@article {711, title = {De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 03}, pages = {538-546}, abstract = {

PURPOSE: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292).

METHODS: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships.

RESULTS: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment.

CONCLUSION: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.

}, keywords = {Adolescent, Autism Spectrum Disorder, Carrier Proteins, Child, Child, Preschool, Female, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Male, Nerve Tissue Proteins, Neurodevelopmental Disorders, Neuroimaging, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-019-0693-9}, author = {Mirzaa, Ghayda M and Chong, Jessica X and Piton, Am{\'e}lie and Popp, Bernt and Foss, Kimberly and Guo, Hui and Harripaul, Ricardo and Xia, Kun and Scheck, Joshua and Aldinger, Kimberly A and Sajan, Samin A and Tang, Sha and Bonneau, Dominique and Beck, Anita and White, Janson and Mahida, Sonal and Harris, Jacqueline and Smith-Hicks, Constance and Hoyer, Juliane and Zweier, Christiane and Reis, Andr{\'e} and Thiel, Christian T and Jamra, Rami Abou and Zeid, Natasha and Yang, Amy and Farach, Laura S and Walsh, Laurence and Payne, Katelyn and Rohena, Luis and Velinov, Milen and Ziegler, Alban and Schaefer, Elise and Gatinois, Vincent and Genevi{\`e}ve, David and Simon, Marleen E H and Kohler, Jennefer and Rotenberg, Joshua and Wheeler, Patricia and Larson, Austin and Ernst, Michelle E and Akman, Cigdem I and Westman, Rachel and Blanchet, Patricia and Schillaci, Lori-Anne and Vincent-Delorme, Catherine and Gripp, Karen W and Mattioli, Francesca and Guyader, Gwena{\"e}l Le and Gerard, B{\'e}n{\'e}dicte and Mathieu-Dramard, Mich{\`e}le and Morin, Gilles and Sasanfar, Roksana and Ayub, Muhammad and Vasli, Nasim and Yang, Sandra and Person, Rick and Monaghan, Kristin G and Nickerson, Deborah A and van Binsbergen, Ellen and Enns, Gregory M and Dries, Annika M and Rowe, Leah J and Tsai, Anne C H and Svihovec, Shayna and Friedman, Jennifer and Agha, Zehra and Qamar, Raheel and Rodan, Lance H and Martinez-Agosto, Julian and Ockeloen, Charlotte W and Vincent, Marie and Sunderland, William James and Bernstein, Jonathan A and Eichler, Evan E and Vincent, John B and Bamshad, Michael J} } @article {614, title = {Analysis of 17 genes detects mutations in 81\% of 811 patients with lissencephaly.}, journal = {Genet Med}, volume = {20}, year = {2018}, month = {2018 11}, pages = {1354-1364}, abstract = {

PURPOSE: To estimate diagnostic yield and genotype-phenotype correlations in a cohort of 811 patients with lissencephaly or subcortical band heterotopia.

METHODS: We collected DNA from 756 children with lissencephaly over 30 years. Many were tested for deletion 17p13.3 and mutations of LIS1, DCX, and ARX, but few other genes. Among those tested, 216 remained unsolved and were tested by a targeted panel of 17 genes (ACTB, ACTG1, ARX, CRADD, DCX, LIS1, TUBA1A, TUBA8, TUBB2B, TUBB, TUBB3, TUBG1, KIF2A, KIF5C, DYNC1H1, RELN, and VLDLR) or by whole-exome sequencing. Fifty-five patients studied at another institution were added as a validation cohort.

RESULTS: The overall mutation frequency in the entire cohort was 81\%. LIS1 accounted for 40\% of patients, followed by DCX (23\%), TUBA1A (5\%), and DYNC1H1 (3\%). Other genes accounted for 1\% or less of patients. Nineteen percent remained unsolved, which suggests that several additional genes remain to be discovered. The majority of unsolved patients had posterior pachygyria, subcortical band heterotopia, or mild frontal pachygyria.

CONCLUSION: The brain-imaging pattern correlates with mutations in single lissencephaly-associated genes, as well as in biological pathways. We propose the first LIS classification system based on the underlying molecular mechanisms.

}, keywords = {Brain, Classical Lissencephalies and Subcortical Band Heterotopias, DNA Mutational Analysis, Female, Genetic Association Studies, Humans, Lissencephaly, Male, Mutation, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/gim.2018.8}, author = {Di Donato, Nataliya and Timms, Andrew E and Aldinger, Kimberly A and Mirzaa, Ghayda M and Bennett, James T and Collins, Sarah and Olds, Carissa and Mei, Davide and Chiari, Sara and Carvill, Gemma and Myers, Candace T and Rivi{\`e}re, Jean-Baptiste and Zaki, Maha S and Gleeson, Joseph G and Rump, Andreas and Conti, Valerio and Parrini, Elena and Ross, M Elizabeth and Ledbetter, David H and Guerrini, Renzo and Dobyns, William B} }