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

被引：20

作者：

Li, Dong ^{[1
]}

Wang, Qin ^{[2
]}

Gong, Naihua N. ^{[3
]}

Kurolap, Alina ^{[4
]}

Feldman, Hagit Baris ^{[4
,5
]}

Boy, Nikolas ^{[6
]}

Brugger, Melanie ^{[7
,8
]}

Grand, Katheryn ^{[9
]}

McWalter, Kirsty ^{[10
]}

Sacoto, Maria J. Guillen ^{[10
]}

Wakeling, Emma ^{[11
]}

Hurst, Jane ^{[11
]}

March, Michael E. ^{[1
]}

Bhoj, Elizabeth J. ^{[1
]}

Nowaczyk, Malgorzata J. M. ^{[12
]}

Gonzaga-Jauregui, Claudia ^{[13
]}

Mathew, Mariam ^{[14
]}

Dava-Wala, Ashita ^{[14
]}

Siemon, Amy ^{[15
]}

Bartholomew, Dennis ^{[15
]}

Huang, Yue ^{[16
,17
]}

Lee, Hane ^{[17
,18
,19
]}

Martinez-Agosto, Julian A. ^{[16
,17
]}

Schwaibold, Eva M. C. ^{[17
,18
,19
]}

Brunet, Theresa ^{[7
]}

Choukair, Daniela ^{[20
]}

Pais, Lynn S. ^{[21
]}

White, Susan M. ^{[22
,23
]}

Christodoulou, John ^{[22
,23
]}

Brown, Dana ^{[24
]}

Lindstrom, Kristin ^{[24
]}

Grebe, Theresa ^{[24
,25
]}

Tiosano, Dov ^{[26
,27
]}

Kayser, Matthew S. ^{[3
]}

Tan, Tiong Yang ^{[22
,23
]}

Deardorff, Matthew A. ^{[28
,29
,30
]}

Song, Yuanquan ^{[2
,31
]}

Hakonarson, Hakon ^{[1
,32
]}

机构：

[1] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA

[2] Childrens Hosp Philadelphia, Raymond G Perelman Ctr Cellular & Mol Therapeut, Philadelphia, PA 19104 USA

[3] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA

[4] Tel Aviv Sourasky Med Ctr, Genet Inst, Tel Aviv, Israel

[5] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel

[6] Univ Hosp Heidelberg, Ctr Child & Adolescent Med, Div Child Neurol & Metab Med, Heidelberg, Germany

[7] Tech Univ Munich, Inst Human Genet, Munich, Germany

[8] Univ Hosp LMU Munich, Inst Human Genet, Goethestr 29, Munich, Germany

[9] Cedars Sinai Med Ctr, Dept Pediat, Los Angeles, CA 90048 USA

[10] GeneDx, Gaithersburg, MD USA

[11] Great Ormond St Hosp Children NHS Fdn Trust, North East Thames Reg Genet Serv, London, England

[12] McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada

[13] Regeneron Genet Ctr, New York, NY USA

[14] Nationwide Childrens Hosp, Inst Genom Med, Columbus, OH USA

[15] Nationwide Childrens Hosp, Dept Pediat & Clin Genet, Columbus, OH USA

[16] Univ Calif Los Angeles, Dept Pediat, Dept Human Genet Div Med Genet, Los Angeles, CA 90024 USA

[17] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA

[18] Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA USA

[19] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA

[20] Univ Hosp Heidelberg, Dept Paediat, Div Paediat Endocrinol & Diabet, Heidelberg, Germany

[21] Broad Inst MIT & Harvard, Program Med & Populat Genet, Broad Ctr Mendelian Genom, Cambridge, MA 02142 USA

[22] Murdoch Childrens Res Inst, Victorian Clin Genet Serv, Melbourne, Vic, Australia

[23] Univ Melbourne, Dept Paediat, Melbourne, Vic, Australia

[24] Phoenix Childrens Hosp, Div Genet & Metab, Phoenix, AZ USA

[25] Univ Arizona, Coll Med, 475 N 5th St, Phoenix, AZ USA

[26] Ruth Rappaport Childrens Hosp, Pediat Endocrinol Unit, Rambam Healthcare Campus, Haifa, Israel

[27] Technion, Israel Inst Technol, Ruth & Bruce Rappaport Fac Med, Haifa, Israel

[28] Childrens Hosp Los Angeles, Dept Pathol, Los Angeles, CA 90027 USA

[29] Childrens Hosp Los Angeles, Dept Pediat, Los Angeles, CA 90027 USA

[30] Univ Southern Calif, Los Angeles, CA 90007 USA

[31] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[32] Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA

来源：

SCIENCE ADVANCES | 2021年 / 7卷 / 20期

关键词：

INTELLECTUAL DISABILITY SYNDROME; DE-NOVO MUTATIONS; GENOTYPE-PHENOTYPE; ISWI; COMPLEX; GENE; FAMILY; CONTAINS; DELETION; MEMBER;

D O I：

10.1126/sciadv.abf2066

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：13

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