@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 {846, title = {Genetic diagnoses in epilepsy: The impact of dynamic exome analysis in a pediatric cohort.}, journal = {Epilepsia}, volume = {61}, year = {2020}, month = {2020 02}, pages = {249-258}, abstract = {

OBJECTIVE: We evaluated the yield of systematic analysis and/or reanalysis of whole exome sequencing (WES) data from a cohort of well-phenotyped pediatric patients with epilepsy and suspected but previously undetermined genetic etiology.

METHODS: We identified and phenotyped 125 participants with pediatric epilepsy. Etiology was unexplained at the time of enrollment despite clinical testing, which included chromosomal microarray (57 patients), epilepsy gene panel (n = 48), both (n = 28), or WES (n = 8). Clinical epilepsy diagnoses included developmental and epileptic encephalopathy (DEE), febrile infection-related epilepsy syndrome, Rasmussen encephalitis, and other focal and generalized epilepsies. We analyzed WES data and compared the yield in participants with and without prior clinical genetic testing.

RESULTS: Overall, we identified pathogenic or likely pathogenic variants in 40\% (50/125) of our study participants. Nine patients with DEE had genetic variants in recently published genes that had not been recognized as epilepsy-related at the time of clinical testing (FGF12, GABBR1, GABBR2, ITPA, KAT6A, PTPN23, RHOBTB2, SATB2), and eight patients had genetic variants in candidate epilepsy genes (CAMTA1, FAT3, GABRA6, HUWE1, PTCHD1). Ninety participants had concomitant or subsequent clinical genetic testing, which was ultimately explanatory for 26\% (23/90). Of the 67 participants whose molecular diagnoses were "unsolved" through clinical genetic testing, we identified pathogenic or likely pathogenic variants in 17 (25\%).

SIGNIFICANCE: Our data argue for early consideration of WES with iterative reanalysis for patients with epilepsy, particularly those with DEE or epilepsy with intellectual disability. Rigorous analysis of WES data of well-phenotyped patients with epilepsy leads to a broader understanding of gene-specific phenotypic spectra as well as candidate disease gene identification. We illustrate the dynamic nature of genetic diagnosis over time, with analysis and in some cases reanalysis of exome data leading to the identification of disease-associated variants among participants with previously nondiagnostic results from a variety of clinical testing strategies.

}, keywords = {Adolescent, Adult, Age of Onset, Brain Diseases, Child, Child, Preschool, Chromosomes, Human, Cohort Studies, Epilepsy, Epilepsy, Generalized, Exome, Female, Genetic Testing, Genetic Variation, Humans, Infant, Male, Microarray Analysis, Phenotype, Whole Exome Sequencing, Young Adult}, issn = {1528-1167}, doi = {10.1111/epi.16427}, author = {Rochtus, Anne and Olson, Heather E and Smith, Lacey and Keith, Louisa G and El Achkar, Christelle and Taylor, Alan and Mahida, Sonal and Park, Meredith and Kelly, McKenna and Shain, Catherine and Rockowitz, Shira and Rosen Sheidley, Beth and Poduri, Annapurna} } @article {580, title = {De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome.}, journal = {Genome Med}, volume = {11}, year = {2019}, month = {2019 02 28}, pages = {12}, abstract = {

BACKGROUND: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity).

METHODS: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes.

RESULTS: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances.

CONCLUSIONS: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.

}, keywords = {Adolescent, Child, Child, Preschool, Craniofacial Abnormalities, Developmental Disabilities, Female, Humans, INDEL Mutation, Infant, Intellectual Disability, Male, Muscle Hypotonia, Smith-Magenis Syndrome, Transcription Factors, Young Adult}, issn = {1756-994X}, doi = {10.1186/s13073-019-0623-0}, author = {Vetrini, Francesco and McKee, Shane and Rosenfeld, Jill A and Suri, Mohnish and Lewis, Andrea M and Nugent, Kimberly Margaret and Roeder, Elizabeth and Littlejohn, Rebecca O and Holder, Sue and Zhu, Wenmiao and Alaimo, Joseph T and Graham, Brett and Harris, Jill M and Gibson, James B and Pastore, Matthew and McBride, Kim L and Komara, Makanko and Al-Gazali, Lihadh and Al Shamsi, Aisha and Fanning, Elizabeth A and Wierenga, Klaas J and Scott, Daryl A and Ben-Neriah, Ziva and Meiner, Vardiella and Cassuto, Hanoch and Elpeleg, Orly and Holder, J Lloyd and Burrage, Lindsay C and Seaver, Laurie H and Van Maldergem, Lionel and Mahida, Sonal and Soul, Janet S and Marlatt, Margaret and Matyakhina, Ludmila and Vogt, Julie and Gold, June-Anne and Park, Soo-Mi and Varghese, Vinod and Lampe, Anne K and Kumar, Ajith and Lees, Melissa and Holder-Espinasse, Muriel and McConnell, Vivienne and Bernhard, Birgitta and Blair, Ed and Harrison, Victoria and Muzny, Donna M and Gibbs, Richard A and Elsea, Sarah H and Posey, Jennifer E and Bi, Weimin and Lalani, Seema and Xia, Fan and Yang, Yaping and Eng, Christine M and Lupski, James R and Liu, Pengfei} } @article {464, title = {Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 05 03}, pages = {985-994}, abstract = {

N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.

}, keywords = {Abnormalities, Multiple, Adolescent, Adult, Autism Spectrum Disorder, Cell Line, Child, Exons, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Genetic Variation, Humans, Intellectual Disability, Male, Middle Aged, Mutation, N-Terminal Acetyltransferase A, N-Terminal Acetyltransferase E, Pedigree, Phenotype, RNA, Messenger, Saccharomyces cerevisiae}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.03.004}, author = {Cheng, Hanyin and Dharmadhikari, Avinash V and Varland, Sylvia and Ma, Ning and Domingo, Deepti and Kleyner, Robert and Rope, Alan F and Yoon, Margaret and Stray-Pedersen, Asbj{\o}rg and Posey, Jennifer E and Crews, Sarah R and Eldomery, Mohammad K and Akdemir, Zeynep Coban and Lewis, Andrea M and Sutton, Vernon R and Rosenfeld, Jill A and Conboy, Erin and Agre, Katherine and Xia, Fan and Walkiewicz, Magdalena and Longoni, Mauro and High, Frances A and van Slegtenhorst, Marjon A and Mancini, Grazia M S and Finnila, Candice R and van Haeringen, Arie and den Hollander, Nicolette and Ruivenkamp, Claudia and Naidu, Sakkubai and Mahida, Sonal and Palmer, Elizabeth E and Murray, Lucinda and Lim, Derek and Jayakar, Parul and Parker, Michael J and Giusto, Stefania and Stracuzzi, Emanuela and Romano, Corrado and Beighley, Jennifer S and Bernier, Raphael A and K{\"u}ry, S{\'e}bastien and Nizon, Mathilde and Corbett, Mark A and Shaw, Marie and Gardner, Alison and Barnett, Christopher and Armstrong, Ruth and Kassahn, Karin S and Van Dijck, Anke and Vandeweyer, Geert and Kleefstra, Tjitske and Schieving, Jolanda and Jongmans, Marjolijn J and de Vries, Bert B A and Pfundt, Rolph and Kerr, Bronwyn and Rojas, Samantha K and Boycott, Kym M and Person, Richard and Willaert, Rebecca and Eichler, Evan E and Kooy, R Frank and Yang, Yaping and Wu, Joseph C and Lupski, James R and Arnesen, Thomas and Cooper, Gregory M and Chung, Wendy K and Gecz, Jozef and Stessman, Holly A F and Meng, Linyan and Lyon, Gholson J} }