@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} } @article {335, title = {De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Feb 02}, pages = {352-363}, abstract = {

Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.

}, keywords = {Adolescent, Animals, Child, Child, Preschool, Disease Models, Animal, DNA Copy Number Variations, Down-Regulation, Female, Gene Deletion, Humans, Infant, Intellectual Disability, Male, Microcephaly, Neurodevelopmental Disorders, Polymorphism, Single Nucleotide, Proteasome Endopeptidase Complex, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.01.003}, author = {K{\"u}ry, S{\'e}bastien and Besnard, Thomas and Ebstein, Fr{\'e}d{\'e}ric and Khan, Tahir N and Gambin, Tomasz and Douglas, Jessica and Bacino, Carlos A and Craigen, William J and Sanders, Stephan J and Lehmann, Andrea and Latypova, X{\'e}nia and Khan, Kamal and Pacault, Mathilde and Sacharow, Stephanie and Glaser, Kimberly and Bieth, Eric and Perrin-Sabourin, Laurence and Jacquemont, Marie-Line and Cho, Megan T and Roeder, Elizabeth and Denomm{\'e}-Pichon, Anne-Sophie and Monaghan, Kristin G and Yuan, Bo and Xia, Fan and Simon, Sylvain and Bonneau, Dominique and Parent, Philippe and Gilbert-Dussardier, Brigitte and Odent, Sylvie and Toutain, Annick and Pasquier, Laurent and Barbouth, Deborah and Shaw, Chad A and Patel, Ankita and Smith, Janice L and Bi, Weimin and Schmitt, S{\'e}bastien and Deb, Wallid and Nizon, Mathilde and Mercier, Sandra and Vincent, Marie and Rooryck, Caroline and Malan, Val{\'e}rie and Brice{\~n}o, Ignacio and G{\'o}mez, Alberto and Nugent, Kimberly M and Gibson, James B and Cogn{\'e}, Benjamin and Lupski, James R and Stessman, Holly A F and Eichler, Evan E and Retterer, Kyle and Yang, Yaping and Redon, Richard and Katsanis, Nicholas and Rosenfeld, Jill A and Kloetzel, Peter-Michael and Golzio, Christelle and B{\'e}zieau, St{\'e}phane and Stankiewicz, Pawe{\l} and Isidor, Bertrand} } @article {376, title = {Identification of novel candidate disease genes from de novo exonic copy number variants.}, journal = {Genome Med}, volume = {9}, year = {2017}, month = {2017 09 21}, pages = {83}, abstract = {

BACKGROUND: Exon-targeted microarrays can detect small (<1000~bp) intragenic copy number variants (CNVs), including those that affect only a single exon. This genome-wide high-sensitivity approach increases the molecular diagnosis for conditions with known disease-associated genes, enables better genotype-phenotype correlations, and facilitates variant allele detection allowing novel disease gene discovery.

METHODS: We retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association.

RESULTS: In this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11\%), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 single-gene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224~bp to 1.6~Mb in size) were compared to those in individuals with larger-sized deletions (up to 5~Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation of disease association for two recently proposed disease genes (MEIS2 and PTCHD1). Notably, exon-targeted CMA detected several pathogenic single-exon CNVs missed by clinical WES analyses.

CONCLUSIONS: Together, these data document the efficacy of exon-targeted CMA for detection of genic and exonic CNVs, complementing and extending WES in clinical diagnostics, and the potential for discovery of novel disease genes by genome-wide assay.

}, keywords = {Cohort Studies, DNA Copy Number Variations, Exons, Genetic Diseases, Inborn, Genome, Human, Homeodomain Proteins, Humans, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Neurodevelopmental Disorders, Protein-Serine-Threonine Kinases, Retrospective Studies, Transcription Factors, Whole Genome Sequencing}, issn = {1756-994X}, doi = {10.1186/s13073-017-0472-7}, author = {Gambin, Tomasz and Yuan, Bo and Bi, Weimin and Liu, Pengfei and Rosenfeld, Jill A and Coban-Akdemir, Zeynep and Pursley, Amber N and Nagamani, Sandesh C S and Marom, Ronit and Golla, Sailaja and Dengle, Lauren and Petrie, Heather G and Matalon, Reuben and Emrick, Lisa and Proud, Monica B and Treadwell-Deering, Diane and Chao, Hsiao-Tuan and Koillinen, Hannele and Brown, Chester and Urraca, Nora and Mostafavi, Roya and Bernes, Saunder and Roeder, Elizabeth R and Nugent, Kimberly M and Bader, Patricia I and Bellus, Gary and Cummings, Michael and Northrup, Hope and Ashfaq, Myla and Westman, Rachel and Wildin, Robert and Beck, Anita E and Immken, LaDonna and Elton, Lindsay and Varghese, Shaun and Buchanan, Edward and Faivre, Laurence and Lefebvre, Mathilde and Schaaf, Christian P and Walkiewicz, Magdalena and Yang, Yaping and Kang, Sung-Hae L and Lalani, Seema R and Bacino, Carlos A and Beaudet, Arthur L and Breman, Amy M and Smith, Janice L and Cheung, Sau Wai and Lupski, James R and Patel, Ankita and Shaw, Chad A and Stankiewicz, Pawe{\l}} } @article {442, title = {Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders.}, journal = {Genome Med}, volume = {9}, year = {2017}, month = {2017 08 14}, pages = {73}, abstract = {

BACKGROUND: De novo missense variants in CDK13 have been described as the cause of syndromic congenital heart defects in seven individuals ascertained from a large congenital cardiovascular malformations cohort. We aimed to further define the phenotypic and molecular spectrum of this newly described disorder.

METHODS: To minimise ascertainment bias, we recruited nine additional individuals with CDK13 pathogenic variants from clinical and research exome laboratory sequencing cohorts. Each individual underwent dysmorphology exam and comprehensive medical history review.

RESULTS: We demonstrate greater than expected phenotypic heterogeneity, including 33\% (3/9) of individuals without structural heart disease on echocardiogram. There was a high penetrance for a unique constellation of facial dysmorphism and global developmental delay, as well as less frequently seen renal and sacral anomalies. Two individuals had novel CDK13 variants (p.Asn842Asp, p.Lys734Glu), while the remaining seven unrelated individuals had a recurrent, previously published p.Asn842Ser variant. Summary of all variants published to date demonstrates apparent restriction of pathogenic variants to the protein kinase domain with clustering in the ATP and magnesium binding sites.

CONCLUSIONS: Here we provide detailed phenotypic and molecular characterisation of individuals with pathogenic variants in CDK13 and propose management guidelines based upon the estimated prevalence of anomalies identified.

}, keywords = {Adolescent, Adult, CDC2 Protein Kinase, Child, Child, Preschool, Face, Female, Heart Defects, Congenital, Humans, Infant, Intellectual Disability, Male, Mutation, Phenotype, Syndrome}, issn = {1756-994X}, doi = {10.1186/s13073-017-0463-8}, author = {Bostwick, Bret L and McLean, Scott and Posey, Jennifer E and Streff, Haley E and Gripp, Karen W and Blesson, Alyssa and Powell-Hamilton, Nina and Tusi, Jessica and Stevenson, David A and Farrelly, Ellyn and Hudgins, Louanne and Yang, Yaping and Xia, Fan and Wang, Xia and Liu, Pengfei and Walkiewicz, Magdalena and McGuire, Marianne and Grange, Dorothy K and Andrews, Marisa V and Hummel, Marybeth and Madan-Khetarpal, Suneeta and Infante, Elena and Coban-Akdemir, Zeynep and Miszalski-Jamka, Karol and Jefferies, John L and Rosenfeld, Jill A and Emrick, Lisa and Nugent, Kimberly M and Lupski, James R and Belmont, John W and Lee, Brendan and Lalani, Seema R} }