@article {779,
	title = {Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures.},
	journal = {Am J Hum Genet},
	volume = {106},
	year = {2020},
	month = {2020 04 02},
	pages = {467-483},
	abstract = {<p>The RNA editing enzyme ADAR2 is essential for the recoding of brain transcripts. Impaired ADAR2 editing leads to early-onset epilepsy and premature death in a mouse model. Here, we report bi-allelic variants in ADARB1, the gene encoding ADAR2, in four unrelated individuals with microcephaly, intellectual disability, and epilepsy. In one individual, a homozygous variant in one of the double-stranded RNA-binding domains (dsRBDs) was identified. In the others, variants were situated in or around the deaminase domain. To evaluate the effects of these variants on ADAR2 enzymatic activity, we performed in~vitro assays with recombinant proteins in HEK293T cells and ex~vivo assays with fibroblasts derived from one of the individuals. We demonstrate that these ADAR2 variants lead to reduced editing activity on a known ADAR2 substrate. We also demonstrate that one variant leads to changes in splicing of ADARB1 transcript isoforms. These findings reinforce the importance of RNA editing in brain development and introduce ADARB1 as a genetic etiology in individuals with intellectual disability, microcephaly, and epilepsy.</p>},
	keywords = {Adenosine Deaminase, Alleles, Alternative Splicing, Child, Child, Preschool, Genetic Predisposition to Disease, Genetic Variation, HEK293 Cells, Humans, Intellectual Disability, Male, Microcephaly, RNA Splicing, RNA-Binding Proteins, Seizures},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2020.02.015},
	author = {Tan, Tiong Yang and Sedm{\'\i}k, Ji{\v r}{\'\i} and Fitzgerald, Mark P and Halevy, Rivka Sukenik and Keegan, Liam P and Helbig, Ingo and Basel-Salmon, Lina and Cohen, Lior and Straussberg, Rachel and Chung, Wendy K and Helal, Mayada and Maroofian, Reza and Houlden, Henry and Juusola, Jane and Sadedin, Simon and Pais, Lynn and Howell, Katherine B and White, Susan M and Christodoulou, John and O{\textquoteright}Connell, Mary A}
}
@article {74,
	title = {Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis.},
	journal = {Am J Hum Genet},
	volume = {98},
	year = {2016},
	month = {2016 Mar 03},
	pages = {579-587},
	abstract = {<p>Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic condition characterized by ocular, cutaneous, and central nervous system anomalies. Key clinical features include a well-demarcated hairless fatty nevus on the scalp, benign ocular tumors, and central nervous system lipomas. Seizures, spasticity, and intellectual disability can be present, although affected individuals without seizures and with normal intellect have also been reported. Given the patchy and asymmetric nature of the malformations, ECCL has been hypothesized to be due to a post-zygotic, mosaic mutation. Despite phenotypic overlap with several other disorders associated with mutations in the RAS-MAPK and PI3K-AKT pathways, the molecular etiology of ECCL remains unknown. Using exome sequencing of DNA from multiple affected tissues from five unrelated individuals with ECCL, we identified two mosaic mutations, c.1638C>A (p.Asn546Lys) and c.1966A>G (p.Lys656Glu) within the tyrosine kinase domain of FGFR1, in two affected individuals each. These two residues are the most commonly mutated residues in FGFR1 in human cancers and are associated primarily with CNS tumors. Targeted resequencing of FGFR1 in multiple tissues from an independent cohort of individuals with ECCL identified one additional individual with a c.1638C>A (p.Asn546Lys) mutation in FGFR1. Functional studies of ECCL fibroblast cell lines show increased levels of phosphorylated FGFRs and phosphorylated FRS2, a direct substrate of FGFR1, as well as constitutive activation of RAS-MAPK signaling. In addition to identifying the molecular etiology of ECCL, our results support the emerging overlap between mosaic developmental disorders and tumorigenesis.</p>},
	keywords = {Adolescent, Cell Line, Tumor, Central Nervous System Neoplasms, Child, Preschool, Exome, Eye, Eye Diseases, Female, Humans, Infant, Lipomatosis, Male, Mutation, Mutation, Missense, Neurocutaneous Syndromes, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Receptor, Fibroblast Growth Factor, Type 1, Seizures, Sequence Analysis, DNA},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2016.02.006},
	author = {Bennett, James T and Tan, Tiong Yang and Alcantara, Diana and T{\'e}trault, Martine and Timms, Andrew E and Jensen, Dana and Collins, Sarah and Nowaczyk, Malgorzata J M and Lindhurst, Marjorie J and Christensen, Katherine M and Braddock, Stephen R and Brandling-Bennett, Heather and Hennekam, Raoul C M and Chung, Brian and Lehman, Anna and Su, John and Ng, SuYuen and Amor, David J and Majewski, Jacek and Biesecker, Les G and Boycott, Kym M and Dobyns, William B and O{\textquoteright}Driscoll, Mark and Moog, Ute and McDonell, Laura M}
}
