Pathogenic variants in SMARCA5 , a chromatin remodeler, cause a range of syndromic neurodevelopmental features

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 remo...

Full description

Saved in:
Bibliographic Details
Published in:Science advances 2021-05, Vol.7 (20)
Main Authors: Li, Dong, Wang, Qin, Gong, Naihua N, Kurolap, Alina, Feldman, Hagit Baris, Boy, Nikolas, Brugger, Melanie, Grand, Katheryn, McWalter, Kirsty, Guillen Sacoto, Maria J, Wakeling, Emma, Hurst, Jane, March, Michael E, Bhoj, Elizabeth J, Nowaczyk, Małgorzata J M, Gonzaga-Jauregui, Claudia, Mathew, Mariam, Dava-Wala, Ashita, Siemon, Amy, Bartholomew, Dennis, Huang, Yue, Lee, Hane, Martinez-Agosto, Julian A, Schwaibold, Eva M C, Brunet, Theresa, Choukair, Daniela, Pais, Lynn S, White, Susan M, Christodoulou, John, Brown, Dana, Lindstrom, Kristin, Grebe, Theresa, Tiosano, Dov, Kayser, Matthew S, Tan, Tiong Yang, Deardorff, Matthew A, Song, Yuanquan, Hakonarson, Hakon
Format: Article
Language:English
Subjects:
Developmental Neuroscience
Human Genetics
SciAdv r-articles
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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
2375-2548
DOI:10.1126/sciadv.abf2066