@article {586, title = {Contribution of noncoding pathogenic variants to RPGRIP1-mediated inherited retinal degeneration.}, journal = {Genet Med}, volume = {21}, year = {2019}, month = {2019 03}, pages = {694-704}, abstract = {

PURPOSE: With the advent of gene therapies for inherited retinal degenerations (IRDs), genetic diagnostics will have an increasing role in clinical decision-making. Yet the genetic cause of disease cannot be identified using exon-based sequencing for a significant portion of patients. We hypothesized that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and evaluated patients with single coding pathogenic variants in RPGRIP1 to test this hypothesis.

METHODS: IRD families underwent targeted panel sequencing. Unsolved cases were explored by exome and genome sequencing looking for additional pathogenic variants. Candidate pathogenic variants were then validated by Sanger sequencing, quantitative polymerase chain reaction, and in vitro splicing assays in two cell lines analyzed through amplicon sequencing.

RESULTS: Among 1722 families, 3 had biallelic loss-of-function pathogenic variants in RPGRIP1 while 7 had a single disruptive coding pathogenic variants. Exome and genome sequencing revealed potential noncoding pathogenic variants in these 7 families. In 6, the noncoding pathogenic variants were shown to lead to loss of function in vitro.

CONCLUSION: Noncoding pathogenic variants were identified in 6 of 7 families with single coding pathogenic variants in RPGRIP1. The results suggest that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and RPGRIP1-mediated IRDs are more common than previously thought.

}, keywords = {Adult, Chromosome Mapping, DNA Mutational Analysis, DNA, Intergenic, Female, HEK293 Cells, Humans, Male, Mutation, Pedigree, Proteins, Retinal Degeneration, Whole Exome Sequencing, Whole Genome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-018-0104-7}, author = {Jamshidi, Farzad and Place, Emily M and Mehrotra, Sudeep and Navarro-Gomez, Daniel and Maher, Mathew and Branham, Kari E and Valkanas, Elise and Cherry, Timothy J and Lek, Monkol and Macarthur, Daniel and Pierce, Eric A and Bujakowska, Kinga M} } @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} }