%0 Journal Article %J Am J Hum Genet %D 2017 %T Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism. %A Harms, Frederike Leonie %A Girisha, Katta M %A Hardigan, Andrew A %A Kortüm, Fanny %A Shukla, Anju %A Alawi, Malik %A Dalal, Ashwin %A Brady, Lauren %A Tarnopolsky, Mark %A Bird, Lynne M %A Ceulemans, Sophia %A Bebin, Martina %A Bowling, Kevin M %A Hiatt, Susan M %A Lose, Edward J %A Primiano, Michelle %A Chung, Wendy K %A Juusola, Jane %A Akdemir, Zeynep C %A Bainbridge, Matthew %A Charng, Wu-Lin %A Drummond-Borg, Margaret %A Eldomery, Mohammad K %A El-Hattab, Ayman W %A Saleh, Mohammed A M %A Bézieau, Stéphane %A Cogné, Benjamin %A Isidor, Bertrand %A Küry, Sébastien %A Lupski, James R %A Myers, Richard M %A Cooper, Gregory M %A Kutsche, Kerstin %K Adolescent %K Adult %K Amino Acid Substitution %K Ataxia %K Child %K Child, Preschool %K Chromatin %K Cyclin-Dependent Kinase Inhibitor p21 %K Developmental Disabilities %K Exome %K Face %K Female %K Gene Expression Regulation %K Genes, Reporter %K HEK293 Cells %K Humans %K Intellectual Disability %K Language Development Disorders %K Male %K Models, Molecular %K Mosaicism %K Mutation %K Neurodevelopmental Disorders %K Protein Transport %K Syndrome %K Transcription Factors %K Transcription, Genetic %X

From a GeneMatcher-enabled international collaboration, we identified ten individuals affected by intellectual disability, speech delay, ataxia, and facial dysmorphism and carrying a deleterious EBF3 variant detected by whole-exome sequencing. One 9-bp duplication and one splice-site, five missense, and two nonsense variants in EBF3 were found; the mutations occurred de novo in eight individuals, and the missense variant c.625C>T (p.Arg209Trp) was inherited by two affected siblings from their healthy mother, who is mosaic. EBF3 belongs to the early B cell factor family (also known as Olf, COE, or O/E) and is a transcription factor involved in neuronal differentiation and maturation. Structural assessment predicted that the five amino acid substitutions have damaging effects on DNA binding of EBF3. Transient expression of EBF3 mutant proteins in HEK293T cells revealed mislocalization of all but one mutant in the cytoplasm, as well as nuclear localization. By transactivation assays, all EBF3 mutants showed significantly reduced or no ability to activate transcription of the reporter gene CDKN1A, and in situ subcellular fractionation experiments demonstrated that EBF3 mutant proteins were less tightly associated with chromatin. Finally, in RNA-seq and ChIP-seq experiments, EBF3 acted as a transcriptional regulator, and mutant EBF3 had reduced genome-wide DNA binding and gene-regulatory activity. Our findings demonstrate that variants disrupting EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay and are present in ∼0.1% of individuals with unexplained neurodevelopmental disorders.

%B Am J Hum Genet %V 100 %P 117-127 %8 2017 Jan 05 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/28017373?dopt=Abstract %R 10.1016/j.ajhg.2016.11.012 %0 Journal Article %J JAMA Neurol %D 2016 %T Whole-Exome Sequencing in Familial Parkinson Disease. %A Farlow, Janice L %A Robak, Laurie A %A Hetrick, Kurt %A Bowling, Kevin %A Boerwinkle, Eric %A Coban-Akdemir, Zeynep H %A Gambin, Tomasz %A Gibbs, Richard A %A Gu, Shen %A Jain, Preti %A Jankovic, Joseph %A Jhangiani, Shalini %A Kaw, Kaveeta %A Lai, Dongbing %A Lin, Hai %A Ling, Hua %A Liu, Yunlong %A Lupski, James R %A Muzny, Donna %A Porter, Paula %A Pugh, Elizabeth %A White, Janson %A Doheny, Kimberly %A Myers, Richard M %A Shulman, Joshua M %A Foroud, Tatiana %K Adult %K Aged %K Cohort Studies %K Exome %K Female %K Genetic Predisposition to Disease %K Genetic Variation %K Humans %K Male %K Middle Aged %K Parkinsonian Disorders %K Protein-Tyrosine Kinases %K Sequence Analysis, DNA %K Tenascin %X

IMPORTANCE: Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors.

OBJECTIVE: To identify genetic variants contributing to disease risk in familial PD.

DESIGN, SETTING, AND PARTICIPANTS: A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD.

MAIN OUTCOMES AND MEASURES: Identification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design.

RESULTS: The 93 individuals from 32 families in the discovery cohort (49.5% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes (TNK2 and TNR) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing.

CONCLUSIONS AND RELEVANCE: TNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD.

%B JAMA Neurol %V 73 %P 68-75 %8 2016 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/26595808?dopt=Abstract %R 10.1001/jamaneurol.2015.3266