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

TitlePathogenic variants in , a chromatin remodeler, cause a range of syndromic neurodevelopmental features.
Publication TypeJournal Article
Year of Publication2021
AuthorsLi, D, Wang, Q, Gong, NN, Kurolap, A, Feldman, HBaris, Boy, N, Brugger, M, Grand, K, McWalter, K, Sacoto, MJGuillen, Wakeling, E, Hurst, J, March, ME, Bhoj, EJ, Nowaczyk, MJM, Gonzaga-Jauregui, C, Mathew, M, Dava-Wala, A, Siemon, A, Bartholomew, D, Huang, Y, Lee, H, Martinez-Agosto, JA, Schwaibold, EMC, Brunet, T, Choukair, D, Pais, LS, White, SM, Christodoulou, J, Brown, D, Lindstrom, K, Grebe, T, Tiosano, D, Kayser, MS, Tan, TYang, Deardorff, MA, Song, Y, Hakonarson, H
JournalSci Adv
Date Published2021 May

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.

Alternate JournalSci Adv
PubMed ID33980485
PubMed Central IDPMC8115915
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
T32 HL007953 / HL / NHLBI NIH HHS / United States
R01 HG009141 / HG / NHGRI NIH HHS / United States
DP2 NS111996 / NS / NINDS NIH HHS / United States
/ WT / Wellcome Trust / United Kingdom