1. Pathogenic variants inSMARCA5, a chromatin remodeler, cause a range of syndromic neurodevelopmental features
- Author
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Maria J. Guillen Sacoto, Jane A. Hurst, Yue Huang, Susan M. White, Michael E. March, Daniela Choukair, Qin Wang, Dana Brown, Matthew S. Kayser, Hane Lee, Tiong Yang Tan, Kristin Lindstrom, Hagit Baris Feldman, Dov Tiosano, Dong Li, Ashita Dava-Wala, Mariam Mathew, Matthew A. Deardorff, Katheryn Grand, Amy Siemon, Lynn Pais, Elizabeth J. Bhoj, Theresa Brunet, Julian A. Martinez-Agosto, Hakon Hakonarson, Naihua N. Gong, Kirsty McWalter, Claudia Gonzaga-Jauregui, Theresa A. Grebe, John Christodoulou, Melanie Brugger, Dennis Bartholomew, Yuanquan Song, Małgorzata J.M. Nowaczyk, Nikolas Boy, Emma Wakeling, Alina Kurolap, and Eva M. C. Schwaibold
- Subjects
Microcephaly ,animal structures ,Biology ,03 medical and health sciences ,fluids and secretions ,0302 clinical medicine ,Neurodevelopmental disorder ,Developmental Neuroscience ,mental disorders ,Intellectual disability ,medicine ,reproductive and urinary physiology ,Research Articles ,Loss function ,030304 developmental biology ,Genetics ,0303 health sciences ,Multidisciplinary ,fungi ,SciAdv r-articles ,Human Genetics ,medicine.disease ,Phenotype ,ddc ,Chromatin ,Mushroom bodies ,Sensory dendrite ,030217 neurology & neurosurgery ,Research Article - Abstract
Exome sequencing and Drosophila modeling revealed variants in SMARCA5 as a novel cause of a neurodevelopmental disorder., 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 SMARCA5, 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 Drosophila ortholog Iswi 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. Iswi loss of function was rescued by wild-type but not mutant SMARCA5. Our results demonstrate that SMARCA5 pathogenic variants cause a neurodevelopmental syndrome with mild facial dysmorphia.
- Published
- 2021