@article {705, title = {Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 Oct 15}, pages = {4679}, abstract = {

Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2-whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes.

}, issn = {2041-1723}, doi = {10.1038/s41467-019-12435-8}, author = {Guo, Hui and Bettella, Elisa and Marcogliese, Paul C and Zhao, Rongjuan and Andrews, Jonathan C and Nowakowski, Tomasz J and Gillentine, Madelyn A and Hoekzema, Kendra and Wang, Tianyun and Wu, Huidan and Jangam, Sharayu and Liu, Cenying and Ni, Hailun and Willemsen, Marjolein H and van Bon, Bregje W and Rinne, Tuula and Stevens, Servi J C and Kleefstra, Tjitske and Brunner, Han G and Yntema, Helger G and Long, Min and Zhao, Wenjing and Hu, Zhengmao and Colson, Cindy and Richard, Nicolas and Schwartz, Charles E and Romano, Corrado and Castiglia, Lucia and Bottitta, Maria and Dhar, Shweta U and Erwin, Deanna J and Emrick, Lisa and Keren, Boris and Afenjar, Alexandra and Zhu, Baosheng and Bai, Bing and Stankiewicz, Pawel and Herman, Kristin and Mercimek-Andrews, Saadet and Juusola, Jane and Wilfert, Amy B and Abou Jamra, Rami and B{\"u}ttner, Benjamin and Mefford, Heather C and Muir, Alison M and Scheffer, Ingrid E and Regan, Brigid M and Malone, Stephen and Gecz, Jozef and Cobben, Jan and Weiss, Marjan M and Waisfisz, Quinten and Bijlsma, Emilia K and Hoffer, Mariette J V and Ruivenkamp, Claudia A L and Sartori, Stefano and Xia, Fan and Rosenfeld, Jill A and Bernier, Raphael A and Wangler, Michael F and Yamamoto, Shinya and Xia, Kun and Stegmann, Alexander P A and Bellen, Hugo J and Murgia, Alessandra and Eichler, Evan E} } @article {28, title = {De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Sep 01}, pages = {711-719}, abstract = {

The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and~HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.

}, keywords = {Animals, Brain, Developmental Disabilities, DNA-Binding Proteins, Eye Abnormalities, Female, Genes, Essential, Haploinsufficiency, Head, Heterozygote, Humans, Intellectual Disability, Male, Metabolic Diseases, Minor Histocompatibility Antigens, Mutation, Pedigree, RNA Splicing, RNA, Messenger, Spine, Syndrome, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.06.029}, author = {Kim, Jung-Hyun and Shinde, Deepali N and Reijnders, Margot R F and Hauser, Natalie S and Belmonte, Rebecca L and Wilson, Gregory R and Bosch, Dani{\"e}lle G M and Bubulya, Paula A and Shashi, Vandana and Petrovski, Slav{\'e} and Stone, Joshua K and Park, Eun Young and Veltman, Joris A and Sinnema, Margje and Stumpel, Connie T R M and Draaisma, Jos M and Nicolai, Joost and Yntema, Helger G and Lindstrom, Kristin and de Vries, Bert B A and Jewett, Tamison and Santoro, Stephanie L and Vogt, Julie and Bachman, Kristine K and Seeley, Andrea H and Krokosky, Alyson and Turner, Clesson and Rohena, Luis and Hempel, Maja and Kort{\"u}m, Fanny and Lessel, Davor and Neu, Axel and Strom, Tim M and Wieczorek, Dagmar and Bramswig, Nuria and Laccone, Franco A and Behunova, Jana and Rehder, Helga and Gordon, Christopher T and Rio, Marl{\`e}ne and Romana, Serge and Tang, Sha and El-Khechen, Dima and Cho, Megan T and McWalter, Kirsty and Douglas, Ganka and Baskin, Berivan and Begtrup, Amber and Funari, Tara and Schoch, Kelly and Stegmann, Alexander P A and Stevens, Servi J C and Zhang, Dong-Er and Traver, David and Yao, Xu and MacArthur, Daniel G and Brunner, Han G and Mancini, Grazia M and Myers, Richard M and Owen, Laurie B and Lim, Ssang-Taek and Stachura, David L and Vissers, Lisenka E L M and Ahn, Eun-Young Erin} } @article {122, title = {Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2.}, journal = {Am J Hum Genet}, volume = {97}, year = {2015}, month = {2015 Nov 05}, pages = {647-60}, abstract = {

Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS-UHL/AHL) revealed a heterozygous truncating mutation, c.286_303delinsT (p.Ser96Ter), in KITLG. This mutation co-segregated with NS-UHL/AHL as a dominant trait with reduced penetrance. By screening a panel of probands with NS-UHL/AHL, we found an additional mutation, c.200_202del (p.His67_Cys68delinsArg). In~vitro studies revealed that the p.His67_Cys68delinsArg transmembrane isoform of KITLG is not detectable at the cell membrane, supporting pathogenicity. KITLG encodes a ligand for the KIT receptor. Also, KITLG-KIT signaling and MITF are suggested to mutually interact in melanocyte development. Because mutations in MITF are causative of Waardenburg syndrome type 2 (WS2), we screened KITLG in suspected WS2-affected probands. A heterozygous missense mutation, c.310C>G (p.Leu104Val), that segregated with WS2 was identified in a small family. In~vitro studies revealed that the p.Leu104Val transmembrane isoform of KITLG is located at the cell membrane, as is wild-type KITLG. However, in culture media of transfected cells, the p.Leu104Val soluble isoform of KITLG was reduced, and no soluble p.His67_Cys68delinsArg and p.Ser96Ter KITLG could be detected. These data suggest that mutations in KITLG associated with NS-UHL/AHL have a loss-of-function effect. We speculate that the mechanism of the mutation underlying WS2 and leading to membrane incorporation and reduced secretion of KITLG occurs via a dominant-negative or gain-of-function effect. Our study unveils different phenotypes associated with KITLG, previously associated with pigmentation abnormalities, and will thereby improve the genetic counseling given to individuals with KITLG variants.

}, keywords = {Alleles, Animals, Female, Fluorescent Antibody Technique, Genetic Linkage, Hearing Loss, Unilateral, Humans, Male, Mice, Mutation, NIH 3T3 Cells, Pedigree, Phenotype, Prognosis, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Stem Cell Factor, Waardenburg Syndrome}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.09.011}, author = {Zazo Seco, Celia and Serr{\~a}o de Castro, Luciana and van Nierop, Josephine W and Mor{\'\i}n, Mat{\'\i}as and Jhangiani, Shalini and Verver, Eva J J and Schraders, Margit and Maiwald, Nadine and Wesdorp, Mieke and Venselaar, Hanka and Spruijt, Liesbeth and Oostrik, Jaap and Schoots, Jeroen and van Reeuwijk, Jeroen and Lelieveld, Stefan H and Huygen, Patrick L M and Insenser, Mar{\'\i}a and Admiraal, Ronald J C and Pennings, Ronald J E and Hoefsloot, Lies H and Arias-V{\'a}squez, Alejandro and de Ligt, Joep and Yntema, Helger G and Jansen, Joop H and Muzny, Donna M and Huls, Gerwin and van Rossum, Michelle M and Lupski, James R and Moreno-Pelayo, Miguel Angel and Kunst, Henricus P M and Kremer, Hannie} } @article {271, title = {NR2F1 mutations cause optic atrophy with intellectual disability.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Feb 06}, pages = {303-9}, abstract = {

Optic nerve atrophy and hypoplasia can be primary disorders or can result from trans-synaptic degeneration arising from cerebral visual impairment (CVI). Here we report six individuals with CVI and/or optic nerve abnormalities, born after an uneventful pregnancy and delivery, who have either de novo heterozygous missense mutations in NR2F1, also known as COUP-TFI, or deletions encompassing NR2F1. All affected individuals show mild to moderate intellectual impairment. NR2F1 encodes a nuclear receptor protein that regulates transcription. A reporter assay showed that missense mutations in the zinc-finger DNA-binding domain and the putative ligand-binding domain decrease NR2F1 transcriptional activity. These findings indicate that NR2F1 plays an important role in the neurodevelopment of the visual system and that its disruption can lead to optic atrophy with intellectual disability.

}, keywords = {Adolescent, Adult, Amino Acid Sequence, Child, Child, Preschool, COUP Transcription Factor I, DNA-Binding Proteins, Female, Genotype, Humans, Intellectual Disability, Male, Molecular Sequence Data, Mutation, Missense, Optic Atrophy, Phenotype, Young Adult, Zinc Fingers}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.01.002}, author = {Bosch, Dani{\"e}lle G M and Boonstra, F Nienke and Gonzaga-Jauregui, Claudia and Xu, Mafei and de Ligt, Joep and Jhangiani, Shalini and Wiszniewski, Wojciech and Muzny, Donna M and Yntema, Helger G and Pfundt, Rolph and Vissers, Lisenka E L M and Spruijt, Liesbeth and Blokland, Ellen A W and Chen, Chun-An and Lewis, Richard A and Tsai, Sophia Y and Gibbs, Richard A and Tsai, Ming-Jer and Lupski, James R and Zoghbi, Huda Y and Cremers, Frans P M and de Vries, Bert B A and Schaaf, Christian P} }