@article {1019, title = {Association of De Novo Variants With Childhood Onset Moyamoya Disease and Diffuse Occlusive Vasculopathy.}, journal = {Neurology}, volume = {96}, year = {2021}, month = {2021 03 30}, pages = {e1783-e1791}, abstract = {

OBJECTIVE: To test the hypothesis that de novo genetic variants are responsible for moyamoya disease (MMD) in children with unaffected relatives, we performed exome sequencing of 28 affected children and their unaffected parents.

METHODS: Exome sequencing was performed on 28 trios of affected patients with MMD and unaffected parents.

RESULTS: We identified 3 novel rare de novo variants, 1 in the RING domain and 2 in a highly conserved region distal to the RING domain (4,114-4,120). These de novo cases of MMD present at a young age with aggressive MMD and uniquely have additional occlusive vascular lesions, including renal artery stenosis. Two previously reported cases had de novo variants in the same limited region and presented young with aggressive MMD, and 1 case had narrowing of the inferior abdominal aorta.

CONCLUSIONS: These results indicate a novel syndrome associated with rare variants defined by de novo mutations disrupting highly conserved amino acids in the RING domain and a discrete region distal to the RING domain delimited by amino acids 4,114 to 4,120 leading to onset of severe MMD before 3 years of age and occlusion of other arteries, including the abdominal aorta, renal, iliac, and femoral arteries.

}, keywords = {Adenosine Triphosphatases, Adult, Age of Onset, Aortic Diseases, Arterial Occlusive Diseases, Child, Preschool, Female, Femoral Artery, Humans, Iliac Artery, Male, Moyamoya Disease, Mutation, Renal Artery Obstruction, Ubiquitin-Protein Ligases}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000011653}, author = {Pinard, Amelie and Fiander, Maximillian D J and Cecchi, Alana C and Rideout, Andrea L and Azouz, Mohamed and Fraser, Stuart M and McNeely, P Daniel and Walling, Simon and Novara, Sarah C and Hurst, Anna C E and Guo, Dongchuan and Parkash, Sandhya and Bamshad, Michael J and Nickerson, Deborah A and Vandersteen, Anthony M and Milewicz, Dianna M} } @article {1005, title = {Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.}, journal = {J Exp Med}, volume = {218}, year = {2021}, month = {2021 Jul 05}, abstract = {

The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1{\textquoteright}s critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.

}, issn = {1540-9538}, doi = {10.1084/jem.20201750}, author = {Le Coz, Carole and Nguyen, David N and Su, Chun and Nolan, Brian E and Albrecht, Amanda V and Xhani, Suela and Sun, Di and Demaree, Benjamin and Pillarisetti, Piyush and Khanna, Caroline and Wright, Francis and Chen, Peixin Amy and Yoon, Samuel and Stiegler, Amy L and Maurer, Kelly and Garifallou, James P and Rymaszewski, Amy and Kroft, Steven H and Olson, Timothy S and Seif, Alix E and Wertheim, Gerald and Grant, Struan F A and Vo, Linda T and Puck, Jennifer M and Sullivan, Kathleen E and Routes, John M and Zakharova, Viktoria and Shcherbina, Anna and Mukhina, Anna and Rudy, Natasha L and Hurst, Anna C E and Atkinson, T Prescott and Boggon, Titus J and Hakonarson, Hakon and Abate, Adam R and Hajjar, Joud and Nicholas, Sarah K and Lupski, James R and Verbsky, James and Chinn, Ivan K and Gonzalez, Michael V and Wells, Andrew D and Marson, Alex and Poon, Gregory M K and Romberg, Neil} } @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 {949, title = {A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome.}, journal = {Eur J Hum Genet}, volume = {29}, year = {2021}, month = {2021 Feb}, pages = {271-279}, abstract = {

Trafficking protein particle (TRAPP) complexes, which include the TRAPPC4 protein, regulate membrane trafficking between lipid organelles in a process termed vesicular tethering. TRAPPC4 was recently implicated in a recessive neurodevelopmental condition in four unrelated families due to a shared c.454+3A>G splice variant. Here, we report 23 patients from 17 independent families with an early-infantile-onset neurodegenerative presentation, where we also identified the homozygous variant hg38:11:119020256 A>G (NM_016146.5:c.454+3A>G) in TRAPPC4 through exome or genome sequencing. No other clinically relevant TRAPPC4 variants were identified among any of over 10,000 patients with neurodevelopmental conditions. We found the carrier frequency of TRAPPC4 c.454+3A>G was 2.4-5.4 per 10,000 healthy individuals. Affected individuals with the homozygous TRAPPC4 c.454+3A>G variant showed profound psychomotor delay, developmental regression, early-onset epilepsy, microcephaly and progressive spastic tetraplegia. Based upon RNA sequencing, the variant resulted in partial exon 3 skipping and generation of an aberrant transcript owing to use of a downstream cryptic splice donor site, predicting a premature stop codon and nonsense mediated decay. These data confirm the pathogenicity of the TRAPPC4 c.454+3A>G variant, and refine the clinical presentation of TRAPPC4-related encephalopathy.

}, issn = {1476-5438}, doi = {10.1038/s41431-020-00717-5}, author = {Ghosh, Shereen G and Scala, Marcello and Beetz, Christian and Helman, Guy and Stanley, Valentina and Yang, Xiaoxu and Breuss, Martin W and Mazaheri, Neda and Selim, Laila and Hadipour, Fatemeh and Pais, Lynn and Stutterd, Chloe A and Karageorgou, Vasiliki and Begtrup, Amber and Crunk, Amy and Juusola, Jane and Willaert, Rebecca and Flore, Leigh A and Kennelly, Kelly and Spencer, Christopher and Brown, Martha and Trapane, Pamela and Hurst, Anna C E and Lane Rutledge, S and Goodloe, Dana H and McDonald, Marie T and Shashi, Vandana and Schoch, Kelly and Tomoum, Hoda and Zaitoun, Raghda and Hadipour, Zahra and Galehdari, Hamid and Pagnamenta, Alistair T and Mojarrad, Majid and Sedaghat, Alireza and Dias, Patr{\'\i}cia and Quintas, Sofia and Eslahi, Atiyeh and Shariati, Gholamreza and Bauer, Peter and Simons, Cas and Houlden, Henry and Issa, Mahmoud Y and Zaki, MAH S and Maroofian, Reza and Gleeson, Joseph G} } @article {753, title = {Recurrent arginine substitutions in the ACTG2 gene are the primary driver of disease burden and severity in visceral myopathy.}, journal = {Hum Mutat}, volume = {41}, year = {2020}, month = {2020 03}, pages = {641-654}, abstract = {

Visceral myopathy with abnormal intestinal and bladder peristalsis includes a clinical spectrum with megacystis-microcolon intestinal hypoperistalsis syndrome and chronic intestinal pseudo-obstruction. The vast majority of cases are caused by dominant variants in ACTG2; however, the overall genetic architecture of visceral myopathy has not been well-characterized. We ascertained 53 families, with visceral myopathy based on megacystis, functional bladder/gastrointestinal obstruction, or microcolon. A combination of targeted ACTG2 sequencing and exome sequencing was used. We report a molecular diagnostic rate of 64\% (34/53), of which 97\% (33/34) is attributed to ACTG2. Strikingly, missense mutations in five conserved arginine residues involving CpG dinucleotides accounted for 49\% (26/53) of disease in the cohort. As a group, the ACTG2-negative cases had a more favorable clinical outcome and more restricted disease. Within the ACTG2-positive group, poor outcomes (characterized by total parenteral nutrition dependence, death, or transplantation) were invariably due to one of the arginine missense alleles. Analysis of specific residues suggests a severity spectrum of p.Arg178>p.Arg257>p.Arg40 along with other less-frequently reported sites p.Arg63 and p.Arg211. These results provide genotype-phenotype correlation for ACTG2-related disease and demonstrate the importance of arginine missense changes in visceral myopathy.

}, issn = {1098-1004}, doi = {10.1002/humu.23960}, author = {Assia Batzir, Nurit and Kishor Bhagwat, Pranjali and Larson, Austin and Coban Akdemir, Zeynep and Bag{\l}aj, Maciej and Bofferding, Leon and Bosanko, Katherine B and Bouassida, Skander and Callewaert, Bert and Cannon, Ashley and Enchautegui Colon, Yazmin and Garnica, Adolfo D and Harr, Margaret H and Heck, Sandra and Hurst, Anna C E and Jhangiani, Shalini N and Isidor, Bertrand and Littlejohn, Rebecca O and Liu, Pengfei and Magoulas, Pilar and Mar Fan, Helen and Marom, Ronit and McLean, Scott and Nezarati, Marjan M and Nugent, Kimberly M and Petersen, Michael B and Rocha, Maria L and Roeder, Elizabeth and Smigiel, Robert and Tully, Ian and Weisfeld-Adams, James and Wells, Katerina O and Posey, Jennifer E and Lupski, James R and Beaudet, Arthur L and Wangler, Michael F} }