@article {55, title = {Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes.}, journal = {J Med Genet}, volume = {53}, year = {2016}, month = {2016 09}, pages = {608-15}, abstract = {

BACKGROUND: Ciliopathies are an extensive group of autosomal recessive or X-linked disorders with considerable genetic and clinical overlap, which collectively share multiple organ involvement and may result in lethal or viable phenotypes. In large numbers of cases the genetic defect remains yet to be determined. The aim of this study is to describe the mutational frequency and phenotypic spectrum of the CEP120 gene.

METHODS: Exome sequencing was performed in 145 patients with Joubert syndrome (JS), including 15 children with oral-facial-digital syndrome type VI (OFDVI) and 21 Meckel syndrome (MKS) fetuses. Moreover, exome sequencing was performed in one fetus with tectocerebellar dysraphia with occipital encephalocele (TCDOE), molar tooth sign and additional skeletal abnormalities. As a parallel study, 346 probands with a phenotype consistent with JS or related ciliopathies underwent next-generation sequencing-based targeted sequencing of 120 previously described and candidate ciliopathy genes.

RESULTS: We present six probands carrying nine distinct mutations (of which eight are novel) in the CEP120 gene, previously found mutated only in Jeune asphyxiating thoracic dystrophy (JATD). The CEP120-associated phenotype ranges from mild classical JS in four patients to more severe conditions in two fetuses, with overlapping features of distinct ciliopathies that include TCDOE, MKS, JATD and OFD syndromes. No obvious correlation is evident between the type or location of identified mutations and the ciliopathy phenotype.

CONCLUSION: Our findings broaden the spectrum of phenotypes caused by CEP120 mutations that account for nearly 1\% of patients with JS as well as for more complex ciliopathy phenotypes. The lack of clear genotype-phenotype correlation highlights the relevance of comprehensive genetic analyses in the diagnostics of ciliopathies.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, Cell Cycle Proteins, Cerebellar Diseases, Cerebellum, Child, Ciliopathies, Encephalocele, Eye Abnormalities, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Testing, Humans, Kidney Diseases, Cystic, Male, Mutation, Mutation Rate, Orofaciodigital Syndromes, Pedigree, Phenotype, Retina, Sequence Alignment}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2016-103832}, author = {Roosing, Susanne and Romani, Marta and Isrie, Mala and Rosti, Rasim Ozgur and Micalizzi, Alessia and Musaev, Damir and Mazza, Tommaso and Al-Gazali, Lihadh and Altunoglu, Umut and Boltshauser, Eugen and D{\textquoteright}Arrigo, Stefano and De Keersmaecker, Bart and Kayserili, H{\"u}lya and Brandenberger, Sarah and Kraoua, Ichraf and Mark, Paul R and McKanna, Trudy and Van Keirsbilck, Joachim and Moerman, Philippe and Poretti, Andrea and Puri, Ratna and Van Esch, Hilde and Gleeson, Joseph G and Valente, Enza Maria} } @article {208, title = {Brain malformations associated with Knobloch syndrome--review of literature, expanding clinical spectrum, and identification of novel mutations.}, journal = {Pediatr Neurol}, volume = {51}, year = {2014}, month = {2014 Dec}, pages = {806-813.e8}, abstract = {

BACKGROUND: Knobloch syndrome is a rare, autosomal recessive, developmental disorder characterized by stereotyped ocular abnormalities with or without occipital skull deformities (encephalocele, bone defects, and cutis aplasia). Although there is clear heterogeneity in clinical presentation, central nervous system malformations, aside from the characteristic encephalocele, have not typically been considered a component of the disease phenotype.

METHODS: Four patients originally presented for genetic evaluation of symptomatic structural brain malformations. Whole-genome genotyping, whole-exome sequencing, and confirmatory Sanger sequencing were performed. Using immunohistochemical analysis, we investigated the protein expression pattern of COL18A1 in the mid-fetal and adult human cerebral cortex and then analyzed the spatial and temporal changes in the expression pattern of COL18A1 during human cortical development using the Human Brain Transcriptome database.

RESULTS: We identified two novel homozygous deleterious frame-shift mutations in the COL18A1 gene. On further investigation of these patients and their families, we found that many exhibited certain characteristics of Knobloch syndrome, including pronounced ocular defects. Our data strongly support an important role for COL18A1 in brain development, and this report contributes to an enhanced characterization of the brain malformations that can result from deficiencies of collagen XVIII.

CONCLUSIONS: This case series highlights the diagnostic power and clinical utility of whole-exome sequencing technology-allowing clinicians and physician scientists to better understand the pathophysiology and presentations of rare diseases. We suggest that patients who are clinically diagnosed with Knobloch syndrome and/or found to have COL18A1 mutations via genetic screening should be investigated for potential structural brain abnormalities even in the absence of an encephalocele.

}, keywords = {Adolescent, Adult, Cerebral Cortex, Collagen Type XVIII, Consanguinity, Encephalocele, Exome, Female, Fetus, Humans, Male, Mutation, Retinal Degeneration, Retinal Detachment, Young Adult}, issn = {1873-5150}, doi = {10.1016/j.pediatrneurol.2014.08.025}, author = {{\c C}a{\u g}layan, Ahmet Okay and Baranoski, Jacob F and Aktar, Fesih and Han, Wengi and Tuysuz, Beyhan and Guzel, Aslan and Guclu, Bulent and Kaymak{\c c}alan, Hande and Aktekin, Berrin and Akg{\"u}m{\"u}{\c s}, G{\"o}zde Tu{\u g}ce and Murray, Phillip B and Erson-Omay, Emine Z and Caglar, Caner and Bakircioglu, Mehmet and Sakalar, Yildirim Bayezit and Guzel, Ebru and Demir, Nihat and Tuncer, Oguz and Senturk, Senem and Ekici, Bar{\i}{\c s} and Minja, Frank J and {\v S}estan, Nenad and Yasuno, Katsuhito and Bilguvar, Kaya and Caksen, Huseyin and G{\"u}nel, Murat} } @article {309, title = {Mutations in LAMB1 cause cobblestone brain malformation without muscular or ocular abnormalities.}, journal = {Am J Hum Genet}, volume = {92}, year = {2013}, month = {2013 Mar 07}, pages = {468-74}, abstract = {

Cobblestone brain malformation (COB) is a neuronal migration disorder characterized by protrusions of neurons beyond the first cortical layer at the pial surface of the brain. It is usually seen in association with dystroglycanopathy types of congenital muscular dystrophies (CMDs) and ocular abnormalities termed muscle-eye-brain disease. Here we report homozygous deleterious mutations in LAMB1, encoding laminin subunit beta-1, in two families with autosomal-recessive COB. Affected individuals displayed a constellation of brain malformations including cortical gyral and white-matter signal abnormalities, severe cerebellar dysplasia, brainstem hypoplasia, and occipital encephalocele, but they had less apparent ocular or muscular abnormalities than are typically observed in COB. LAMB1 is localized to the pial basement membrane, suggesting that defective connection between radial glial cells and the pial surface mediated by LAMB1 leads to this malformation.

}, keywords = {Basement Membrane, Brain, Cerebellum, Cerebral Cortex, Encephalocele, Female, Genetic Predisposition to Disease, Homozygote, Humans, Laminin, Male, Muscular Dystrophies, Nervous System Malformations, Neuroglia, Neurons, Sequence Deletion, Walker-Warburg Syndrome}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.02.005}, author = {Radmanesh, Farid and {\c C}a{\u g}layan, Ahmet Okay and Silhavy, Jennifer L and Yilmaz, Cahide and Cantagrel, Vincent and Omar, Tarek and Rosti, Basak and Kaymak{\c c}alan, Hande and Gabriel, Stacey and Li, Mingfeng and {\v S}estan, Nenad and Bilguvar, Kaya and Dobyns, William B and Zaki, Maha S and G{\"u}nel, Murat and Gleeson, Joseph G} }