@article {1022, title = {POLRMT mutations impair mitochondrial transcription causing neurological disease.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 02 18}, pages = {1135}, abstract = {

While >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase γ, no mitochondrial phenotypes have been associated with POLRMT, the RNA polymerase responsible for transcription of the mitochondrial genome. Here, we characterise the clinical and molecular nature of POLRMT variants in eight individuals from seven unrelated families. Patients present with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype. Massive parallel sequencing of all subjects identifies recessive and dominant variants in the POLRMT gene. Patient fibroblasts have a defect in mitochondrial mRNA synthesis, but no mtDNA deletions or copy number abnormalities. The in vitro characterisation of the recombinant POLRMT mutants reveals variable, but deleterious effects on mitochondrial transcription. Together, our in vivo and in vitro functional studies of POLRMT variants establish defective mitochondrial transcription as an important disease mechanism.

}, keywords = {Adolescent, Adult, Child, DNA, Mitochondrial, DNA-Directed RNA Polymerases, Female, Fibroblasts, Humans, Infant, Male, Mitochondria, Mutation, Nervous System Diseases, Oxidative Phosphorylation, Pedigree, Protein Domains, Protein Subunits, RNA, Messenger, Transcription, Genetic, Young Adult}, issn = {2041-1723}, doi = {10.1038/s41467-021-21279-0}, author = {Ol{\'a}hov{\'a}, Monika and Peter, Bradley and Szilagyi, Zsolt and Diaz-Maldonado, Hector and Singh, Meenakshi and Sommerville, Ewen W and Blakely, Emma L and Collier, Jack J and Hoberg, Emily and Str{\'a}neck{\'y}, Viktor and Hartmannov{\'a}, Hana and Bleyer, Anthony J and McBride, Kim L and Bowden, Sasigarn A and Korandov{\'a}, Zuzana and Pecinov{\'a}, Alena and Ropers, Hans-Hilger and Kahrizi, Kimia and Najmabadi, Hossein and Tarnopolsky, Mark A and Brady, Lauren I and Weaver, K Nicole and Prada, Carlos E and {\~O}unap, Katrin and Wojcik, Monica H and Pajusalu, Sander and Syeda, Safoora B and Pais, Lynn and Estrella, Elicia A and Bruels, Christine C and Kunkel, Louis M and Kang, Peter B and Bonnen, Penelope E and Mr{\'a}{\v c}ek, Tom{\'a}{\v s} and Kmoch, Stanislav and Gorman, Gr{\'a}inne S and Falkenberg, Maria and Gustafsson, Claes M and Taylor, Robert W} } @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} } @article {628, title = {Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly.}, journal = {Cell}, volume = {172}, year = {2018}, month = {2018 02 22}, pages = {897-909.e21}, abstract = {

X-linked Dystonia-Parkinsonism (XDP) is a Mendelian~neurodegenerative disease that is endemic to the Philippines and is associated with a founder haplotype. We integrated multiple genome and transcriptome assembly technologies to narrow the causal mutation to the TAF1 locus, which included a SINE-VNTR-Alu (SVA) retrotransposition into intron 32 of the gene. Transcriptome analyses identified decreased expression of the canonical cTAF1 transcript among XDP probands, and de novo assembly~across multiple pluripotent stem-cell-derived neuronal lineages discovered aberrant TAF1 transcription that involved alternative splicing and intron retention (IR) in proximity to the SVA that was anti-correlated with overall TAF1 expression. CRISPR/Cas9 excision of the SVA rescued this XDP-specific~transcriptional signature and normalized TAF1 expression in probands. These data suggest an SVA-mediated aberrant transcriptional mechanism associated with XDP and may provide a roadmap for layered technologies and integrated assembly-based analyses for other unsolved Mendelian disorders.

}, keywords = {Alternative Splicing, Alu Elements, Base Sequence, Cohort Studies, CRISPR-Cas Systems, Dystonic Disorders, Family, Female, Genetic Diseases, X-Linked, Genetic Loci, Genome, Human, Haplotypes, High-Throughput Nucleotide Sequencing, Histone Acetyltransferases, Humans, Induced Pluripotent Stem Cells, Introns, Male, Minisatellite Repeats, Models, Genetic, Nerve Degeneration, Neural Stem Cells, Neurons, RNA, Messenger, Short Interspersed Nucleotide Elements, TATA-Binding Protein Associated Factors, Transcription Factor TFIID, Transcriptome}, issn = {1097-4172}, doi = {10.1016/j.cell.2018.02.011}, author = {Aneichyk, Tatsiana and Hendriks, William T and Yadav, Rachita and Shin, David and Gao, Dadi and Vaine, Christine A and Collins, Ryan L and Domingo, Aloysius and Currall, Benjamin and Stortchevoi, Alexei and Multhaupt-Buell, Trisha and Penney, Ellen B and Cruz, Lilian and Dhakal, Jyotsna and Brand, Harrison and Hanscom, Carrie and Antolik, Caroline and Dy, Marisela and Ragavendran, Ashok and Underwood, Jason and Cantsilieris, Stuart and Munson, Katherine M and Eichler, Evan E and Acu{\~n}a, Patrick and Go, Criscely and Jamora, R Dominic G and Rosales, Raymond L and Church, Deanna M and Williams, Stephen R and Garcia, Sarah and Klein, Christine and M{\"u}ller, Ulrich and Wilhelmsen, Kirk C and Timmers, H T Marc and Sapir, Yechiam and Wainger, Brian J and Henderson, Daniel and Ito, Naoto and Weisenfeld, Neil and Jaffe, David and Sharma, Nutan and Breakefield, Xandra O and Ozelius, Laurie J and Bragg, D Cristopher and Talkowski, Michael E} } @article {473, title = {Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 06 07}, pages = {1126-1142}, abstract = {

The proteasome processes proteins to facilitate immune recognition and host defense. When inherently defective, it can lead to aberrant immunity resulting in a dysregulated response that can cause autoimmunity and/or autoinflammation. Biallelic or digenic loss-of-function variants in some of the proteasome subunits have been described as causing a primary immunodeficiency disease that manifests as a severe dysregulatory syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). Proteasome maturation protein (POMP) is a chaperone for proteasome assembly and is critical for the incorporation of catalytic subunits into the proteasome. Here, we characterize and describe POMP-related autoinflammation and immune dysregulation disease (PRAID) discovered in two unrelated individuals with a unique constellation of early-onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity. We also begin to delineate a complex genetic mechanism whereby de novo heterozygous frameshift variants in the penultimate exon of POMP escape nonsense-mediated mRNA decay (NMD) and result in a truncated protein that~perturbs proteasome assembly by a dominant-negative mechanism. To our knowledge, this mechanism has not been reported in~any primary immunodeficiencies, autoinflammatory syndromes, or autoimmune diseases. Here, we define a unique hypo- and hyper-immune~phenotype and report an immune dysregulation syndrome caused by frameshift mutations that escape NMD.

}, keywords = {Base Sequence, Cell Line, Endoplasmic Reticulum Stress, Exons, Family, Frameshift Mutation, Genetic Predisposition to Disease, Heterozygote, Humans, Immunologic Deficiency Syndromes, Immunophenotyping, Infant, Newborn, Inflammation, Interferon Type I, Male, Molecular Chaperones, Mutant Proteins, Mutation, Nonsense Mediated mRNA Decay, Phenotype, Proteasome Endopeptidase Complex, RNA, Messenger, Syndrome, Unfolded Protein Response}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.04.010}, author = {Poli, M Cecilia and Ebstein, Fr{\'e}d{\'e}ric and Nicholas, Sarah K and de Guzman, Marietta M and Forbes, Lisa R and Chinn, Ivan K and Mace, Emily M and Vogel, Tiphanie P and Carisey, Alexandre F and Benavides, Felipe and Coban-Akdemir, Zeynep H and Gibbs, Richard A and Jhangiani, Shalini N and Muzny, Donna M and Carvalho, Claudia M B and Schady, Deborah A and Jain, Mahim and Rosenfeld, Jill A and Emrick, Lisa and Lewis, Richard A and Lee, Brendan and Zieba, Barbara A and K{\"u}ry, S{\'e}bastien and Kr{\"u}ger, Elke and Lupski, James R and Bostwick, Bret L and Orange, Jordan S} } @article {432, title = {Nemaline myopathy and distal arthrogryposis associated with an autosomal recessive~TNNT3~splice variant.}, journal = {Hum Mutat}, volume = {39}, year = {2018}, month = {2018 03}, pages = {383-388}, abstract = {

A male neonate presented with severe weakness, hypotonia, contractures and congenital scoliosis. Skeletal muscle specimens showed marked atrophy and degeneration of fast fibers with striking nemaline rods and hypertrophy of slow fibers that were ultrastructurally normal. A neuromuscular gene panel identified a homozygous essential splice variant in TNNT3 (chr11:1956150G~>~A, NM_006757.3:c.681+1G~>~A). TNNT3 encodes skeletal troponin-T and is associated with autosomal dominant distal arthrogryposis. TNNT3 has not previously been associated with nemaline myopathy (NM), a rare congenital myopathy linked to defects in proteins associated with thin filament structure and regulation. cDNA studies confirmed pathogenic consequences of the splice variant, eliciting exon-skipping and intron retention events leading to a frameshift. Western blot showed deficiency of troponin-T protein with secondary loss of troponin-I . We establish a homozygous splice variant in TNNT3 as the likely cause of severe congenital NM with distal arthrogryposis, characterized by specific involvement of Type-2 fibers and deficiency of troponin-T .

}, keywords = {Arthrogryposis, Genes, Recessive, Humans, Infant, Infant, Newborn, Male, Myopathies, Nemaline, RNA Splice Sites, RNA Splicing, RNA, Messenger, Troponin T}, issn = {1098-1004}, doi = {10.1002/humu.23385}, author = {Sandaradura, Sarah A and Bournazos, Adam and Mallawaarachchi, Amali and Cummings, Beryl B and Waddell, Leigh B and Jones, Kristi J and Troedson, Christopher and Sudarsanam, Annapurna and Nash, Benjamin M and Peters, Gregory B and Algar, Elizabeth M and MacArthur, Daniel G and North, Kathryn N and Brammah, Susan and Charlton, Amanda and Laing, Nigel G and Wilson, Meredith J and Davis, Mark R and Cooper, Sandra T} } @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} } @article {351, title = {Biallelic mutations in the 3{\textquoteright} exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Mar}, pages = {457-464}, abstract = {

Deadenylases are best known for degrading the poly(A) tail during mRNA decay. The deadenylase family has expanded throughout evolution and, in mammals, consists of 12 Mg-dependent 3{\textquoteright}-end RNases with substrate specificity that is mostly unknown. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration and ambiguous genitalia. We studied 12 human families with PCH7, uncovering biallelic, loss-of-function mutations in TOE1, which encodes an unconventional deadenylase. toe1-morphant zebrafish displayed midbrain and hindbrain degeneration, modeling PCH-like structural defects in vivo. Surprisingly, we found that TOE1 associated with small nuclear RNAs (snRNAs) incompletely processed spliceosomal. These pre-snRNAs contained 3{\textquoteright} genome-encoded tails often followed by post-transcriptionally added adenosines. Human cells with reduced levels of TOE1 accumulated 3{\textquoteright}-end-extended pre-snRNAs, and the immunoisolated TOE1 complex was sufficient for 3{\textquoteright}-end maturation of snRNAs. Our findings identify the cause of a neurodegenerative syndrome linked to snRNA maturation and uncover a key factor involved in the processing of snRNA 3{\textquoteright} ends.

}, keywords = {Alleles, Animals, Cerebellar Diseases, Exonucleases, Female, Humans, Male, Mice, Mutation, Neurodegenerative Diseases, Nuclear Proteins, RNA, Messenger, RNA, Small Nuclear, Spliceosomes, Zebrafish}, issn = {1546-1718}, doi = {10.1038/ng.3762}, author = {Lardelli, Rea M and Schaffer, Ashleigh E and Eggens, Veerle R C and Zaki, Maha S and Grainger, Stephanie and Sathe, Shashank and Van Nostrand, Eric L and Schlachetzki, Zinayida and Rosti, Basak and Akizu, Naiara and Scott, Eric and Silhavy, Jennifer L and Heckman, Laura Dean and Rosti, Rasim Ozgur and Dikoglu, Esra and Gregor, Anne and Guemez-Gamboa, Alicia and Musaev, Damir and Mande, Rohit and Widjaja, Ari and Shaw, Tim L and Markmiller, Sebastian and Marin-Valencia, Isaac and Davies, Justin H and de Meirleir, Linda and Kayserili, H{\"u}lya and Altunoglu, Umut and Freckmann, Mary Louise and Warwick, Linda and Chitayat, David and Blaser, Susan and {\c C}a{\u g}layan, Ahmet Okay and Bilguvar, Kaya and Per, H{\"u}seyin and Fagerberg, Christina and Christesen, Henrik T and Kibaek, Maria and Aldinger, Kimberly A and Manchester, David and Matsumoto, Naomichi and Muramatsu, Kazuhiro and Saitsu, Hirotomo and Shiina, Masaaki and Ogata, Kazuhiro and Foulds, Nicola and Dobyns, William B and Chi, Neil C and Traver, David and Spaccini, Luigina and Bova, Stefania Maria and Gabriel, Stacey B and G{\"u}nel, Murat and Valente, Enza Maria and Nassogne, Marie-Cecile and Bennett, Eric J and Yeo, Gene W and Baas, Frank and Lykke-Andersen, Jens and Gleeson, Joseph G} } @article {493, title = {Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Nov 02}, pages = {856-865}, abstract = {

Approximately one in every 200 mammalian proteins is anchored to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor. These proteins play important roles notably in neurological development and function. To date, more than 20 genes have been implicated in the biogenesis of GPI-anchored proteins. GPAA1 (glycosylphosphatidylinositol anchor attachment 1) is an essential component of the transamidase complex along with PIGK, PIGS, PIGT, and PIGU (phosphatidylinositol-glycan biosynthesis classes K, S, T, and U, respectively). This complex orchestrates the attachment of the GPI anchor to the C terminus of precursor proteins in the endoplasmic reticulum. Here, we report bi-allelic mutations in GPAA1 in ten individuals from five families. Using whole-exome sequencing, we identified two frameshift mutations (c.981_993del [p.Gln327Hisfs102] and c.920delG [p.Gly307Alafs11]), one intronic splicing mutation (c.1164+5C>T), and six missense mutations (c.152C>T [p.Ser51Leu], c.160_161delinsAA [p.Ala54Asn], c.527G>C [p.Trp176Ser], c.869T>C [p.Leu290Pro], c.872T>C [p.Leu291Pro], and c.1165G>C [p.Ala389Pro]). Most individuals presented with global developmental delay, hypotonia, early-onset seizures, cerebellar atrophy, and osteopenia. The splicing mutation was found to decrease GPAA1 mRNA. Moreover, flow-cytometry analysis of five available individual samples showed that several GPI-anchored proteins had decreased cell-surface abundance in leukocytes (FLAER, CD16, and CD59) or fibroblasts (CD73 and CD109). Transduction of fibroblasts with a lentivirus encoding the wild-type protein partially rescued the deficiency of GPI-anchored proteins. These findings highlight the role of the transamidase complex in the development and function of the cerebellum and the skeletal system.

}, keywords = {Acyltransferases, Adolescent, Adult, Alleles, Atrophy, Bone Diseases, Metabolic, Cerebellum, Child, Child, Preschool, Developmental Disabilities, Epilepsy, Exome, Female, Fibroblasts, Glycosylphosphatidylinositols, Humans, Male, Membrane Glycoproteins, Muscle Hypotonia, Mutation, Pedigree, RNA, Messenger, Seizures}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.020}, author = {Nguyen, Thi Tuyet Mai and Murakami, Yoshiko and Sheridan, Eamonn and Ehresmann, Sophie and Rousseau, Justine and St-Denis, Anik and Chai, Guoliang and Ajeawung, Norbert F and Fairbrother, Laura and Reimschisel, Tyler and Bateman, Alexandra and Berry-Kravis, Elizabeth and Xia, Fan and Tardif, Jessica and Parry, David A and Logan, Clare V and Diggle, Christine and Bennett, Christopher P and Hattingh, Louise and Rosenfeld, Jill A and Perry, Michael Scott and Parker, Michael J and Le Deist, Fran{\c c}oise and Zaki, Maha S and Ignatius, Erika and Isohanni, Pirjo and L{\"o}nnqvist, Tuula and Carroll, Christopher J and Johnson, Colin A and Gleeson, Joseph G and Kinoshita, Taroh and Campeau, Philippe M} } @article {103, title = {Chimeric transcripts resulting from complex duplications in chromosome Xq28.}, journal = {Hum Genet}, volume = {135}, year = {2016}, month = {2016 Feb}, pages = {253-6}, abstract = {

Gene fusions have been observed in somatic alterations in cancer and in schizophrenia. However, the underlying mechanism(s) for their formation are poorly understood. We experimentally demonstrated the expression of splicing variants of in silico predicted chimeric genes F8/CSAG1 and BCAP31/TEX28 in two individuals with de novo complex genomic rearrangements of Xq28; F8/CSAG1 includes exonization of an ERVL-MaLR intronic repetitive element. We provide evidence that replicative repair may contribute to exon shuffling processes and diversify the repertoire of expressed transcripts.

}, keywords = {Antigens, Neoplasm, Base Sequence, Cell Line, Chromosomes, Human, X, Exons, Gene Duplication, Gene Expression Regulation, Gene Rearrangement, Humans, Introns, Male, Membrane Proteins, Molecular Sequence Data, Neoplasm Proteins, RNA Splicing, RNA, Messenger, Transcription, Genetic}, issn = {1432-1203}, doi = {10.1007/s00439-015-1614-x}, author = {Zuccherato, Luciana W and Alleva, Benjamin and Whiters, Marjorie A and Carvalho, Claudia M B and Lupski, James R} } @article {28, title = {De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Sep 01}, pages = {711-719}, abstract = {

The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and~HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.

}, keywords = {Animals, Brain, Developmental Disabilities, DNA-Binding Proteins, Eye Abnormalities, Female, Genes, Essential, Haploinsufficiency, Head, Heterozygote, Humans, Intellectual Disability, Male, Metabolic Diseases, Minor Histocompatibility Antigens, Mutation, Pedigree, RNA Splicing, RNA, Messenger, Spine, Syndrome, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.06.029}, author = {Kim, Jung-Hyun and Shinde, Deepali N and Reijnders, Margot R F and Hauser, Natalie S and Belmonte, Rebecca L and Wilson, Gregory R and Bosch, Dani{\"e}lle G M and Bubulya, Paula A and Shashi, Vandana and Petrovski, Slav{\'e} and Stone, Joshua K and Park, Eun Young and Veltman, Joris A and Sinnema, Margje and Stumpel, Connie T R M and Draaisma, Jos M and Nicolai, Joost and Yntema, Helger G and Lindstrom, Kristin and de Vries, Bert B A and Jewett, Tamison and Santoro, Stephanie L and Vogt, Julie and Bachman, Kristine K and Seeley, Andrea H and Krokosky, Alyson and Turner, Clesson and Rohena, Luis and Hempel, Maja and Kort{\"u}m, Fanny and Lessel, Davor and Neu, Axel and Strom, Tim M and Wieczorek, Dagmar and Bramswig, Nuria and Laccone, Franco A and Behunova, Jana and Rehder, Helga and Gordon, Christopher T and Rio, Marl{\`e}ne and Romana, Serge and Tang, Sha and El-Khechen, Dima and Cho, Megan T and McWalter, Kirsty and Douglas, Ganka and Baskin, Berivan and Begtrup, Amber and Funari, Tara and Schoch, Kelly and Stegmann, Alexander P A and Stevens, Servi J C and Zhang, Dong-Er and Traver, David and Yao, Xu and MacArthur, Daniel G and Brunner, Han G and Mancini, Grazia M and Myers, Richard M and Owen, Laurie B and Lim, Ssang-Taek and Stachura, David L and Vissers, Lisenka E L M and Ahn, Eun-Young Erin} } @article {9, title = {Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics.}, journal = {Genome Med}, volume = {8}, year = {2016}, month = {2016 Nov 01}, pages = {105}, abstract = {

BACKGROUND: Smith-Magenis syndrome (SMS) is a developmental disability/multiple congenital anomaly disorder resulting from haploinsufficiency of RAI1. It is characterized by distinctive facial features, brachydactyly, sleep disturbances, and stereotypic behaviors.

METHODS: We investigated a cohort of 15 individuals with a clinical suspicion of SMS who showed neither deletion in the SMS critical region nor damaging variants in RAI1 using whole exome sequencing. A combination of network analysis (co-expression and biomedical text mining), transcriptomics, and circularized chromatin conformation capture (4C-seq) was applied to verify whether modified genes are part of the same disease network as known SMS-causing genes.

RESULTS: Potentially deleterious variants were identified in nine of these individuals using whole-exome sequencing. Eight of these changes affect KMT2D, ZEB2, MAP2K2, GLDC, CASK, MECP2, KDM5C, and POGZ, known to be associated with Kabuki syndrome 1, Mowat-Wilson syndrome, cardiofaciocutaneous syndrome, glycine encephalopathy, mental retardation and microcephaly with pontine and cerebellar hypoplasia, X-linked mental retardation 13, X-linked mental retardation Claes-Jensen type, and White-Sutton syndrome, respectively. The ninth individual carries a de novo variant in JAKMIP1, a regulator of neuronal translation that was recently found deleted in a patient with autism spectrum disorder. Analyses of co-expression and biomedical text mining suggest that these pathologies and SMS are part of the same disease network. Further support for this hypothesis was obtained from transcriptome profiling that showed that the expression levels of both Zeb2 and Map2k2 are perturbed in Rai1 mice. As an orthogonal approach to potentially contributory disease gene variants, we used chromatin conformation capture to reveal chromatin contacts between RAI1 and the loci flanking ZEB2 and GLDC, as well as between RAI1 and human orthologs of the genes that show perturbed expression in our Rai1 mouse model.

CONCLUSIONS: These holistic studies of RAI1 and its interactions allow insights into SMS and other disorders associated with intellectual disability and behavioral abnormalities. Our findings support a pan-genomic approach to the molecular diagnosis of a distinctive disorder.

}, keywords = {Animals, Embryo, Mammalian, Exome, Female, Gene Regulatory Networks, Genomics, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Phenotype, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Smith-Magenis Syndrome, Trans-Activators, Transcription Factors, Transcriptome}, issn = {1756-994X}, doi = {10.1186/s13073-016-0359-z}, author = {Loviglio, Maria Nicla and Beck, Christine R and White, Janson J and Leleu, Marion and Harel, Tamar and Guex, Nicolas and Niknejad, Anne and Bi, Weimin and Chen, Edward S and Crespo, Isaac and Yan, Jiong and Charng, Wu-Lin and Gu, Shen and Fang, Ping and Coban-Akdemir, Zeynep and Shaw, Chad A and Jhangiani, Shalini N and Muzny, Donna M and Gibbs, Richard A and Rougemont, Jacques and Xenarios, Ioannis and Lupski, James R and Reymond, Alexandre} } @article {122, title = {Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2.}, journal = {Am J Hum Genet}, volume = {97}, year = {2015}, month = {2015 Nov 05}, pages = {647-60}, abstract = {

Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS-UHL/AHL) revealed a heterozygous truncating mutation, c.286_303delinsT (p.Ser96Ter), in KITLG. This mutation co-segregated with NS-UHL/AHL as a dominant trait with reduced penetrance. By screening a panel of probands with NS-UHL/AHL, we found an additional mutation, c.200_202del (p.His67_Cys68delinsArg). In~vitro studies revealed that the p.His67_Cys68delinsArg transmembrane isoform of KITLG is not detectable at the cell membrane, supporting pathogenicity. KITLG encodes a ligand for the KIT receptor. Also, KITLG-KIT signaling and MITF are suggested to mutually interact in melanocyte development. Because mutations in MITF are causative of Waardenburg syndrome type 2 (WS2), we screened KITLG in suspected WS2-affected probands. A heterozygous missense mutation, c.310C>G (p.Leu104Val), that segregated with WS2 was identified in a small family. In~vitro studies revealed that the p.Leu104Val transmembrane isoform of KITLG is located at the cell membrane, as is wild-type KITLG. However, in culture media of transfected cells, the p.Leu104Val soluble isoform of KITLG was reduced, and no soluble p.His67_Cys68delinsArg and p.Ser96Ter KITLG could be detected. These data suggest that mutations in KITLG associated with NS-UHL/AHL have a loss-of-function effect. We speculate that the mechanism of the mutation underlying WS2 and leading to membrane incorporation and reduced secretion of KITLG occurs via a dominant-negative or gain-of-function effect. Our study unveils different phenotypes associated with KITLG, previously associated with pigmentation abnormalities, and will thereby improve the genetic counseling given to individuals with KITLG variants.

}, keywords = {Alleles, Animals, Female, Fluorescent Antibody Technique, Genetic Linkage, Hearing Loss, Unilateral, Humans, Male, Mice, Mutation, NIH 3T3 Cells, Pedigree, Phenotype, Prognosis, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Stem Cell Factor, Waardenburg Syndrome}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.09.011}, author = {Zazo Seco, Celia and Serr{\~a}o de Castro, Luciana and van Nierop, Josephine W and Mor{\'\i}n, Mat{\'\i}as and Jhangiani, Shalini and Verver, Eva J J and Schraders, Margit and Maiwald, Nadine and Wesdorp, Mieke and Venselaar, Hanka and Spruijt, Liesbeth and Oostrik, Jaap and Schoots, Jeroen and van Reeuwijk, Jeroen and Lelieveld, Stefan H and Huygen, Patrick L M and Insenser, Mar{\'\i}a and Admiraal, Ronald J C and Pennings, Ronald J E and Hoefsloot, Lies H and Arias-V{\'a}squez, Alejandro and de Ligt, Joep and Yntema, Helger G and Jansen, Joop H and Muzny, Donna M and Huls, Gerwin and van Rossum, Michelle M and Lupski, James R and Moreno-Pelayo, Miguel Angel and Kunst, Henricus P M and Kremer, Hannie} } @article {196, title = {Mutations in RAD21 disrupt regulation of APOB in patients with chronic intestinal pseudo-obstruction.}, journal = {Gastroenterology}, volume = {148}, year = {2015}, month = {2015 Apr}, pages = {771-782.e11}, abstract = {

BACKGROUND \& AIMS: Chronic intestinal pseudo-obstruction (CIPO) is characterized by severe intestinal dysmotility that mimics a mechanical subocclusion with no~evidence of gut obstruction. We searched for genetic variants associated with CIPO to increase our understanding of its pathogenesis and to identify potential biomarkers.

METHODS: We performed whole-exome sequencing of genomic DNA from patients with familial CIPO syndrome. Blood and lymphoblastoid cells were collected from patients and controls (individuals without CIPO); levels of messenger RNA (mRNA) and proteins were analyzed by quantitative reverse-transcription polymerase chain reaction, immunoblot, and mobility shift assays. Complementary DNAs were transfected into HEK293 cells. Expression of rad21 was suppressed in zebrafish embryos using a splice-blocking morpholino (rad21a). Gut tissues were collected and analyzed.

RESULTS: We identified a homozygous mutation (p.622, encodes Ala>Thr) in RAD21 in patients from a consanguineous family with CIPO. Expression of RUNX1, a target of RAD21, was reduced in cells from patients with CIPO compared with controls. In zebrafish, suppression of rad21a reduced expression of runx1; this phenotype was corrected by injection of human RAD21 mRNA, but not with the mRNA from the mutated p.622 allele. rad21a Morpholino zebrafish had delayed intestinal transit and greatly reduced numbers of enteric neurons, similar to patients with CIPO. This defect was greater in zebrafish with suppressed expression of ret and rad21, indicating their interaction in the regulation of gut neurogenesis. The promoter region of APOB bound RAD21 but not RAD21 p.622 Ala>Thr; expression of wild-type RAD21 in HEK293 cells repressed expression of APOB, compared with control vector. The gut-specific isoform of APOB (APOB48) is overexpressed in sera from patients with CIPO who carry the RAD21 mutation. APOB48 also is overexpressed in sporadic CIPO in sera and gut biopsy specimens.

CONCLUSIONS: Some patients with CIPO carry mutations in RAD21 that disrupt the ability of its product to regulate genes such as RUNX1 and APOB. Reduced expression of rad21 in zebrafish, and dysregulation of these target genes, disrupts intestinal transit and the development of enteric neurons.

}, keywords = {Adult, Animals, Apolipoprotein B-100, Case-Control Studies, Cell Cycle Proteins, Chronic Disease, Core Binding Factor Alpha 2 Subunit, Enteric Nervous System, Female, Gastrointestinal Motility, Gene Expression Profiling, Gene Knockdown Techniques, HEK293 Cells, Humans, Intestinal Pseudo-Obstruction, Male, Middle Aged, Nuclear Proteins, Phosphoproteins, RNA, Messenger, Sequence Analysis, DNA, Young Adult, Zebrafish, Zebrafish Proteins}, issn = {1528-0012}, doi = {10.1053/j.gastro.2014.12.034}, author = {Bonora, Elena and Bianco, Francesca and Cordeddu, Lina and Bamshad, Michael and Francescatto, Ludmila and Dowless, Dustin and Stanghellini, Vincenzo and Cogliandro, Rosanna F and Lindberg, Greger and Mungan, Zeynel and Cefle, Kivanc and Ozcelik, Tayfun and Palanduz, Sukru and Ozturk, Sukru and Gedikbasi, Asuman and Gori, Alessandra and Pippucci, Tommaso and Graziano, Claudio and Volta, Umberto and Caio, Giacomo and Barbara, Giovanni and D{\textquoteright}Amato, Mauro and Seri, Marco and Katsanis, Nicholas and Romeo, Giovanni and De Giorgio, Roberto} } @article {274, title = {Mutations in TBC1D24, a gene associated with epilepsy, also cause nonsyndromic deafness DFNB86.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Jan 02}, pages = {144-52}, abstract = {

Inherited deafness is clinically and genetically heterogeneous. We recently mapped DFNB86, a locus associated with nonsyndromic deafness, to chromosome 16p. In this study, whole-exome sequencing was performed with genomic DNA from affected individuals from three large consanguineous families in which markers linked to DFNB86 segregate with profound deafness. Analyses of these data revealed homozygous mutation c.208G>T (p.Asp70Tyr) or c.878G>C (p.Arg293Pro) in TBC1D24 as the underlying cause of deafness in the three families. Sanger sequence analysis of TBC1D24 in an additional large family in which deafness segregates with DFNB86 identified the c.208G>T (p.Asp70Tyr) substitution. These mutations affect TBC1D24 amino acid residues that are conserved in orthologs ranging from fruit fly to human. Neither variant was observed in databases of single-nucleotide variants or in 634 chromosomes from ethnically matched control subjects. TBC1D24 in the mouse inner ear was immunolocalized predominantly to spiral ganglion neurons, indicating that DFNB86 deafness might be an auditory neuropathy spectrum disorder. Previously, six recessive mutations in TBC1D24 were reported to cause seizures (hearing loss was not reported) ranging in severity from epilepsy with otherwise normal development to epileptic encephalopathy resulting in childhood death. Two of our four families in which deafness segregates with mutant alleles of TBC1D24 were available for neurological examination. Cosegregation of epilepsy and deafness was not observed in these two families. Although the causal relationship between genotype and phenotype is not presently understood, our findings, combined with published data, indicate that recessive alleles of TBC1D24 can cause either epilepsy or nonsyndromic deafness.

}, keywords = {Alleles, Amino Acid Sequence, Carrier Proteins, Chromosomes, Human, Pair 16, Consanguinity, Deafness, Epilepsy, Exome, Exons, Female, Genes, Recessive, Genetic Loci, Genome-Wide Association Study, Heterozygote, Homozygote, Humans, Male, Molecular Sequence Data, Mutation, Pakistan, Pedigree, Phenotype, Polymorphism, Single Nucleotide, RNA, Messenger, Sequence Analysis, DNA}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.12.004}, author = {Rehman, Atteeq U and Santos-Cortez, Regie Lyn P and Morell, Robert J and Drummond, Meghan C and Ito, Taku and Lee, Kwanghyuk and Khan, Asma A and Basra, Muhammad Asim R and Wasif, Naveed and Ayub, Muhammad and Ali, Rana A and Raza, Syed I and Nickerson, Deborah A and Shendure, Jay and Bamshad, Michael and Riazuddin, Saima and Billington, Neil and Khan, Shaheen N and Friedman, Penelope L and Griffith, Andrew J and Ahmad, Wasim and Riazuddin, Sheikh and Leal, Suzanne M and Friedman, Thomas B} }