@article {918, title = {De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy.}, journal = {Genet Med}, volume = {23}, year = {2021}, month = {2021 04}, pages = {653-660}, abstract = {

PURPOSE: This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals.

METHODS: Individuals harboring heterozygous missense or loss-of-function variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms, and literature review. For each individual, detailed phenotyping, classification, and structural modeling of the identified variant were performed.

RESULTS: The cohort comprises 23 individuals with pathogenic or likely pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cerebral visual impairment, and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex.

CONCLUSION: We provide a comprehensive description of SNAP25-DEE with intellectual disability and early-onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1, or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed "SNAREopathies."

}, keywords = {Brain Diseases, Child, Preschool, Epilepsy, Humans, Intellectual Disability, Neurodevelopmental Disorders, Phenotype, Synaptosomal-Associated Protein 25}, issn = {1530-0366}, doi = {10.1038/s41436-020-01020-w}, author = {Kl{\"o}ckner, Chiara and Sticht, Heinrich and Zacher, Pia and Popp, Bernt and Babcock, Holly E and Bakker, Dewi P and Barwick, Katy and Bonfert, Michaela V and B{\"o}nnemann, Carsten G and Brilstra, Eva H and Chung, Wendy K and Clarke, Angus J and Devine, Patrick and Donkervoort, Sandra and Fraser, Jamie L and Friedman, Jennifer and Gates, Alyssa and Ghoumid, Jamal and Hobson, Emma and Horvath, Gabriella and Keller-Ramey, Jennifer and Keren, Boris and Kurian, Manju A and Lee, Virgina and Leppig, Kathleen A and Lundgren, Johan and McDonald, Marie T and McLaughlin, Heather M and McTague, Amy and Mefford, Heather C and Mignot, Cyril and Mikati, Mohamad A and Nava, Caroline and Raymond, F Lucy and Sampson, Julian R and Sanchis-Juan, Alba and Shashi, Vandana and Shieh, Joseph T C and Shinawi, Marwan and Slavotinek, Anne and St{\"o}dberg, Tommy and Stong, Nicholas and Sullivan, Jennifer A and Taylor, Ashley C and Toler, Tomi L and van den Boogaard, Marie-Jos{\'e} and van der Crabben, Saskia N and van Gassen, Koen L I and van Jaarsveld, Richard H and Van Ziffle, Jessica and Wadley, Alexandrea F and Wagner, Matias and Wigby, Kristen and Wortmann, Saskia B and Zarate, Yuri A and M{\o}ller, Rikke S and Lemke, Johannes R and Platzer, Konrad} } @article {920, title = {KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 12 05}, pages = {3242-3261}, abstract = {

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden{\textquoteright}s Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50\% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30\%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30\% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2\%) and cervical (50.5\%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9\% at 1 year to 16.2\% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9\%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Chromosome Deletion, Cohort Studies, Computer Simulation, Deep Brain Stimulation, Disease Progression, Dystonic Disorders, Endocrine System Diseases, Female, Fetal Growth Retardation, Gait Disorders, Neurologic, Histone-Lysine N-Methyltransferase, Humans, Laryngeal Diseases, Male, Mutation, Mutation, Missense, Phenotype, Quality of Life, Treatment Outcome, Young Adult}, issn = {1460-2156}, doi = {10.1093/brain/awaa304}, author = {Cif, Laura and Demailly, Diane and Lin, Jean-Pierre and Barwick, Katy E and Sa, Mario and Abela, Lucia and Malhotra, Sony and Chong, Wui K and Steel, Dora and Sanchis-Juan, Alba and Ngoh, Adeline and Trump, Natalie and Meyer, Esther and Vasques, Xavier and Rankin, Julia and Allain, Meredith W and Applegate, Carolyn D and Attaripour IsfAHni, Sanaz and Baleine, Julien and Balint, Bettina and Bassetti, Jennifer A and Baple, Emma L and Bhatia, Kailash P and Blanchet, Catherine and Burglen, Lydie and Cambonie, Gilles and Seng, Emilie Chan and Bastaraud, Sandra Chantot and Cyprien, Fabienne and Coubes, Christine and d{\textquoteright}Hardemare, Vincent and Doja, Asif and Dorison, Nathalie and Doummar, Diane and Dy-Hollins, Marisela E and Farrelly, Ellyn and FitzPatrick, David R and Fearon, Conor and Fieg, Elizabeth L and Fogel, Brent L and Forman, Eva B and Fox, Rachel G and Gahl, William A and Galosi, Serena and Gonzalez, Victoria and Graves, Tracey D and Gregory, Allison and Hallett, Mark and Hasegawa, Harutomo and Hayflick, Susan J and Hamosh, Ada and Hully, Marie and Jansen, Sandra and Jeong, Suh Young and Krier, Joel B and Krystal, Sidney and Kumar, Kishore R and Laurencin, Chlo{\'e} and Lee, Hane and Lesca, Gaetan and Fran{\c c}ois, Laurence Lion and Lynch, Timothy and MAHnt, Neil and Martinez-Agosto, Julian A and Milesi, Christophe and Mills, Kelly A and Mondain, Michel and Morales-Briceno, Hugo and Ostergaard, John R and Pal, Swasti and Pallais, Juan C and Pavillard, Fr{\'e}d{\'e}rique and Perrigault, Pierre-Francois and Petersen, Andrea K and Polo, Gustavo and Poulen, Gaetan and Rinne, Tuula and Roujeau, Thomas and Rogers, Caleb and Roubertie, Agathe and SAHgian, Michelle and Schaefer, Elise and Selim, Laila and Selway, Richard and Sharma, Nutan and Signer, Rebecca and Soldatos, Ariane G and Stevenson, David A and Stewart, Fiona and Tchan, Michel and Verma, Ishwar C and de Vries, Bert B A and Wilson, Jenny L and Wong, Derek A and Zaitoun, Raghda and Zhen, Dolly and Znaczko, Anna and Dale, Russell C and de Gusm{\~a}o, Claudio M and Friedman, Jennifer and Fung, Victor S C and King, Mary D and Mohammad, Shekeeb S and Rohena, Luis and Waugh, Jeff L and Toro, Camilo and Raymond, F Lucy and Topf, Maya and Coubes, Philippe and Gorman, Kathleen M and Kurian, Manju A} } @article {856, title = {Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 05}, pages = {945-953}, abstract = {

PURPOSE: Spinal muscular atrophy (SMA), caused by loss of the SMN1 gene, is a leading cause of early childhood death. Due to the near identical sequences of SMN1 and SMN2, analysis of this region is challenging. Population-wide SMA screening to quantify the SMN1 copy number (CN) is recommended by the American College of Medical Genetics and Genomics.

METHODS: We developed a method that accurately identifies the CN of SMN1 and SMN2 using genome sequencing (GS) data by analyzing read depth and eight informative reference genome differences between SMN1/2.

RESULTS: We characterized SMN1/2 in 12,747 genomes, identified 1568 samples with SMN1 gains or losses and 6615 samples with SMN2 gains or losses, and calculated a pan-ethnic carrier frequency of 2\%, consistent with previous studies. Additionally, 99.8\% of our SMN1 and 99.7\% of SMN2 CN calls agreed with orthogonal methods, with a recall of 100\% for SMA and 97.8\% for carriers, and a precision of 100\% for both SMA and carriers.

CONCLUSION: This SMN copy-number caller can be used to identify both carrier and affected status of SMA, enabling SMA testing to be offered as a comprehensive test in neonatal care and an accurate carrier screening tool in GS sequencing projects.

}, keywords = {Base Sequence, Child, Child, Preschool, Humans, Muscular Atrophy, Spinal, Survival of Motor Neuron 1 Protein}, issn = {1530-0366}, doi = {10.1038/s41436-020-0754-0}, author = {Chen, Xiao and Sanchis-Juan, Alba and French, Courtney E and Connell, Andrew J and Delon, Isabelle and Kingsbury, Zoya and Chawla, Aditi and Halpern, Aaron L and Taft, Ryan J and Bentley, David R and Butchbach, Matthew E R and Raymond, F Lucy and Eberle, Michael A} }