@article {958, title = {Autosomal recessive variants in alter the γ-tubulin ring complex leading to neurodevelopmental disease.}, journal = {iScience}, volume = {24}, year = {2021}, month = {2021 Jan 22}, pages = {101948}, abstract = {

Microtubules help building the cytoskeleton of neurons and other cells. Several components of the gamma-tubulin (γ-tubulin) complex have been previously reported in human neurodevelopmental diseases. We describe two siblings from a consanguineous Turkish family with dysmorphic features, developmental delay, brain malformation, and epilepsy carrying a homozygous mutation (p.Glu311Lys) in encoding the γ-tubulin complex 2 (GCP2) protein. This variant is predicted to disrupt the electrostatic interaction of GCP2 with GCP3. In primary fibroblasts carrying the variant, we observed a faint delocalization of γ-tubulin during the cell cycle but normal GCP2 protein levels. Through mass spectrometry, we observed dysregulation of multiple proteins involved in the assembly and organization of the cytoskeleton and the extracellular matrix, controlling cellular adhesion and of proteins crucial for neuronal homeostasis including axon guidance. In summary, our functional and proteomic studies link TUBGCP2 and the γ-tubulin complex to the development of the central nervous system in humans.

}, issn = {2589-0042}, doi = {10.1016/j.isci.2020.101948}, author = {G{\"u}ng{\"o}r, Serdal and Oktay, Yavuz and Hiz, Semra and Aranguren-Ib{\'a}{\~n}ez, {\'A}lvaro and Kalafatcilar, Ipek and Yaramis, Ahmet and Karaca, Ezgi and Yis, Uluc and Sonmezler, Ece and Ekinci, Burcu and Aslan, Mahmut and Yilmaz, Elmasnur and {\"O}zg{\"o}r, Bilge and Balaraju, Sunitha and Szabo, Nora and Laurie, Steven and Beltran, Sergi and MacArthur, Daniel G and Hathazi, Denisa and Topf, Ana and Roos, Andreas and Lochm{\"u}ller, Hanns and Vernos, Isabelle and Horvath, Rita} } @article {765, title = {-related autosomal recessive encephalopathy in 2 Turkish children.}, journal = {Neurol Genet}, volume = {6}, year = {2020}, month = {2020 Feb}, pages = {e392}, abstract = {

Objective: This study presents the neurologic phenotypes of 2 brothers with a novel homozygous mutation that was identified in a large Turkish consanguineous cohort of neurogenetic diseases.

Methods: Whole-exome sequencing and bioinformatic analysis of consanguineous families with children affected by early-onset, neurogenetic disorders was performed using the RD-Connect Genome-Phenome Analysis Platform. We also performed clinical, EEG, and neuroimaging analyses in unaffected siblings and parents.

Results: We have identified a homozygous missense mutation in (p.Gly1278Ser, NM_001845.5:c.3832G>T) in 2 siblings affected by small vessel brain disease with periventricular leukoencephalopathy and ocular defects. Presenting symptoms included mild weakness, hemiparetic gait, pyramidal findings, and seizures, whereas their intellectual and behavioral functions were normal. Both parents and 5 of the siblings (3 boys and 2 girls) were heterozygous for the variant. They did not show any clinical or laboratory signs of small vessel disease.

Conclusions: has previously been associated with dominant small vessel disease of the brain and other organs, manifesting with high penetrance in heterozygous mutation carriers. Our findings provide evidence that -related encephalopathy can be inherited in an autosomal recessive manner, which is important for counseling, prognosis, and treatment. Genotype-phenotype correlations remain to be established.

}, issn = {2376-7839}, doi = {10.1212/NXG.0000000000000392}, author = {Yaramis, Ahmet and Lochm{\"u}ller, Hanns and Topf, Ana and Sonmezler, Ece and Yilmaz, Elmasnur and Hiz, Semra and Yis, Uluc and G{\"u}ng{\"o}r, Serdal and Ipek Polat, Ayse and Edem, Pinar and Beltran, Sergi and Laurie, Steven and Yaramis, Aysenur and Horvath, Rita and Oktay, Yavuz} } @article {131, title = {The Matchmaker Exchange: a platform for rare disease gene discovery.}, journal = {Hum Mutat}, volume = {36}, year = {2015}, month = {2015 Oct}, pages = {915-21}, abstract = {

There are few better examples of the need for data sharing than in the rare disease community, where patients, physicians, and researchers must search for "the needle in a haystack" to uncover rare, novel causes of disease within the genome. Impeding the pace of discovery has been the existence of many small siloed datasets within individual research or clinical laboratory databases and/or disease-specific organizations, hoping for serendipitous occasions when two distant investigators happen to learn they have a rare phenotype in common and can "match" these cases to build evidence for causality. However, serendipity has never proven to be a reliable or scalable approach in science. As such, the Matchmaker Exchange (MME) was launched to provide a robust and systematic approach to rare disease gene discovery through the creation of a federated network connecting databases of genotypes and rare phenotypes using a common application programming interface (API). The core building blocks of the MME have been defined and assembled. Three MME services have now been connected through the API and are available for community use. Additional databases that support internal matching are anticipated to join the MME network as it continues to grow.

}, keywords = {Database Management Systems, Databases, Genetic, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Information Dissemination, Rare Diseases, Software}, issn = {1098-1004}, doi = {10.1002/humu.22858}, author = {Philippakis, Anthony A and Azzariti, Danielle R and Beltran, Sergi and Brookes, Anthony J and Brownstein, Catherine A and Brudno, Michael and Brunner, Han G and Buske, Orion J and Carey, Knox and Doll, Cassie and Dumitriu, Sergiu and Dyke, Stephanie O M and den Dunnen, Johan T and Firth, Helen V and Gibbs, Richard A and Girdea, Marta and Gonzalez, Michael and Haendel, Melissa A and Hamosh, Ada and Holm, Ingrid A and Huang, Lijia and Hurles, Matthew E and Hutton, Ben and Krier, Joel B and Misyura, Andriy and Mungall, Christopher J and Paschall, Justin and Paten, Benedict and Robinson, Peter N and Schiettecatte, Fran{\c c}ois and Sobreira, Nara L and Swaminathan, Ganesh J and Taschner, Peter E and Terry, Sharon F and Washington, Nicole L and Z{\"u}chner, Stephan and Boycott, Kym M and Rehm, Heidi L} }