Heterozygous loss-of-function SMC3 variants are associated with variable growth and developmental features

被引：2

作者：

Ansari, Morad ^{[1
,2
]}

Faour, Kamli N. W. ^{[3
,4
]}

Shimamura, Akiko ^{[5
]}

Grimes, Graeme ^{[2
]}

Kao, Emeline M. ^{[6
]}

Denhoff, Erica R. ^{[6
]}

Blatnik, Ana ^{[2
,7
]}

Ben-Isvy, Daniel ^{[8
,9
,10
]}

Wang, Lily ^{[8
,9
,10
]}

Helm, Benjamin M. ^{[11
]}

Firth, Helen ^{[12
]}

Breman, Amy M. ^{[11
]}

Bijlsma, Emilia K. ^{[13
]}

Iwata-Otsubo, Aiko ^{[11
]}

de Ravel, Thomy J. L. ^{[14
]}

Fusaro, Vincent ^{[15
]}

Fryer, Alan ^{[16
]}

Nykamp, Keith ^{[15
]}

Stuhn, Lara G. ^{[17
]}

Haack, Tobias B. ^{[17
]}

Korenke, G. Christoph ^{[18
]}

Constantinou, Panayioti ^{[19
]}

Bujakowksa, Kinga M. ^{[20
]}

Low, Karen J. ^{[21
,22
]}

Place, Emily ^{[20
]}

Humberson, Jennifer ^{[23
]}

Napier, Melanie P. ^{[24
]}

Hoffman, Jessica ^{[24
]}

Juusola, Jane ^{[24
]}

Deardorff, Matthew A. ^{[25
,26
,27
]}

Shao, Wanqing ^{[28
]}

Rockowitz, Shira ^{[3
,28
,29
]}

Krantz, Ian ^{[30
]}

Kaur, Maninder ^{[30
]}

Raible, Sarah ^{[30
]}

Dortenzio, Victoria ^{[30
]}

Kliesch, Sabine ^{[31
]}

Singer-Berk, Moriel ^{[9
]}

Groopman, Emily ^{[3
,9
]}

DiTroia, Stephanie ^{[9
]}

Ballal, Sonia ^{[4
,32
]}

Srivastava, Siddharth ^{[4
,33
]}

Rothfelder, Kathrin ^{[34
]}

Biskup, Saskia ^{[34
,35
]}

Rzasa, Jessica ^{[36
,37
]}

Kerkhof, Jennifer ^{[36
,37
]}

McConkey, Haley ^{[36
,37
]}

Sadikovic, Bekim ^{[36
,37
]}

Hilton, Sarah ^{[38
]}

Banka, Siddharth ^{[38
,39
]}

机构：

[1] Western Gen Hosp, South East Scotland Genet Serv, Edinburgh, Midlothian, Scotland

[2] Univ Edinburgh, Inst Genet & Canc, MRC, Human Genet Unit, Edinburgh, Midlothian, Scotland

[3] Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA

[4] Boston Childrens Hosp, Cornelia Lange Syndrome & Related Disorders Clin, Boston, MA 02115 USA

[5] Boston Childrens Hosp, Div Hematol & Oncol, Boston, MA USA

[6] Boston Childrens Hosp, Inst Centers Clin & Translat Res, Boston, MA USA

[7] Inst Oncol Ljubljana, Dept Clin Canc Genet, Ljubljana, Slovenia

[8] Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA

[9] Broad Inst MIT & Harvard, Med & Populat Genet, Cambridge, MA 02142 USA

[10] Harvard Med Sch, Div Med Sci, Boston, MA 02115 USA

[11] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA

[12] Cambridge Univ Hosp, Clin Genet, Addenbrookes Hosp, Cambridge, England

[13] Leiden Univ, Dept Clin Genet, Med Ctr, Leiden, Netherlands

[14] UZ Leuven, Leuven Univ Hosp, Ctr Human Genet, Leuven, Belgium

[15] Invitae, San Francisco, CA USA

[16] Alder Hey Childrens Hosp Liverpool, Dept Clin Genet, Liverpool, Merseyside, England

[17] Univ Tubingen, Inst Med Genet & Appl Genom, Tubingen, Germany

[18] Univ Childrens Hosp Oldenburg, Dept Neuropaediat & Metab Dis, Oldenburg, Germany

[19] Queen Elizabeth Univ Hosp, West Scotland Ctr Genom Med, Glasgow, Lanark, Scotland

[20] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA

[21] Univ Hosp Bristol & Weston NHS Fdn Trust, Bristol, Avon, England

[22] Univ Bristol, Bristol, Avon, England

[23] Univ Virginia Hlth Syst, Charlottesville, VA USA

[24] GeneDx, Gaithersburg, MD USA

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

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

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

[28] Boston Childrens Hosp, Res Comp, Informat Technol, Boston, MA USA

[29] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA USA

[30] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA

[31] Univ Hosp Munster, Ctr Reprod Med & Androl, Dept Clin & Surg Androl, Munster, Germany

[32] Boston Childrens Hosp, Div Gastroenterol, Boston, MA USA

[33] Boston Childrens Hosp, Div Neurol, Boston, MA USA

[34] Zentrum Humangenet, Tubingen, Germany

[35] Ctr Genom & Transcript CeGaT, Tubingen, Germany

[36] London Hlth Sci Ctr, Mol Diagnost Program, London, ON, Canada

[37] London Hlth Sci Ctr, Verspeeten Clin Genome Ctr, London, ON, Canada

[38] Manchester Univ NHS Fdn Trust, Manchester Ctr Genom Med, Hlth Innovat Manchester, Manchester, Lancs, England

[39] Univ Manchester, Fac Biol Med & Hlth, Sch Biol Sci, Div Evolut Infect & Genom, Manchester, Lancs, England

[40] Univ Munster, Inst Reprod Genet, Munster, Germany

[41] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Genet, Portland, OR 97201 USA

[42] Oregon Hlth & Sci Univ, Ctr Embryon Cell & Gene Therapy, Portland, OR 97201 USA

来源：

HUMAN GENETICS AND GENOMICS ADVANCES | 2024年 / 5卷 / 02期

基金：

英国医学研究理事会;

关键词：

DE-LANGE-SYNDROME; SISTER-CHROMATID COHESION; CORNELIA; MUTATIONS; PHENOTYPE; INDIVIDUALS; COMPLEX; ROLES; ACETYLATION; PENETRANCE;

D O I：

10.1016/j.xhgg.2024.100273

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Heterozygous missense variants and in-frame indels in SMC3 are a cause of Cornelia de Lange syndrome (CdLS), marked by intellectual disability, growth deficiency, and dysmorphism, via an apparent dominant-negative mechanism. However, the spectrum of manifestations associated with SMC3 loss-of-function variants has not been reported, leading to hypotheses of alternative phenotypes or even developmental lethality. We used matchmaking servers, patient registries, and other resources to identify individuals with heterozygous, predicted loss-of-function (pLoF) variants in SMC3, and analyzed population databases to characterize mutational intolerance in this gene. Here, we show that SMC3 behaves as an archetypal haploinsufficient gene: it is highly constrained against pLoF variants, strongly depleted for missense variants, and pLoF variants are associated with a range of developmental phenotypes. Among 14 individuals with SMC3 pLoF variants, phenotypes were variable but coalesced on low growth parameters, developmental delay/intellectual disability, and dysmorphism, reminiscent of atypical CdLS. Comparisons to individuals with SMC3 missense/in-frame indel variants demonstrated an overall milder presentation in pLoF carriers. Furthermore, several individuals harboring pLoF variants in SMC3 were nonpenetrant for growth, developmental, and/or dysmorphic features, and some had alternative symptomatologies with rational biological links to SMC3. Analyses of tumor and model system transcriptomic data and epigenetic data in a subset of cases suggest that SMC3 pLoF variants reduce SMC3 expression but do not strongly support clustering with functional genomic signatures of typical CdLS. Our finding of substantial population-scale LoF intolerance in concert with variable growth and developmental features in subjects with SMC3 pLoF variants expands the scope of cohesinopathies, informs on their allelic architecture, and suggests the existence of additional clearly LoF-constrained genes whose disease links will be confirmed only by multilayered genomic data paired with careful phenotyping.

引用

页数：18

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