@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 {676, title = {Pathogenic Variants in NUP214 Cause "Plugged" Nuclear Pore Channels and Acute Febrile Encephalopathy.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Jul 03}, pages = {48-64}, abstract = {

We report biallelic missense and frameshift pathogenic variants in the gene encoding human nucleoporin NUP214 causing acute febrile encephalopathy. Clinical symptoms include neurodevelopmental regression, seizures, myoclonic jerks, progressive microcephaly, and cerebellar atrophy. NUP214 and NUP88 protein levels were reduced in primary skin fibroblasts derived from affected individuals, while the total number and density of nuclear pore complexes remained normal. Nuclear transport assays exhibited defects in the classical protein import and mRNA export pathways in affected cells. Direct surface imaging of fibroblast nuclei by scanning electron microscopy revealed a large increase in the presence of central particles (known as "plugs") in the nuclear pore channels of affected cells. This observation suggests that large transport cargoes may be delayed in passage through the nuclear pore channel, affecting its selective barrier function. Exposure of fibroblasts from affected individuals to heat shock resulted in a marked delay in their stress response, followed by a surge in apoptotic cell death. This suggests a mechanistic link between decreased cell survival in cell culture and severe fever-induced brain damage in affected individuals. Our study provides evidence by direct imaging at the single nuclear pore level of functional changes linked to a human disease.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.05.003}, author = {Fichtman, Boris and Harel, Tamar and Biran, Nitzan and Zagairy, Fadia and Applegate, Carolyn D and Salzberg, Yuval and Gilboa, Tal and Salah, Somaya and Shaag, Avraham and Simanovsky, Natalia and Ayoubieh, Houriya and Sobreira, Nara and Punzi, Giuseppe and Pierri, Ciro Leonardo and Hamosh, Ada and Elpeleg, Orly and Harel, Amnon and Edvardson, Simon} } @article {631, title = {Enrolling Genomics Research Participants through a Clinical Setting: the Impact of Existing Clinical Relationships on Informed Consent and Expectations for Return of Research Results.}, journal = {J Genet Couns}, volume = {27}, year = {2018}, month = {2018 02}, pages = {263-273}, abstract = {

Genetic counselors working in a clinical setting may find themselves recruiting, enrolling, and returning results for genomic research, and existing clinical relationships with study participants may impact these research interactions. We present a qualitative study using semi-structured interviews of participants enrolled in a genome sequencing/exome sequencing (GS/ES) study at the same institution where they receive clinical care. Interviews were coded for motivations to participate and expectations of this research. The interviews revealed common motivations for participation, including altruism and hope for benefit for themselves, family members, and/or others with their condition. Additionally, themes emerged related to unintentional influence based on trust of the clinical provider that recruited them to the study. Participant trust in the enrolling provider at times appeared to extend to the study team to decide which research results to return and to do so in an appropriate format. Participants also based expectations for research results return on previous clinical genetic testing experiences, which may or may not be realistic depending on study design. It is imperative that genetic counselors enrolling patients into research studies be aware of the potential influence of their clinical relationship on potential subjects, be transparent about their role on the study team, and help set expectations about the study process, including results return.

}, keywords = {Base Sequence, Decision Making, Family, Female, Genetic Testing, Humans, Informed Consent, Male, Motivation, Qualitative Research, Research Design, Trust}, issn = {1573-3599}, doi = {10.1007/s10897-017-0143-2}, author = {Berrios, Courtney and James, Cynthia A and Raraigh, Karen and Bollinger, Juli and Murray, Brittney and Tichnell, Crystal and Applegate, Carolyn D and Bergner, Amanda L} } @article {19, title = {Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene.}, journal = {Genet Med}, volume = {19}, year = {2017}, month = {2017 Apr}, pages = {412-420}, abstract = {

PURPOSE: To investigate the utility of whole-exome sequencing (WES) to define a molecular diagnosis for patients clinically diagnosed with congenital anomalies of kidney and urinary tract (CAKUT).

METHODS: WES was performed in 62 families with CAKUT. WES data were analyzed for single-nucleotide variants (SNVs) in 35 known CAKUT genes, putatively deleterious sequence changes in new candidate genes, and potentially disease-associated copy-number variants (CNVs).

RESULTS: In approximately 5\% of families, pathogenic SNVs were identified in PAX2, HNF1B, and EYA1. Observed phenotypes in these families expand the current understanding about the role of these genes in CAKUT. Four pathogenic CNVs were also identified using two CNV detection tools. In addition, we found one deleterious de novo SNV in FOXP1 among the 62 families with CAKUT. The clinical database of the Baylor Miraca Genetics laboratory was queried and seven additional unrelated individuals with novel de novo SNVs in FOXP1 were identified. Six of these eight individuals with FOXP1 SNVs have syndromic urinary tract defects, implicating this gene in urinary tract development.

CONCLUSION: We conclude that WES can be used to identify molecular etiology (SNVs, CNVs) in a subset of individuals with CAKUT. WES can also help identify novel CAKUT genes.Genet Med 19 4, 412-420.

}, keywords = {Adolescent, Child, Child, Preschool, DNA Copy Number Variations, Exome Sequencing, Female, Forkhead Transcription Factors, Genetic Predisposition to Disease, Hepatocyte Nuclear Factor 1-beta, Humans, Infant, Intracellular Signaling Peptides and Proteins, Male, Nuclear Proteins, PAX2 Transcription Factor, Pedigree, Polymorphism, Single Nucleotide, Protein Tyrosine Phosphatases, Repressor Proteins, Urogenital Abnormalities, Vesico-Ureteral Reflux, Young Adult}, issn = {1530-0366}, doi = {10.1038/gim.2016.131}, author = {Bekheirnia, Mir Reza and Bekheirnia, Nasim and Bainbridge, Matthew N and Gu, Shen and Coban Akdemir, Zeynep Hande and Gambin, Tomek and Janzen, Nicolette K and Jhangiani, Shalini N and Muzny, Donna M and Michael, Mini and Brewer, Eileen D and Elenberg, Ewa and Kale, Arundhati S and Riley, Alyssa A and Swartz, Sarah J and Scott, Daryl A and Yang, Yaping and Srivaths, Poyyapakkam R and Wenderfer, Scott E and Bodurtha, Joann and Applegate, Carolyn D and Velinov, Milen and Myers, Angela and Borovik, Lior and Craigen, William J and Hanchard, Neil A and Rosenfeld, Jill A and Lewis, Richard Alan and Gonzales, Edmond T and Gibbs, Richard A and Belmont, John W and Roth, David R and Eng, Christine and Braun, Michael C and Lupski, James R and Lamb, Dolores J} } @article {129, title = {CRB1-Related Maculopathy With Cystoid Macular Edema.}, journal = {JAMA Ophthalmol}, volume = {133}, year = {2015}, month = {2015 Nov}, pages = {1357-60}, keywords = {Administration, Topical, Carbonic Anhydrase Inhibitors, Child, Diseases in Twins, DNA Mutational Analysis, Electroretinography, Eye Proteins, Female, Fluorescein Angiography, Humans, Macular Edema, Membrane Proteins, Mutation, Nerve Tissue Proteins, Ophthalmic Solutions, Retinal Dystrophies, Sulfonamides, Thiophenes, Tomography, Optical Coherence, Twins, Monozygotic, Visual Acuity}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2015.2814}, author = {Wolfson, Yulia and Applegate, Carolyn D and Strauss, Rupert W and Han, Ian C and Scholl, Hendrik P} }