@article {770, title = {MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 01 01}, pages = {55-68}, abstract = {

MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3{\textquoteright} region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.

}, keywords = {Abnormalities, Multiple, Adolescent, Basilar Artery, Carotid Arteries, Cerebellar Vermis, Cerebellum, Child, Child, Preschool, Cohort Studies, Comparative Genomic Hybridization, Craniofacial Abnormalities, Female, Fibroblasts, Humans, Imaging, Three-Dimensional, Infant, Intellectual Disability, Language Development Disorders, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Nervous System Malformations, Nonsense Mediated mRNA Decay, Polymicrogyria, Real-Time Polymerase Chain Reaction, RNA-Seq, Syndrome, Tomography, X-Ray Computed, Trans-Activators, Tumor Suppressor Proteins, Whole Exome Sequencing, Whole Genome Sequencing}, issn = {1460-2156}, doi = {10.1093/brain/awz379}, author = {Mak, Christopher C Y and Doherty, Dan and Lin, Angela E and Vegas, Nancy and Cho, Megan T and Viot, G{\'e}raldine and Dimartino, Cl{\'e}mantine and Weisfeld-Adams, James D and Lessel, Davor and Joss, Shelagh and Li, Chumei and Gonzaga-Jauregui, Claudia and Zarate, Yuri A and Ehmke, Nadja and Horn, Denise and Troyer, Caitlin and Kant, Sarina G and Lee, Youngha and Ishak, Gisele E and Leung, Gordon and Barone Pritchard, Amanda and Yang, Sandra and Bend, Eric G and Filippini, Francesca and Roadhouse, Chelsea and Lebrun, Nicolas and Mehaffey, Michele G and Martin, Pierre-Marie and Apple, Benjamin and Millan, Francisca and Puk, Oliver and Hoffer, Mariette J V and Henderson, Lindsay B and McGowan, Ruth and Wentzensen, Ingrid M and Pei, Steven and Zahir, Farah R and Yu, Mullin and Gibson, William T and Seman, Ann and Steeves, Marcie and Murrell, Jill R and Luettgen, Sabine and Francisco, Elizabeth and Strom, Tim M and Amlie-Wolf, Louise and Kaindl, Angela M and Wilson, William G and Halbach, Sara and Basel-Salmon, Lina and Lev-El, Noa and Denecke, Jonas and Vissers, Lisenka E L M and Radtke, Kelly and Chelly, Jamel and Zackai, Elaine and Friedman, Jan M and Bamshad, Michael J and Nickerson, Deborah A and Reid, Russell R and Devriendt, Koenraad and Chae, Jong-Hee and Stolerman, Elliot and McDougall, Carey and Powis, Z{\"o}e and Bienvenu, Thierry and Tan, Tiong Y and Orenstein, Naama and Dobyns, William B and Shieh, Joseph T and Choi, Murim and Waggoner, Darrel and Gripp, Karen W and Parker, Michael J and Stoler, Joan and Lyonnet, Stanislas and Cormier-Daire, Val{\'e}rie and Viskochil, David and Hoffman, Trevor L and Amiel, Jeanne and Chung, Brian H Y and Gordon, Christopher T} } @article {424, title = {De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Nov 02}, pages = {716-724}, abstract = {

DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in~vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.

}, keywords = {Adenosine Triphosphatases, Adolescent, Amino Acids, Cell Line, Cell Line, Tumor, Central Nervous System, Child, Child, Preschool, Developmental Disabilities, Female, HEK293 Cells, Humans, Intellectual Disability, Male, Mutation, Missense, RNA, RNA Helicases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.014}, author = {Lessel, Davor and Schob, Claudia and K{\"u}ry, S{\'e}bastien and Reijnders, Margot R F and Harel, Tamar and Eldomery, Mohammad K and Coban-Akdemir, Zeynep and Denecke, Jonas and Edvardson, Shimon and Colin, Estelle and Stegmann, Alexander P A and Gerkes, Erica H and Tessarech, Marine and Bonneau, Dominique and Barth, Magalie and Besnard, Thomas and Cogn{\'e}, Benjamin and Revah-Politi, Anya and Strom, Tim M and Rosenfeld, Jill A and Yang, Yaping and Posey, Jennifer E and Immken, LaDonna and Oundjian, Nelly and Helbig, Katherine L and Meeks, Naomi and Zegar, Kelsey and Morton, Jenny and Schieving, Jolanda H and Claasen, Ana and Huentelman, Matthew and Narayanan, Vinodh and Ramsey, Keri and Brunner, Han G and Elpeleg, Orly and Mercier, Sandra and B{\'e}zieau, St{\'e}phane and Kubisch, Christian and Kleefstra, Tjitske and Kindler, Stefan and Lupski, James R and Kreienkamp, Hans-J{\"u}rgen} } @article {357, title = {Lessons learned from additional research analyses of unsolved clinical exome cases.}, journal = {Genome Med}, volume = {9}, year = {2017}, month = {2017 03 21}, pages = {26}, abstract = {

BACKGROUND: Given the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery.

METHODS: We designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent-offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols.

RESULTS: Analysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36\% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51\% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6\%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6\%), 1/1 multiplex family involving three affected siblings, and 3/4 (75\%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3).

CONCLUSION: An efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts.

}, keywords = {Adenosine Triphosphatases, ATPases Associated with Diverse Cellular Activities, Computational Biology, DNA Copy Number Variations, DNA-Binding Proteins, Exome, Female, Genetic Diseases, Inborn, Genomics, GTP-Binding Protein beta Subunits, Humans, Male, Membrane Proteins, Metalloendopeptidases, Mitochondrial Proteins, Pilot Projects, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Transcription Factors}, issn = {1756-994X}, doi = {10.1186/s13073-017-0412-6}, author = {Eldomery, Mohammad K and Coban-Akdemir, Zeynep and Harel, Tamar and Rosenfeld, Jill A and Gambin, Tomasz and Stray-Pedersen, Asbj{\o}rg and K{\"u}ry, S{\'e}bastien and Mercier, Sandra and Lessel, Davor and Denecke, Jonas and Wiszniewski, Wojciech and Penney, Samantha and Liu, Pengfei and Bi, Weimin and Lalani, Seema R and Schaaf, Christian P and Wangler, Michael F and Bacino, Carlos A and Lewis, Richard Alan and Potocki, Lorraine and Graham, Brett H and Belmont, John W and Scaglia, Fernando and Orange, Jordan S and Jhangiani, Shalini N and Chiang, Theodore and Doddapaneni, Harsha and Hu, Jianhong and Muzny, Donna M and Xia, Fan and Beaudet, Arthur L and Boerwinkle, Eric and Eng, Christine M and Plon, Sharon E and Sutton, V Reid and Gibbs, Richard A and Posey, Jennifer E and Yang, Yaping and Lupski, James R} } @article {378, title = {Survival beyond the perinatal period expands the phenotypes caused by mutations in GLE1.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Nov}, pages = {3098-3103}, abstract = {

Mutations in GLE1 underlie Lethal Congenital Contracture syndrome (LCCS) and Lethal Arthrogryposis with Anterior Horn Cell Disease (LAAHD). Both LCCS and LAAHD are characterized by reduced fetal movements, congenital contractures, and a severe form of motor neuron disease that results in fetal death or death in the perinatal period, respectively. We identified bi-allelic mutations in GLE1 in two unrelated individuals with motor delays, feeding difficulties, and respiratory insufficiency who survived beyond the perinatal period. Each affected child had missense variants predicted to result in amino acid substitutions near the C-terminus of GLE1 that are predicted to disrupt protein-protein interaction or GLE1 protein targeting. We hypothesize that mutations that preserve function of the coiled-coil domain of GLE1 cause LAAHD whereas mutations that abolish the function of the coiled-coil domain cause LCCS. The phenotype of LAAHD is now expanded to include multiple individuals surviving into childhood suggesting that LAAHD is a misnomer and should be re-named Arthrogryposis with Anterior Horn Cell Disease (AAHD).

}, keywords = {Arthrogryposis, Child, Preschool, Female, Genetic Predisposition to Disease, Humans, Male, Motor Disorders, Motor Neuron Disease, Mutation, Nucleocytoplasmic Transport Proteins, Pedigree, Pregnancy}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38406}, author = {Said, Edith and Chong, Jessica X and Hempel, Maja and Denecke, Jonas and Soler, Paul and Strom, Tim and Nickerson, Deborah A and Kubisch, Christian and Bamshad, Michael J and Lessel, Davor} }