximately ten times that of the general population. From a cohort of >5,000 families affected by neurodevelopmental disorders, we identified six consanguineous families harboring homozygous inactivating variants in MBOAT7, encoding lysophosphatidylinositol acyltransferase (LPIAT1). Subjects presented with ID frequently accompanied by epilepsy and autistic features. LPIAT1 is a membrane-bound phospholipid-remodeling enzyme that transfers arachidonic acid (AA) to lysophosphatidylinositol to produce AA-containing phosphatidylinositol. This study suggests a role for AA-containing phosphatidylinositols in the development of ID accompanied by epilepsy and autistic features.
Asunto(s)
Aciltransferasas/genética , Trastorno Autístico/genética , Epilepsia/genética , Discapacidad Intelectual/genética , Proteínas de la Membrana/genética , Mutación , Aciltransferasas/metabolismo , Ácido Araquidónico/metabolismo , Trastorno Autístico/complicaciones , Trastorno Autístico/enzimología , Trastorno Autístico/metabolismo , Niño , Preescolar , Consanguinidad , Epilepsia/complicaciones , Epilepsia/enzimología , Epilepsia/metabolismo , Femenino , Homocigoto , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/enzimología , Discapacidad Intelectual/metabolismo , Lisofosfolípidos/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Linaje , Fosfatidilinositoles/metabolismoRESUMEN
The tRNA splicing endonuclease is a highly evolutionarily conserved protein complex, involved in the cleavage of intron-containing tRNAs. In human it consists of the catalytic subunits TSEN2 and TSEN34, as well as the non-catalytic TSEN54 and TSEN15. Recessive mutations in the corresponding genes of the first three are known to cause pontocerebellar hypoplasia (PCH) types 2A-C, 4, and 5. Here, we report three homozygous TSEN15 variants that cause a milder version of PCH2. The affected individuals showed progressive microcephaly, delayed developmental milestones, intellectual disability, and, in two out of four cases, epilepsy. None, however, displayed the central visual failure seen in PCH case subjects where other subunits of the TSEN are mutated, and only one was affected by the extensive motor defects that are typical in other forms of PCH2. The three amino acid substitutions impacted the protein level of TSEN15 and the stoichiometry of the interacting subunits in different ways, but all resulted in an almost complete loss of in vitro tRNA cleavage activity. Taken together, our results demonstrate that mutations in any known subunit of the TSEN complex can cause PCH and progressive microcephaly, emphasizing the importance of its function during brain development.
Asunto(s)
Enfermedades Cerebelosas/genética , Endonucleasas/genética , Genes Recesivos , Microcefalia/genética , Mutación , Secuencia de Aminoácidos , Niño , Preescolar , Endonucleasas/química , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Modelos Moleculares , LinajeRESUMEN
Cell division terminates with cytokinesis and cellular separation. Autosomal-recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by a reduction in brain and head size at birth in addition to non-progressive intellectual disability. MCPH is genetically heterogeneous, and 16 loci are known to be associated with loss-of-function mutations predominantly affecting centrosomal-associated proteins, but the multiple roles of centrosomes in cellular function has left questions about etiology. Here, we identified three families affected by homozygous missense mutations in CIT, encoding citron rho-interacting kinase (CIT), which has established roles in cytokinesis. All mutations caused substitution of conserved amino acid residues in the kinase domain and impaired kinase activity. Neural progenitors that were differentiated from induced pluripotent stem cells (iPSCs) derived from individuals with these mutations exhibited abnormal cytokinesis with delayed mitosis, multipolar spindles, and increased apoptosis, rescued by CRISPR/Cas9 genome editing. Our results highlight the importance of cytokinesis in the pathology of primary microcephaly.
Asunto(s)
Alelos , Citocinesis/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Microcefalia/genética , Microcefalia/patología , Mitosis/genética , Mutación Missense/genética , Proteínas Serina-Treonina Quinasas/genética , Apoptosis/genética , Centrosoma/metabolismo , Niño , Preescolar , Femenino , Genes Recesivos , Humanos , Recién Nacido , Masculino , LinajeRESUMEN
Joubert Syndrome (JS) is an inherited ciliopathy associated with mutations in genes essential in primary cilium function. Whole exome sequencing in a multiplex consanguineous family from India revealed a KIAA0556 homozygous single base pair deletion mutation (c.4420del; p.Met1474Cysfs*11). Knockdown of the gene in zebrafish resulted in a ciliopathy phenotype, rescued by co-injection of wildtype cDNA. Affected siblings present a mild and classical form of Joubert syndrome allowing for further delineation of the JS associated genotypic spectrum.
Asunto(s)
Anomalías Múltiples/genética , Cerebelo/anomalías , Ciliopatías/genética , Codón sin Sentido/genética , Anomalías del Ojo/genética , Enfermedades Renales Quísticas/genética , Proteínas Asociadas a Microtúbulos/genética , Retina/anomalías , Anomalías Múltiples/fisiopatología , Adulto , Animales , Cerebelo/fisiopatología , Niño , Preescolar , Cilios/efectos de los fármacos , Cilios/patología , Ciliopatías/fisiopatología , ADN Complementario/administración & dosificación , Modelos Animales de Enfermedad , Exoma/genética , Anomalías del Ojo/fisiopatología , Femenino , Técnicas de Silenciamiento del Gen , Homocigoto , Humanos , Enfermedades Renales Quísticas/fisiopatología , Masculino , Linaje , Fenotipo , Retina/fisiopatología , Pez Cebra/genéticaRESUMEN
Galloway-Mowat syndrome is a rare autosomal-recessive disorder classically described as the combination of microcephaly and nephrotic syndrome. Recently, homozygous truncating mutations in WDR73 (WD repeat domain 73) were described in two of 31 unrelated families with Galloway-Mowat syndrome which was followed by a report of two sibs in an Egyptian consanguineous family. In this report, seven affecteds from four families showing biallelic missense mutations in WDR73 were identified by exome sequencing and confirmed to follow a recessive model of inheritance. Three-dimensional modeling predicted conformational alterations as a result of the mutation, supporting pathogenicity. An additional 13 families with microcephaly and renal phenotype were negative for WDR73 mutations. Missense mutations in the WDR73 gene are reported for the first time in Galloway-Mowat syndrome. A detailed phenotypic comparison of all reported WDR73-linked Galloway-Mowat syndrome patients with WDR73 negative patients showed that WDR73 mutations are limited to those with classical Galloway-Mowat syndrome features, in addition to cerebellar atrophy, thin corpus callosum, brain stem hypoplasia, occasional coarse face, late-onset and mostly slow progressive nephrotic syndrome, and frequent epilepsy.
Asunto(s)
Hernia Hiatal/diagnóstico , Hernia Hiatal/genética , Homocigoto , Microcefalia/diagnóstico , Microcefalia/genética , Mutación Missense , Nefrosis/diagnóstico , Nefrosis/genética , Proteínas/genética , Estudios de Cohortes , Exoma , Facies , Femenino , Estudios de Asociación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Modelos Moleculares , Linaje , Fenotipo , Conformación Proteica , Proteínas/químicaRESUMEN
Defective primary ciliogenesis or cilium stability forms the basis of human ciliopathies, including Joubert syndrome (JS), with defective cerebellar vermis development. We performed a high-content genome-wide small interfering RNA (siRNA) screen to identify genes regulating ciliogenesis as candidates for JS. We analyzed results with a supervised-learning approach, using SYSCILIA gold standard, Cildb3.0, a centriole siRNA screen and the GTex project, identifying 591 likely candidates. Intersection of this data with whole exome results from 145 individuals with unexplained JS identified six families with predominantly compound heterozygous mutations in KIAA0586. A c.428del base deletion in 0.1% of the general population was found in trans with a second mutation in an additional set of 9 of 163 unexplained JS patients. KIAA0586 is an orthologue of chick Talpid3, required for ciliogenesis and Sonic hedgehog signaling. Our results uncover a relatively high frequency cause for JS and contribute a list of candidates for future gene discoveries in ciliopathies.
Asunto(s)
Proteínas de Ciclo Celular/genética , Cerebelo/anomalías , Predisposición Genética a la Enfermedad , Proteínas Mutantes/genética , Retina/anomalías , Anomalías Múltiples/genética , Anomalías del Ojo/genética , Frecuencia de los Genes , Pruebas Genéticas , Estudio de Asociación del Genoma Completo , Heterocigoto , Humanos , Enfermedades Renales Quísticas/genética , ARN Interferente Pequeño/genéticaRESUMEN
Exome sequencing analysis of over 2,000 children with complex malformations of cortical development identified five independent (four homozygous and one compound heterozygous) deleterious mutations in KATNB1, encoding the regulatory subunit of the microtubule-severing enzyme Katanin. Mitotic spindle formation is defective in patient-derived fibroblasts, a consequence of disrupted interactions of mutant KATNB1 with KATNA1, the catalytic subunit of Katanin, and other microtubule-associated proteins. Loss of KATNB1 orthologs in zebrafish (katnb1) and flies (kat80) results in microcephaly, recapitulating the human phenotype. In the developing Drosophila optic lobe, kat80 loss specifically affects the asymmetrically dividing neuroblasts, which display supernumerary centrosomes and spindle abnormalities during mitosis, leading to cell cycle progression delays and reduced cell numbers. Furthermore, kat80 depletion results in dendritic arborization defects in sensory and motor neurons, affecting neural architecture. Taken together, we provide insight into the mechanisms by which KATNB1 mutations cause human cerebral cortical malformations, demonstrating its fundamental role during brain development.
Asunto(s)
Adenosina Trifosfatasas/genética , Encéfalo/anomalías , Encéfalo/patología , Microcefalia/genética , Células-Madre Neurales/patología , Neurogénesis/genética , Lóbulo Óptico de Animales no Mamíferos/anomalías , Animales , Encéfalo/crecimiento & desarrollo , Recuento de Células , División Celular/genética , Dendritas/genética , Drosophila , Proteínas de Drosophila/genética , Humanos , Katanina , Ratones , Microcefalia/patología , Proteínas Asociadas a Microtúbulos/genética , Mutación , Huso Acromático/genética , Pez CebraRESUMEN
Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease.
Asunto(s)
Exoma/genética , Estudios de Asociación Genética , Enfermedad de la Neurona Motora/genética , Neuronas/metabolismo , Tractos Piramidales/metabolismo , Paraplejía Espástica Hereditaria/genética , Animales , Axones/fisiología , Transporte Biológico/genética , Estudios de Cohortes , Redes Reguladoras de Genes , Humanos , Mutación , Nucleótidos/genética , Nucleótidos/metabolismo , Análisis de Secuencia de ADN , Sinapsis/fisiología , Transcriptoma , Pez CebraRESUMEN
Fukuyama-type congenital muscular dystrophy (FCMD, MIM#253800) is an autosomal recessive disorder characterized by severe muscular dystrophy associated with brain malformations. FCMD is the second most common form of muscular dystrophy after Duchenne muscular dystrophy and one of the most common autosomal recessive diseases among the Japanese population, and yet few patients outside of Japan had been reported with this disorder. We report the first known Egyptian patient with FCMD, established by clinical features of generalized weakness, pseudohypertrophy of calf muscles, progressive joint contractures, severe scoliosis, elevated serum creatine kinase level, myopathic electrodiagnostic changes, brain MRI with cobblestone complex, and mutation in the fukutin gene. In addition, our patient displayed primary microcephaly, not previously reported associated with fukutin mutations. Our results expand the geographic and clinical spectrum of fukutin mutations.
Asunto(s)
Proteínas de la Membrana/genética , Microcefalia/genética , Mutación/genética , Síndrome de Walker-Warburg/genética , Preescolar , Femenino , Humanos , PronósticoRESUMEN
Primary cilia are generally solitary organelles that emanate from the surface of almost all vertebrate cell types. Until recently, details regarding the function of these structures were lacking; however, extensive evidence now suggests that primary cilia have critical roles in sensing the extracellular environment, and in coordinating developmental and homeostatic signalling pathways. Furthermore, disruption of these functions seems to underlie a diverse spectrum of disorders, known as primary ciliopathies. These disorders are characterized by wide-ranging clinical and genetic heterogeneity, but with substantial overlap among distinct conditions. Indeed, ciliopathies are associated with a large variety of manifestations that often include distinctive neurological findings. Herein, we review neurological features associated with primary ciliopathies, highlight genotype-phenotype correlations, and discuss potential mechanisms underlying these findings.