@article {1010, title = {De novo variants in TCF7L2 are associated with a syndromic neurodevelopmental disorder.}, journal = {Am J Med Genet A}, year = {2021}, month = {2021 May 18}, abstract = {

TCF7L2 encodes transcription factor 7-like 2 (OMIM 602228), a key mediator of the evolutionary conserved canonical Wnt signaling pathway. Although several large-scale sequencing studies have implicated TCF7L2 in intellectual disability and autism, both the genetic mechanism and clinical phenotype have remained incompletely characterized. We present here a comprehensive genetic and phenotypic description of 11 individuals who have been identified to carry de novo variants in TCF7L2, both truncating and missense. Missense variation is clustered in or near a high mobility group box domain, involving this region in these variants{\textquoteright} pathogenicity. All affected individuals present with developmental delays in childhood, but most ultimately achieved normal intelligence or had only mild intellectual disability. Myopia was present in approximately half of the individuals, and some individuals also possessed dysmorphic craniofacial features, orthopedic abnormalities, or neuropsychiatric comorbidities including autism and attention-deficit/hyperactivity disorder (ADHD). We thus present an initial clinical and genotypic spectrum associated with variation in TCF7L2, which will be important in informing both medical management and future research.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.62254}, author = {Dias, Caroline and Pfundt, Rolph and Kleefstra, Tjitske and Shuurs-Hoeijmakers, Janneke and Boon, Elles M J and van Hagen, Johanna M and Zwijnenburg, Petra and Weiss, Marjan M and Keren, Boris and Mignot, Cyril and Isapof, Arnaud and Weiss, Karin and Hershkovitz, Tova and Iascone, Maria and Maitz, Silvia and Feichtinger, Ren{\'e} G and Kotzot, Dieter and Mayr, Johannes A and Ben-Omran, Tawfeg and Mahmoud, Laila and Pais, Lynn S and Walsh, Christopher A and Shashi, Vandana and Sullivan, Jennifer A and Stong, Nicholas and Lecoquierre, Francois and Guerrot, Anne-Marie and Charollais, Aude and Rodan, Lance H} } @article {999, title = {DLG4-related synaptopathy: a new rare brain disorder.}, journal = {Genet Med}, volume = {23}, year = {2021}, month = {2021 05}, pages = {888-899}, abstract = {

PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.

METHODS: The clinical and genetic information were~collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing.

RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not~be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies.

CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.

}, keywords = {Autism Spectrum Disorder, Brain, Brain Diseases, Disks Large Homolog 4 Protein, Humans, Intellectual Disability, Neurodevelopmental Disorders, Phenotype}, issn = {1530-0366}, doi = {10.1038/s41436-020-01075-9}, author = {Rodr{\'\i}guez-Palmero, Agust{\'\i} and Boerrigter, Melissa Maria and G{\'o}mez-Andr{\'e}s, David and Aldinger, Kimberly A and Marcos-Alcalde, {\'I}{\~n}igo and Popp, Bernt and Everman, David B and Lovgren, Alysia Kern and Arpin, Stephanie and Bahrambeigi, Vahid and Beunders, Gea and Bisgaard, Anne-Marie and Bjerregaard, V A and Bruel, Ange-Line and Challman, Thomas D and Cogn{\'e}, Benjamin and Coubes, Christine and de Man, Stella A and Denomm{\'e}-Pichon, Anne-Sophie and Dye, Thomas J and Elmslie, Frances and Feuk, Lars and Garcia-Minaur, Sixto and Gertler, Tracy and Giorgio, Elisa and Gruchy, Nicolas and Haack, Tobias B and Haldeman-Englert, Chad R and Haukanes, Bj{\o}rn Ivar and Hoyer, Juliane and Hurst, Anna C E and Isidor, Bertrand and Soller, Maria Johansson and Kushary, Sulagna and Kvarnung, Malin and Landau, Yuval E and Leppig, Kathleen A and Lindstrand, Anna and Kleinendorst, Lotte and MacKenzie, Alex and Mandrile, Giorgia and Mendelsohn, Bryce A and Moghadasi, Setareh and Morton, Jenny E and Moutton, S{\'e}bastien and M{\"u}ller, Amelie J and O{\textquoteright}Leary, Melanie and Pacio-Miguez, Marta and Palomares-Bralo, Maria and Parikh, Sumit and Pfundt, Rolph and Pode-Shakked, Ben and Rauch, Anita and Repnikova, Elena and Revah-Politi, Anya and Ross, Meredith J and Ruivenkamp, Claudia A L and Sarrazin, Elisabeth and Savatt, Juliann M and Schluter, Agatha and Sch{\"o}newolf-Greulich, Bitten and Shad, Zohra and Shaw-Smith, Charles and Shieh, Joseph T and Shohat, Motti and Spranger, Stephanie and Thiese, Heidi and Mau-Them, Frederic Tran and van Bon, Bregje and van de Burgt, Ineke and van de Laar, Ingrid M B H and van Drie, Esm{\'e}e and van Haelst, Mieke M and van Ravenswaaij-Arts, Conny M and Verdura, Edgard and Vitobello, Antonio and Waldm{\"u}ller, Stephan and Whiting, Sharon and Zweier, Christiane and Prada, Carlos E and de Vries, Bert B A and Dobyns, William B and Reiter, Simone F and G{\'o}mez-Puertas, Paulino and Pujol, Aurora and T{\"u}mer, Zeynep} } @article {1008, title = {SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 03 04}, pages = {502-516}, abstract = {

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.

}, keywords = {Adolescent, Autism Spectrum Disorder, Child, Child, Preschool, Chromosome Deletion, Chromosome Disorders, Chromosomes, Human, Pair 1, Chromosomes, Human, X, DNA Methylation, DNA-Binding Proteins, Epigenesis, Genetic, Female, Haploinsufficiency, Humans, Intellectual Disability, Male, Neurodevelopmental Disorders, Phenotype, RNA-Binding Proteins, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.01.015}, author = {Radio, Francesca Clementina and Pang, Kaifang and Ciolfi, Andrea and Levy, Michael A and Hernandez-Garcia, Andres and Pedace, Lucia and Pantaleoni, Francesca and Liu, Zhandong and de Boer, Elke and Jackson, Adam and Bruselles, Alessandro and McConkey, Haley and Stellacci, Emilia and Lo Cicero, Stefania and Motta, Marialetizia and Carrozzo, Rosalba and Dentici, Maria Lisa and McWalter, Kirsty and Desai, Megha and Monaghan, Kristin G and Telegrafi, Aida and Philippe, Christophe and Vitobello, Antonio and Au, Margaret and Grand, Katheryn and Sanchez-Lara, Pedro A and Baez, Joanne and Lindstrom, Kristin and Kulch, Peggy and Sebastian, Jessica and Madan-Khetarpal, Suneeta and Roadhouse, Chelsea and MacKenzie, Jennifer J and Monteleone, Berrin and Saunders, Carol J and Jean Cuevas, July K and Cross, Laura and Zhou, Dihong and Hartley, Taila and Sawyer, Sarah L and Monteiro, Fabiola Paoli and Secches, Tania Vertemati and Kok, Fernando and Schultz-Rogers, Laura E and Macke, Erica L and Morava, Eva and Klee, Eric W and Kemppainen, Jennifer and Iascone, Maria and Selicorni, Angelo and Tenconi, Romano and Amor, David J and Pais, Lynn and Gallacher, Lyndon and Turnpenny, Peter D and Stals, Karen and Ellard, Sian and Cabet, Sara and Lesca, Gaetan and Pascal, Joset and Steindl, Katharina and Ravid, Sarit and Weiss, Karin and Castle, Alison M R and Carter, Melissa T and Kalsner, Louisa and de Vries, Bert B A and van Bon, Bregje W and Wevers, Marijke R and Pfundt, Rolph and Stegmann, Alexander P A and Kerr, Bronwyn and Kingston, Helen M and Chandler, Kate E and Sheehan, Willow and Elias, Abdallah F and Shinde, Deepali N and Towne, Meghan C and Robin, Nathaniel H and Goodloe, Dana and Vanderver, Adeline and Sherbini, Omar and Bluske, Krista and Hagelstrom, R Tanner and Zanus, Caterina and Faletra, Flavio and Musante, Luciana and Kurtz-Nelson, Evangeline C and Earl, Rachel K and Anderlid, Britt-Marie and Morin, Gilles and van Slegtenhorst, Marjon and Diderich, Karin E M and Brooks, Alice S and Gribnau, Joost and Boers, Ruben G and Finestra, Teresa Robert and Carter, Lauren B and Rauch, Anita and Gasparini, Paolo and Boycott, Kym M and Barakat, Tahsin Stefan and GrAHm, John M and Faivre, Laurence and Banka, Siddharth and Wang, Tianyun and Eichler, Evan E and Priolo, Manuela and Dallapiccola, Bruno and Vissers, Lisenka E L M and Sadikovic, Bekim and Scott, Daryl A and Holder, Jimmy Lloyd and Tartaglia, Marco} } @article {670, title = {CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum.}, journal = {Genet Med}, volume = {21}, year = {2019}, month = {2019 12}, pages = {2723-2733}, abstract = {

PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD).

METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function.

RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits.

CONCLUSION: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.

}, issn = {1530-0366}, doi = {10.1038/s41436-019-0585-z}, author = {Konrad, Enrico D H and Nardini, Niels and Caliebe, Almuth and Nagel, Inga and Young, Dana and Horvath, Gabriella and Santoro, Stephanie L and Shuss, Christine and Ziegler, Alban and Bonneau, Dominique and Kempers, Marlies and Pfundt, Rolph and Legius, Eric and Bouman, Arjan and Stuurman, Kyra E and {\~O}unap, Katrin and Pajusalu, Sander and Wojcik, Monica H and Vasileiou, Georgia and Le Guyader, Gwena{\"e}l and Schnelle, Hege M and Berland, Siren and Zonneveld-Huijssoon, Evelien and Kersten, Simone and Gupta, Aditi and Blackburn, Patrick R and Ellingson, Marissa S and Ferber, Matthew J and Dhamija, Radhika and Klee, Eric W and McEntagart, Meriel and Lichtenbelt, Klaske D and Kenney, Amy and Vergano, Samantha A and Abou Jamra, Rami and Platzer, Konrad and Ella Pierpont, Mary and Khattar, Divya and Hopkin, Robert J and Martin, Richard J and Jongmans, Marjolijn C J and Chang, Vivian Y and Martinez-Agosto, Julian A and Kuismin, Outi and Kurki, Mitja I and Pietil{\"a}inen, Olli and Palotie, Aarno and Maarup, Timothy J and Johnson, Diana S and Venborg Pedersen, Katja and Laulund, Lone W and Lynch, Sally A and Blyth, Moira and Prescott, Katrina and Canham, Natalie and Ibitoye, Rita and Brilstra, Eva H and Shinawi, Marwan and Fassi, Emily and Sticht, Heinrich and Gregor, Anne and Van Esch, Hilde and Zweier, Christiane} } @article {697, title = {De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Aug 01}, pages = {403-412}, abstract = {

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.06.007}, author = {Snijders Blok, Lot and Kleefstra, Tjitske and Venselaar, Hanka and Maas, Saskia and Kroes, Hester Y and Lachmeijer, Augusta M A and van Gassen, Koen L I and Firth, Helen V and Tomkins, Susan and Bodek, Simon and {\~O}unap, Katrin and Wojcik, Monica H and Cunniff, Christopher and Bergstrom, Katherine and Powis, Z{\"o}e and Tang, Sha and Shinde, Deepali N and Au, Catherine and Iglesias, Alejandro D and Izumi, Kosuke and Leonard, Jacqueline and Abou Tayoun, Ahmad and Baker, Samuel W and Tartaglia, Marco and Niceta, Marcello and Dentici, Maria Lisa and Okamoto, Nobuhiko and Miyake, Noriko and Matsumoto, Naomichi and Vitobello, Antonio and Faivre, Laurence and Philippe, Christophe and Gilissen, Christian and Wiel, Laurens and Pfundt, Rolph and Deriziotis, Pelagia and Brunner, Han G and Fisher, Simon E} } @article {589, title = {Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 03 07}, pages = {530-541}, abstract = {

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.01.010}, author = {Cogn{\'e}, Benjamin and Ehresmann, Sophie and Beauregard-Lacroix, Eliane and Rousseau, Justine and Besnard, Thomas and Garcia, Thomas and Petrovski, Slav{\'e} and Avni, Shiri and McWalter, Kirsty and Blackburn, Patrick R and Sanders, Stephan J and Uguen, K{\'e}vin and Harris, Jacqueline and Cohen, Julie S and Blyth, Moira and Lehman, Anna and Berg, Jonathan and Li, Mindy H and Kini, Usha and Joss, Shelagh and von der Lippe, Charlotte and Gordon, Christopher T and Humberson, Jennifer B and Robak, Laurie and Scott, Daryl A and Sutton, Vernon R and Skraban, Cara M and Johnston, Jennifer J and Poduri, Annapurna and Nordenskj{\"o}ld, Magnus and Shashi, Vandana and Gerkes, Erica H and Bongers, Ernie M H F and Gilissen, Christian and Zarate, Yuri A and Kvarnung, Malin and Lally, Kevin P and Kulch, Peggy A and Daniels, Brina and Hernandez-Garcia, Andres and Stong, Nicholas and McGaughran, Julie and Retterer, Kyle and Tveten, Kristian and Sullivan, Jennifer and Geisheker, Madeleine R and Stray-Pedersen, Asbjorg and Tarpinian, Jennifer M and Klee, Eric W and Sapp, Julie C and Zyskind, Jacob and Holla, {\O}ystein L and Bedoukian, Emma and Filippini, Francesca and Guimier, Anne and Picard, Arnaud and Busk, {\O}yvind L and Punetha, Jaya and Pfundt, Rolph and Lindstrand, Anna and Nordgren, Ann and Kalb, Fayth and Desai, Megha and Ebanks, Ashley Harmon and Jhangiani, Shalini N and Dewan, Tammie and Coban Akdemir, Zeynep H and Telegrafi, Aida and Zackai, Elaine H and Begtrup, Amber and Song, Xiaofei and Toutain, Annick and Wentzensen, Ingrid M and Odent, Sylvie and Bonneau, Dominique and Latypova, X{\'e}nia and Deb, Wallid and Redon, Sylvia and Bilan, Fr{\'e}d{\'e}ric and Legendre, Marine and Troyer, Caitlin and Whitlock, Kerri and Caluseriu, Oana and Murphree, Marine I and Pichurin, Pavel N and Agre, Katherine and Gavrilova, Ralitza and Rinne, Tuula and Park, Meredith and Shain, Catherine and Heinzen, Erin L and Xiao, Rui and Amiel, Jeanne and Lyonnet, Stanislas and Isidor, Bertrand and Biesecker, Leslie G and Lowenstein, Dan and Posey, Jennifer E and Denomm{\'e}-Pichon, Anne-Sophie and F{\'e}rec, Claude and Yang, Xiang-Jiao and Rosenfeld, Jill A and Gilbert-Dussardier, Brigitte and Audebert-Bellanger, S{\'e}verine and Redon, Richard and Stessman, Holly A F and Nellaker, Christoffer and Yang, Yaping and Lupski, James R and Goldstein, David B and Eichler, Evan E and Bolduc, Francois and B{\'e}zieau, St{\'e}phane and K{\"u}ry, S{\'e}bastien and Campeau, Philippe M} } @article {728, title = {Pathogenic Variants in GPC4 Cause Keipert Syndrome.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 May 02}, pages = {914-924}, abstract = {

Glypicans are a family of cell-surface heparan sulfate proteoglycans that regulate growth-factor signaling during development and are thought to play a role in the regulation of morphogenesis. Whole-exome sequencing of the Australian family that defined Keipert syndrome (nasodigitoacoustic syndrome) identified a hemizygous truncating variant in the gene encoding glypican 4 (GPC4). This variant, located in the final exon of GPC4, results in premature termination of the protein 51 amino acid residues prior to the stop codon, and in concomitant loss of functionally important N-linked glycosylation (Asn514) and glycosylphosphatidylinositol (GPI) anchor (Ser529) sites. We subsequently identified seven affected males from five additional kindreds with novel and predicted pathogenic variants in GPC4. Segregation analysis and X-inactivation studies in carrier females provided supportive evidence that the GPC4 variants caused the condition. Furthermore, functional studies of recombinant protein suggested that the truncated proteins p.Gln506 and p.Glu496 were less stable than the wild type. Clinical features of Keipert syndrome included a prominent forehead, a flat midface, hypertelorism, a broad nose, downturned corners of mouth, and digital abnormalities, whereas cognitive impairment and deafness were variable features. Studies of Gpc4 knockout mice showed evidence of the two primary features of Keipert syndrome: craniofacial abnormalities and digital abnormalities. Phylogenetic analysis demonstrated that GPC4 is most closely related to GPC6, which is associated with a bone dysplasia that has a phenotypic overlap with Keipert syndrome. Overall, we have shown that pathogenic variants in GPC4 cause a loss of function that results in Keipert syndrome, making GPC4 the third human glypican to be linked to a genetic syndrome.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.02.026}, author = {Amor, David J and Stephenson, Sarah E M and Mustapha, Mirna and Mensah, Martin A and Ockeloen, Charlotte W and Lee, Wei Shern and Tankard, Rick M and Phelan, Dean G and Shinawi, Marwan and de Brouwer, Arjan P M and Pfundt, Rolph and Dowling, Cari and Toler, Tomi L and Sutton, V Reid and Agolini, Emanuele and Rinelli, Martina and Capolino, Rossella and Martinelli, Diego and Zampino, Giuseppe and Dumi{\'c}, Miroslav and Reardon, William and Shaw-Smith, Charles and Leventer, Richard J and Delatycki, Martin B and Kleefstra, Tjitske and Mundlos, Stefan and Mortier, Geert and Bahlo, Melanie and Allen, Nicola J and Lockhart, Paul J} } @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 {340, title = {Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Jan 05}, pages = {21-30}, abstract = {

Fibromuscular dysplasia (FMD) is a heterogeneous group of non-atherosclerotic and non-inflammatory arterial diseases that primarily involves the renal and cerebrovascular arteries. Grange syndrome is an autosomal-recessive condition characterized by severe and early-onset vascular disease similar to FMD and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Exome-sequencing analysis of DNA from three affected siblings with Grange syndrome identified compound heterozygous nonsense variants in YY1AP1, and homozygous nonsense or frameshift YY1AP1 variants were subsequently identified in additional unrelated probands with Grange syndrome. YY1AP1 encodes yin yang 1 (YY1)-associated protein 1 and is an activator of the YY1 transcription factor. We determined that YY1AP1 localizes to the nucleus and is a component of the INO80 chromatin remodeling complex, which is responsible for transcriptional regulation, DNA repair, and replication. Molecular studies revealed that loss of YY1AP1 in vascular smooth muscle cells leads to cell cycle arrest with decreased proliferation and increased levels of the cell cycle regulator p21/WAF/CDKN1A and disrupts TGF-β-driven differentiation of smooth muscle cells. Identification of YY1AP1 mutations as a cause of FMD indicates that this condition can result from underlying genetic variants that significantly alter the phenotype of vascular smooth muscle cells.

}, keywords = {Adolescent, Adult, Bone and Bones, Brachydactyly, Cell Cycle Checkpoints, Exome, Female, Fibromuscular Dysplasia, Genes, Recessive, Heterozygote, Homozygote, Humans, Learning Disorders, Male, Middle Aged, Muscle, Smooth, Vascular, Mutation, Nuclear Proteins, Pedigree, Syndactyly, Syndrome, Transcription Factors}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.11.008}, author = {Guo, Dong-Chuan and Duan, Xue-Yan and Regalado, Ellen S and Mellor-Crummey, Lauren and Kwartler, Callie S and Kim, Dong and Lieberman, Kenneth and de Vries, Bert B A and Pfundt, Rolph and Schinzel, Albert and Kotzot, Dieter and Shen, Xuetong and Yang, Min-Lee and Bamshad, Michael J and Nickerson, Deborah A and Gornik, Heather L and Ganesh, Santhi K and Braverman, Alan C and Grange, Dorothy K and Milewicz, Dianna M} } @article {127, title = {Novel genetic causes for cerebral visual impairment.}, journal = {Eur J Hum Genet}, volume = {24}, year = {2016}, month = {2016 May}, pages = {660-5}, abstract = {

Cerebral visual impairment (CVI) is a major cause of low vision in children due to impairment in projection and/or interpretation of the visual input in the brain. Although acquired causes for CVI are well known, genetic causes underlying CVI are largely unidentified. DNAs of 25 patients with CVI and intellectual disability, but without acquired (eg, perinatal) damage, were investigated by whole-exome sequencing. The data were analyzed for de novo, autosomal-recessive, and X-linked variants, and subsequently classified into known, candidate, or unlikely to be associated with CVI. This classification was based on the Online Mendelian Inheritance in Man database, literature reports, variant characteristics, and functional relevance of the gene. After classification, variants in four genes known to be associated with CVI (AHDC1, NGLY1, NR2F1, PGAP1) in 5 patients (20\%) were identified, establishing a conclusive genetic diagnosis for CVI. In addition, in 11 patients (44\%) with CVI, variants in one or more candidate genes were identified (ACP6, AMOT, ARHGEF10L, ATP6V1A, DCAF6, DLG4, GABRB2, GRIN1, GRIN2B, KCNQ3, KCTD19, RERE, SLC1A1, SLC25A16, SLC35A2, SOX5, UFSP2, UHMK1, ZFP30). Our findings show that diverse genetic causes underlie CVI, some of which will provide insight into the biology underlying this disease process.

}, keywords = {Adolescent, Blindness, Cortical, Child, Child, Preschool, Female, Genetic Loci, Humans, Male, Polymorphism, Single Nucleotide, Young Adult}, issn = {1476-5438}, doi = {10.1038/ejhg.2015.186}, author = {Bosch, Dani{\"e}lle G M and Boonstra, F Nienke and de Leeuw, Nicole and Pfundt, Rolph and Nillesen, Willy M and de Ligt, Joep and Gilissen, Christian and Jhangiani, Shalini and Lupski, James R and Cremers, Frans P M and de Vries, Bert B A} } @article {12, title = {Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis.}, journal = {Genet Med}, volume = {18}, year = {2016}, month = {2016 11}, pages = {1158-1162}, abstract = {

PURPOSE: We aimed to identify a novel genetic cause of tooth agenesis (TA) and/or orofacial clefting (OFC) by combining whole-exome sequencing (WES) and targeted resequencing in a large cohort of TA and OFC patients.

METHODS: WES was performed in two unrelated patients: one with severe TA and OFC and another with severe TA only. After deleterious mutations were identified in a gene encoding low-density lipoprotein receptor-related protein 6 (LRP6), all its exons were resequenced with molecular inversion probes in 67 patients with TA, 1,072 patients with OFC, and 706 controls.

RESULTS: We identified a frameshift (c.4594delG, p.Cys1532fs) and a canonical splice-site mutation (c.3398-2A>C, p.?) in LRP6, respectively, in the patient with TA and OFC and in the patient with severe TA only. The targeted resequencing showed significant enrichment of unique LRP6 variants in TA patients but not in nonsyndromic OFC patients. Of the five variants in patients with TA, two affected the canonical splice site and three were missense variants; all variants segregated with the dominant phenotype, and in one case the missense mutation occurred de novo.

CONCLUSION: Mutations in LRP6 cause TA in humans.Genet Med 18 11, 1158-1162.

}, keywords = {Adolescent, Anodontia, Child, Exome, Female, Frameshift Mutation, Genetic Predisposition to Disease, Humans, Low Density Lipoprotein Receptor-Related Protein-6, Male, Mutation, Missense, Pedigree, Sequence Analysis, DNA, Wnt Signaling Pathway}, issn = {1530-0366}, doi = {10.1038/gim.2016.10}, author = {Ockeloen, Charlotte W and Khandelwal, Kriti D and Dreesen, Karoline and Ludwig, Kerstin U and Sullivan, Robert and van Rooij, Iris A L M and Thonissen, Michelle and Swinnen, Steven and Phan, Milien and Conte, Federica and Ishorst, Nina and Gilissen, Christian and RoaFuentes, Laury and van de Vorst, Maartje and Henkes, Arjen and Steehouwer, Marloes and van Beusekom, Ellen and Bloemen, Marjon and Vankeirsbilck, Bruno and Berg{\'e}, Stefaan and Hens, Greet and Schoenaers, Joseph and Poorten, Vincent Vander and Roosenboom, Jasmien and Verdonck, An and Devriendt, Koen and Roeleveldt, Nel and Jhangiani, Shalini N and Vissers, Lisenka E L M and Lupski, James R and de Ligt, Joep and Von den Hoff, Johannes W and Pfundt, Rolph and Brunner, Han G and Zhou, Huiqing and Dixon, Jill and Mangold, Elisabeth and van Bokhoven, Hans and Dixon, Michael J and Kleefstra, Tjitske and Hoischen, Alexander and Carels, Carine E L} } @article {185, title = {Absence of heterozygosity due to template switching during replicative rearrangements.}, journal = {Am J Hum Genet}, volume = {96}, year = {2015}, month = {2015 Apr 02}, pages = {555-64}, abstract = {

We investigated complex genomic rearrangements (CGRs) consisting of triplication copy-number variants (CNVs) that were accompanied by extended regions of copy-number-neutral absence of heterozygosity (AOH) in subjects with multiple congenital abnormalities. Molecular analyses provided observational evidence that in humans, post-zygotically generated CGRs can lead to regional uniparental disomy (UPD) due to template switches between homologs versus sister chromatids by using microhomology to prime DNA replication-a prediction of the replicative repair model, MMBIR. Our findings suggest that replication-based mechanisms might underlie the formation of diverse types of genomic alterations (CGRs and AOH) implicated in constitutional disorders.

}, keywords = {Base Sequence, DNA Copy Number Variations, DNA Repair, DNA Replication, Gene Rearrangement, Humans, In Situ Hybridization, Fluorescence, Loss of Heterozygosity, Models, Genetic, Molecular Sequence Data, Netherlands, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Uniparental Disomy}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.01.021}, author = {Carvalho, Claudia M B and Pfundt, Rolph and King, Daniel A and Lindsay, Sarah J and Zuccherato, Luciana W and Macville, Merryn V E and Liu, Pengfei and Johnson, Diana and Stankiewicz, Pawel and Brown, Chester W and Shaw, Chad A and Hurles, Matthew E and Ira, Grzegorz and Hastings, P J and Brunner, Han G and Lupski, James R} } @article {271, title = {NR2F1 mutations cause optic atrophy with intellectual disability.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Feb 06}, pages = {303-9}, abstract = {

Optic nerve atrophy and hypoplasia can be primary disorders or can result from trans-synaptic degeneration arising from cerebral visual impairment (CVI). Here we report six individuals with CVI and/or optic nerve abnormalities, born after an uneventful pregnancy and delivery, who have either de novo heterozygous missense mutations in NR2F1, also known as COUP-TFI, or deletions encompassing NR2F1. All affected individuals show mild to moderate intellectual impairment. NR2F1 encodes a nuclear receptor protein that regulates transcription. A reporter assay showed that missense mutations in the zinc-finger DNA-binding domain and the putative ligand-binding domain decrease NR2F1 transcriptional activity. These findings indicate that NR2F1 plays an important role in the neurodevelopment of the visual system and that its disruption can lead to optic atrophy with intellectual disability.

}, keywords = {Adolescent, Adult, Amino Acid Sequence, Child, Child, Preschool, COUP Transcription Factor I, DNA-Binding Proteins, Female, Genotype, Humans, Intellectual Disability, Male, Molecular Sequence Data, Mutation, Missense, Optic Atrophy, Phenotype, Young Adult, Zinc Fingers}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.01.002}, author = {Bosch, Dani{\"e}lle G M and Boonstra, F Nienke and Gonzaga-Jauregui, Claudia and Xu, Mafei and de Ligt, Joep and Jhangiani, Shalini and Wiszniewski, Wojciech and Muzny, Donna M and Yntema, Helger G and Pfundt, Rolph and Vissers, Lisenka E L M and Spruijt, Liesbeth and Blokland, Ellen A W and Chen, Chun-An and Lewis, Richard A and Tsai, Sophia Y and Gibbs, Richard A and Tsai, Ming-Jer and Lupski, James R and Zoghbi, Huda Y and Cremers, Frans P M and de Vries, Bert B A and Schaaf, Christian P} } @article {229, title = {Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Aug 07}, pages = {173-82}, abstract = {

New human mutations are thought to originate in germ cells, thus making a recurrence of the same mutation in a sibling exceedingly rare. However, increasing sensitivity of genomic technologies has anecdotally revealed mosaicism for mutations in somatic tissues of apparently healthy parents. Such somatically mosaic parents might also have germline mosaicism that can potentially cause unexpected intergenerational recurrences. Here, we show that somatic mosaicism for transmitted mutations among parents of children with simplex genetic disease is more common than currently appreciated. Using the sensitivity of individual-specific breakpoint PCR, we prospectively screened 100 families with children affected by genomic disorders due to rare deletion copy-number variants (CNVs) determined to be de novo by clinical analysis of parental DNA. Surprisingly, we identified four cases of low-level somatic mosaicism for the transmitted CNV in DNA isolated from parental blood. Integrated probabilistic modeling of gametogenesis developed in response to our observations predicts that mutations in parental blood increase recurrence risk substantially more than parental mutations confined to the germline. Moreover, despite the fact that maternally transmitted mutations are the minority of alleles, our model suggests that sexual dimorphisms in gametogenesis result in a greater proportion of somatically mosaic transmitting mothers who are thus at increased risk of recurrence. Therefore, somatic mosaicism together with sexual differences in gametogenesis might explain a considerable fraction of unexpected recurrences of X-linked recessive disease. Overall, our results underscore an important role for somatic mosaicism and mitotic replicative mutational mechanisms in transmission genetics.

}, keywords = {Cell Division, DNA Copy Number Variations, Female, Gametogenesis, Genetic Diseases, Inborn, Genomics, Germ Cells, Germ-Line Mutation, Humans, Male, Models, Genetic, Mosaicism, Mutation, Pedigree, Prospective Studies, Recurrence, Risk, Sex Characteristics, Smith-Magenis Syndrome}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.07.003}, author = {Campbell, Ian M and Yuan, Bo and Robberecht, Caroline and Pfundt, Rolph and Szafranski, Przemyslaw and McEntagart, Meriel E and Nagamani, Sandesh C S and Erez, Ayelet and Bartnik, Magdalena and Wi{\'s}niowiecka-Kowalnik, Barbara and Plunkett, Katie S and Pursley, Amber N and Kang, Sung-Hae L and Bi, Weimin and Lalani, Seema R and Bacino, Carlos A and Vast, Mala and Marks, Karen and Patton, Michael and Olofsson, Peter and Patel, Ankita and Veltman, Joris A and Cheung, Sau Wai and Shaw, Chad A and Vissers, Lisenka E L M and Vermeesch, Joris R and Lupski, James R and Stankiewicz, Pawe{\l}} }