@article {720, title = {Xq22 deletions and correlation with distinct neurological disease traits in females: Further evidence for a contiguous gene syndrome.}, journal = {Hum Mutat}, volume = {41}, year = {2020}, month = {2020 01}, pages = {150-168}, abstract = {

Xq22 deletions that encompass PLP1 (Xq22-PLP1-DEL) are notable for variable expressivity of neurological disease traits in females ranging from a mild late-onset form of spastic paraplegia type 2 (MIM$\#$ 312920), sometimes associated with skewed X-inactivation, to an early-onset neurological disease trait (EONDT) of severe developmental delay, intellectual disability, and behavioral abnormalities. Size and gene content of Xq22-PLP1-DEL vary and were proposed as potential molecular etiologies underlying variable expressivity in carrier females where two smallest regions of overlap (SROs) were suggested to influence disease. We ascertained a cohort of eight unrelated patients harboring Xq22-PLP1-DEL and performed high-density array comparative genomic hybridization~and breakpoint-junction sequencing. Molecular characterization of Xq22-PLP1-DEL from 17 cases (eight herein and nine published) revealed an overrepresentation of breakpoints that reside within repeats (11/17, ~65\%) and the clustering of ~47\% of proximal breakpoints in a genomic instability hotspot with characteristic non-B DNA density. These findings implicate a potential role for genomic architecture in stimulating the formation of Xq22-PLP1-DEL. The correlation of Xq22-PLP1-DEL gene content with neurological disease trait in female cases enabled refinement of the associated SROs to a single genomic interval containing six genes. Our data support the hypothesis that genes contiguous to PLP1 contribute to EONDT.

}, keywords = {Child, Child, Preschool, Chromosome Breakpoints, Chromosome Deletion, Chromosome Mapping, Chromosomes, Human, X, Comparative Genomic Hybridization, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Nervous System Diseases, Pedigree, Phenotype, Quantitative Trait, Heritable, Repetitive Sequences, Nucleic Acid, Sex Factors, Syndrome, X Chromosome Inactivation}, issn = {1098-1004}, doi = {10.1002/humu.23902}, author = {Hijazi, Hadia and Coelho, Fernanda S and Gonzaga-Jauregui, Claudia and Bernardini, Laura and Mar, Soe S and Manning, Melanie A and Hanson-Kahn, Andrea and Naidu, Sakkubai and Srivastava, Siddharth and Lee, Jennifer A and Jones, Julie R and Friez, Michael J and Alberico, Thomas and Torres, Barbara and Fang, Ping and Cheung, Sau Wai and Song, Xiaofei and Davis-Williams, Angelique and Jornlin, Carly and Wight, Patricia A and Patyal, Pankaj and Taube, Jennifer and Poretti, Andrea and Inoue, Ken and Zhang, Feng and Pehlivan, Davut and Carvalho, Claudia M B and Hobson, Grace M and Lupski, James R} } @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} }