@article {1012, title = {Pathogenic variants in , a chromatin remodeler, cause a range of syndromic neurodevelopmental features.}, journal = {Sci Adv}, volume = {7}, year = {2021}, month = {2021 May}, abstract = {

Intellectual disability encompasses a wide spectrum of neurodevelopmental disorders, with many linked genetic loci. However, the underlying molecular mechanism for more than 50\% of the patients remains elusive. We describe pathogenic variants in , encoding the ATPase motor of the ISWI chromatin remodeler, as a cause of a previously unidentified neurodevelopmental disorder, identifying 12 individuals with de novo or dominantly segregating rare heterozygous variants. Accompanying phenotypes include mild developmental delay, frequent postnatal short stature and microcephaly, and recurrent dysmorphic features. Loss of function of the SMARCA5 ortholog led to smaller body size, reduced sensory dendrite complexity, and tiling defects in larvae. In adult flies, Iswi neural knockdown caused decreased brain size, aberrant mushroom body morphology, and abnormal locomotor function. loss of function was rescued by wild-type but not mutant SMARCA5. Our results demonstrate that pathogenic variants cause a neurodevelopmental syndrome with mild facial dysmorphia.

}, issn = {2375-2548}, doi = {10.1126/sciadv.abf2066}, author = {Li, Dong and Wang, Qin and Gong, Naihua N and Kurolap, Alina and Feldman, Hagit Baris and Boy, Nikolas and Brugger, Melanie and Grand, Katheryn and McWalter, Kirsty and Guillen Sacoto, Maria J and Wakeling, Emma and Hurst, Jane and March, Michael E and Bhoj, Elizabeth J and Nowaczyk, Ma{\l}gorzata J M and Gonzaga-Jauregui, Claudia and Mathew, Mariam and Dava-Wala, Ashita and Siemon, Amy and Bartholomew, Dennis and Huang, Yue and Lee, Hane and Martinez-Agosto, Julian A and Schwaibold, Eva M C and Brunet, Theresa and Choukair, Daniela and Pais, Lynn S and White, Susan M and Christodoulou, John and Brown, Dana and Lindstrom, Kristin and Grebe, Theresa and Tiosano, Dov and Kayser, Matthew S and Tan, Tiong Yang and Deardorff, Matthew A and Song, Yuanquan and Hakonarson, Hakon} } @article {594, title = {Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein 2, cause intellectual disability and seizures.}, journal = {Eur J Hum Genet}, volume = {27}, year = {2019}, month = {2019 May}, pages = {747-759}, abstract = {

CYFIP2, encoding the evolutionary highly conserved cytoplasmic FMRP interacting protein 2, has previously been proposed as a candidate gene for intellectual disability and autism because of its important role linking FMRP-dependent transcription regulation and actin polymerization via the WAVE regulatory complex (WRC). Recently, de novo variants affecting the amino acid p.Arg87 of CYFIP2 were reported in four individuals with epileptic encephalopathy. We here report 12 independent patients harboring a variety of de novo variants in CYFIP2 broadening the molecular and clinical spectrum of a novel CYFIP2-related neurodevelopmental disorder. Using trio whole-exome or -genome sequencing, we identified 12 independent patients carrying a total of eight distinct de novo variants in CYFIP2 with a shared phenotype of intellectual disability, seizures, and muscular hypotonia. We detected seven different missense variants, of which two occurred recurrently (p.(Arg87Cys) and p.(Ile664Met)), and a splice donor variant in the last intron for which we showed exon skipping in the transcript. The latter is expected to escape nonsense-mediated mRNA decay resulting in a truncated protein. Despite the large spacing in the primary structure, the variants spatially cluster in the tertiary structure and are all predicted to weaken the interaction with WAVE1 or NCKAP1 of the actin polymerization regulating WRC-complex. Preliminary genotype-phenotype correlation indicates a profound phenotype in p.Arg87 substitutions and a more variable phenotype in other alterations. This study evidenced a variety of de novo variants in CYFIP2 as a novel cause of mostly severe intellectual disability with seizures and muscular hypotonia.

}, issn = {1476-5438}, doi = {10.1038/s41431-018-0331-z}, author = {Zweier, Markus and Begemann, Ana{\"\i}s and McWalter, Kirsty and Cho, Megan T and Abela, Lucia and Banka, Siddharth and Behring, Bettina and Berger, Andrea and Brown, Chester W and Carneiro, Maryline and Chen, Jiani and Cooper, Gregory M and Finnila, Candice R and Guillen Sacoto, Maria J and Henderson, Alex and H{\"u}ffmeier, Ulrike and Joset, Pascal and Kerr, Bronwyn and Lesca, Gaetan and Leszinski, Gloria S and McDermott, John Henry and Meltzer, Meira R and Monaghan, Kristin G and Mostafavi, Roya and {\~O}unap, Katrin and Plecko, Barbara and Powis, Z{\"o}e and Purcarin, Gabriela and Reimand, Tiia and Riedhammer, Korbinian M and Schreiber, John M and Sirsi, Deepa and Wierenga, Klaas J and Wojcik, Monica H and Papuc, Sorina M and Steindl, Katharina and Sticht, Heinrich and Rauch, Anita} } @article {491, title = {Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 05 03}, pages = {744-759}, abstract = {

RORĪ±, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D.~rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in~vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.

}, keywords = {Adolescent, Adult, Aged, 80 and over, Alleles, Animals, Autistic Disorder, Brain, Cerebellar Ataxia, Child, Child, Preschool, Disease Models, Animal, DNA Copy Number Variations, Female, Genes, Dominant, Genetic Complementation Test, Humans, Intellectual Disability, Larva, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Missense, Nuclear Receptor Subfamily 1, Group F, Member 1, Purkinje Cells, Syndrome, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.02.021}, author = {Guissart, Claire and Latypova, X{\'e}nia and Rollier, Paul and Khan, Tahir N and Stamberger, Hannah and McWalter, Kirsty and Cho, Megan T and Kjaergaard, Susanne and Weckhuysen, Sarah and Lesca, Gaetan and Besnard, Thomas and {\~O}unap, Katrin and Schema, Lynn and Chiocchetti, Andreas G and McDonald, Marie and de Bellescize, Julitta and Vincent, Marie and Van Esch, Hilde and Sattler, Shannon and Forghani, Irman and Thiffault, Isabelle and Freitag, Christine M and Barbouth, Deborah Sara and Cadieux-Dion, Maxime and Willaert, Rebecca and Guillen Sacoto, Maria J and Safina, Nicole P and Dubourg, Christ{\`e}le and Grote, Lauren and Carr{\'e}, Wilfrid and Saunders, Carol and Pajusalu, Sander and Farrow, Emily and Boland, Anne and Karlowicz, Danielle Hays and Deleuze, Jean-Fran{\c c}ois and Wojcik, Monica H and Pressman, Rena and Isidor, Bertrand and Vogels, Annick and Van Paesschen, Wim and Al-Gazali, Lihadh and Al Shamsi, Aisha Mohamed and Claustres, Mireille and Pujol, Aurora and Sanders, Stephan J and Rivier, Fran{\c c}ois and Leboucq, Nicolas and Cogn{\'e}, Benjamin and Sasorith, Souphatta and Sanlaville, Damien and Retterer, Kyle and Odent, Sylvie and Katsanis, Nicholas and B{\'e}zieau, St{\'e}phane and Koenig, Michel and Davis, Erica E and Pasquier, Laurent and K{\"u}ry, S{\'e}bastien} }