@article {1007, title = {De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 02 04}, pages = {357-367}, abstract = {

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28~{\texttimes} 10). In all six cases with available parental DNA, we demonstrated de novo inheritance (p~=~2.21~{\texttimes} 10). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.

}, keywords = {Adult, Animals, Carrier Proteins, Cell Line, Child, Child, Preschool, Codon, Nonsense, Developmental Disabilities, Epilepsy, Female, Glomerulosclerosis, Focal Segmental, Humans, Intranuclear Space, Kidney, Male, Mice, Mutation, Nephrotic Syndrome, Nerve Tissue Proteins, Phenotype, Podocytes, Whole Exome Sequencing}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.01.008}, author = {Weng, Patricia L and Majmundar, Amar J and Khan, Kamal and Lim, Tze Y and Shril, Shirlee and Jin, Gina and Musgrove, John and Wang, Minxian and Ahram, Dina F and Aggarwal, Vimla S and Bier, Louise E and Heinzen, Erin L and Onuchic-Whitford, Ana C and Mann, Nina and Buerger, Florian and Schneider, Ronen and Deutsch, Konstantin and Kitzler, Thomas M and Kl{\"a}mbt, Verena and Kolb, Amy and Mao, Youying and Moufawad El Achkar, Christelle and Mitrotti, Adele and Martino, Jeremiah and Beck, Bodo B and Altm{\"u}ller, Janine and Benz, Marcus R and Yano, Shoji and Mikati, Mohamad A and Gunduz, Talha and Cope, Heidi and Shashi, Vandana and Trachtman, Howard and Bodria, Monica and Caridi, Gianluca and Pisani, Isabella and Fiaccadori, Enrico and AbuMaziad, Asmaa S and Martinez-Agosto, Julian A and Yadin, Ora and Zuckerman, Jonathan and Kim, Arang and John-Kroegel, Ulrike and Tyndall, Amanda V and Parboosingh, Jillian S and Innes, A Micheil and Bierzynska, Agnieszka and Koziell, Ania B and Muorah, Mordi and Saleem, Moin A and Hoefele, Julia and Riedhammer, Korbinian M and Gharavi, Ali G and Jobanputra, Vaidehi and Pierce-Hoffman, Emma and Seaby, Eleanor G and O{\textquoteright}Donnell-Luria, Anne and Rehm, Heidi L and Mane, Shrikant and D{\textquoteright}Agati, Vivette D and Pollak, Martin R and Ghiggeri, Gian Marco and Lifton, Richard P and Goldstein, David B and Davis, Erica E and Hildebrandt, Friedhelm and Sanna-Cherchi, Simone} } @article {769, title = {Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency.}, journal = {Am J Hum Genet}, volume = {106}, year = {2020}, month = {2020 02 06}, pages = {234-245}, abstract = {

Germline pathogenic variants in chromatin-modifying enzymes are a common cause of pediatric developmental disorders. These enzymes catalyze reactions that regulate epigenetic inheritance via histone post-translational modifications and DNA methylation. Cytosine methylation (5-methylcytosine [5mC]) of DNA is the quintessential epigenetic mark, yet no human Mendelian disorder of DNA demethylation has yet been delineated. Here, we describe in detail a Mendelian disorder caused by the disruption of DNA demethylation. TET3 is a methylcytosine dioxygenase that initiates DNA demethylation during early zygote formation, embryogenesis, and neuronal differentiation and is intolerant to haploinsufficiency in mice and humans. We identify and characterize 11 cases of human TET3 deficiency in eight families with the common phenotypic features of intellectual disability and/or global developmental delay; hypotonia; autistic traits; movement disorders; growth abnormalities; and facial dysmorphism. Mono-allelic frameshift and nonsense variants in TET3 occur throughout the coding region. Mono-allelic and bi-allelic missense variants localize to conserved residues; all but one such variant occur within the catalytic domain, and most display hypomorphic function in an assay of catalytic activity. TET3 deficiency and other Mendelian disorders of the epigenetic machinery show substantial phenotypic overlap, including features of intellectual disability and abnormal growth, underscoring shared disease mechanisms.

}, keywords = {Adult, Amino Acid Sequence, Autistic Disorder, Child, Child, Preschool, Developmental Disabilities, Dioxygenases, DNA Demethylation, Embryonic Development, Female, Gene Expression Regulation, Developmental, Growth Disorders, Humans, Infant, Male, Middle Aged, Movement Disorders, Pedigree, Protein Conformation, Sequence Homology, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.12.007}, author = {Beck, David B and Petracovici, Ana and He, Chongsheng and Moore, Hannah W and Louie, Raymond J and Ansar, Muhammad and Douzgou, Sofia and Sithambaram, Sivagamy and Cottrell, Trudie and Santos-Cortez, Regie Lyn P and Prijoles, Eloise J and Bend, Renee and Keren, Boris and Mignot, Cyril and Nougues, Marie-Christine and {\~O}unap, Katrin and Reimand, Tiia and Pajusalu, Sander and Zahid, Muhammad and Saqib, Muhammad Arif Nadeem and Buratti, Julien and Seaby, Eleanor G and McWalter, Kirsty and Telegrafi, Aida and Baldridge, Dustin and Shinawi, Marwan and Leal, Suzanne M and Schaefer, G Bradley and Stevenson, Roger E and Banka, Siddharth and Bonasio, Roberto and Fahrner, Jill A} } @article {784, title = {The mutational constraint spectrum quantified from variation in 141,456 humans.}, journal = {Nature}, volume = {581}, year = {2020}, month = {2020 05}, pages = {434-443}, abstract = {

Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes. Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.

}, keywords = {Adult, Brain, Cardiovascular Diseases, Cohort Studies, Databases, Genetic, Exome, Female, Genes, Essential, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Genome-Wide Association Study, Humans, Loss of Function Mutation, Male, Mutation Rate, Proprotein Convertase 9, Reproducibility of Results, RNA, Messenger, Whole Exome Sequencing, Whole Genome Sequencing}, issn = {1476-4687}, doi = {10.1038/s41586-020-2308-7}, author = {Karczewski, Konrad J and Francioli, Laurent C and Tiao, Grace and Cummings, Beryl B and Alf{\"o}ldi, Jessica and Wang, Qingbo and Collins, Ryan L and Laricchia, Kristen M and Ganna, Andrea and Birnbaum, Daniel P and Gauthier, Laura D and Brand, Harrison and Solomonson, Matthew and Watts, Nicholas A and Rhodes, Daniel and Singer-Berk, Moriel and England, Eleina M and Seaby, Eleanor G and Kosmicki, Jack A and Walters, Raymond K and Tashman, Katherine and Farjoun, Yossi and Banks, Eric and Poterba, Timothy and Wang, Arcturus and Seed, Cotton and Whiffin, Nicola and Chong, Jessica X and Samocha, Kaitlin E and Pierce-Hoffman, Emma and Zappala, Zachary and O{\textquoteright}Donnell-Luria, Anne H and Minikel, Eric Vallabh and Weisburd, Ben and Lek, Monkol and Ware, James S and Vittal, Christopher and Armean, Irina M and Bergelson, Louis and Cibulskis, Kristian and Connolly, Kristen M and Covarrubias, Miguel and Donnelly, Stacey and Ferriera, Steven and Gabriel, Stacey and Gentry, Jeff and Gupta, Namrata and Jeandet, Thibault and Kaplan, Diane and Llanwarne, Christopher and Munshi, Ruchi and Novod, Sam and Petrillo, Nikelle and Roazen, David and Ruano-Rubio, Valentin and Saltzman, Andrea and Schleicher, Molly and Soto, Jose and Tibbetts, Kathleen and Tolonen, Charlotte and Wade, Gordon and Talkowski, Michael E and Neale, Benjamin M and Daly, Mark J and MacArthur, Daniel G} }