Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

被引：14

作者：

Schirwani, Schaida ^{[1
,2
]}

Albaba, Shadi ^{[3
]}

Carere, Deanna Alexis ^{[4
]}

Guillen Sacoto, Maria J. ^{[4
]}

Milan Zamora, Francisca ^{[4
]}

Si, Yue ^{[4
]}

Rabin, Rachel ^{[5
]}

Pappas, John ^{[5
]}

Renaud, Deborah L. ^{[6
,7
]}

Hauser, Natalie ^{[8
]}

Reid, Evan ^{[9
]}

Blanchet, Patricia ^{[10
]}

Foulds, Nichola ^{[11
,12
]}

Dixit, Abhijit ^{[13
]}

Fisher, Richard ^{[14
]}

Armstrong, Ruth ^{[15
,16
]}

Isidor, Bertrand ^{[17
]}

Cogne, Benjamin ^{[17
]}

Schrier Vergano, Samantha ^{[18
]}

Demirdas, Serwet ^{[19
]}

Dykzeul, Natalie ^{[20
]}

Cohen, Julie S. ^{[21
,22
]}

Grand, Katheryn ^{[23
]}

Morel, Dayna ^{[24
]}

Slavotinek, Anne ^{[25
]}

Albassam, Hessa F. ^{[26
]}

Naik, Swati ^{[27
]}

Dean, John ^{[28
]}

Ragge, Nicola ^{[27
]}

Cinzia, Costa ^{[29
]}

Tedesco, Maria Giovanna ^{[30
,31
]}

Harrison, Rachel E. ^{[13
]}

Bouman, Arjan ^{[19
]}

Palen, Emily ^{[32
]}

Challman, Thomas D. ^{[32
]}

Willemsen, Marjolein H. ^{[33
]}

Vogt, Julie ^{[27
]}

Cunniff, Christopher ^{[34
]}

Bergstrom, Katherine ^{[34
]}

Walia, Jagdeep S. ^{[35
]}

Bruel, Ange-Line ^{[36
]}

Kini, Usha ^{[37
]}

Alkuraya, Fowzan S. ^{[38
]}

Slegesky, Valerie ^{[39
,40
]}

Meeks, Naomi ^{[39
,40
]}

Girotto, Paula ^{[41
]}

Johnson, Diana ^{[1
,42
]}

Newbury-Ecob, Ruth ^{[44
]}

Ockeloen, Charlotte W. ^{[33
]}

机构：

[1] Sheffield Childrens NHS Fdn Trust, Sheffield Clin Genet Serv, Sheffield, S Yorkshire, England

[2] Univ Sheffield, Acad Unit Child Hlth, Dept Oncol & Metab, Sheffield, S Yorkshire, England

[3] Sheffield Childrens NHS Fdn Trust, Sheffield Diagnost Genet Serv, Sheffield, S Yorkshire, England

[4] GeneDx Inc, Gaithersburg, MD USA

[5] NYU, Sch Med, Dept Pediat, New York, NY USA

[6] Mayo Clin, Dept Neurol, Div Child & Adolescent Neurol, Rochester, MN USA

[7] Mayo Clin, Dept Pediat, Div Child & Adolescent Neurol, Rochester, MN USA

[8] Inova Hlth Syst, Dept Pediat, Div Genom Med, Falls Church, VA USA

[9] Univ Cambridge, Cambridge Inst Med Res, Dept Med Genet, Cambridge, England

[10] CHU Montpellier, Dept Genet Med, Montpellier, France

[11] Univ Hosp Southampton NHS Fdn Trust, Wessex Clin Genet Serv, Southampton, Hants, England

[12] Univ Southampton, Fac Med, Southampton, Hants, England

[13] Nottingham Univ Hosp NHS Trust, Clin Genet Serv, Nottingham, England

[14] James Cook Univ Hosp, Teesside Genet Unit, Middlesbrough, Cleveland, England

[15] Cambridge Univ Hosp NHS Fdn Trust, Dept Med Genet, Cambridge, England

[16] Cambridge Univ Hosp NHS Fdn Trust, Dept Paediat Neurol, Cambridge, England

[17] CHU Nantes, Serv Genet Med, Nantes, France

[18] Eastern Virginia Med Sch, Childrens Hosp Kings Daughters, Med Genet & Metab, Norfolk, VA 23501 USA

[19] Erasmus MC, Univ Med Ctr, Dept Clin Genet, Rotterdam, Netherlands

[20] Lucile Packard Childrens Hosp, Stanford Childrens Hlth, Palo Alto, CA USA

[21] Kennedy Krieger Inst, Div Neurogenet, Baltimore, MD USA

[22] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA

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

[24] Univ Miami, Miller Sch Med, Miami, FL 33136 USA

[25] Univ Calif San Francisco, Dept Pediat, Div Genet, San Francisco, CA 94143 USA

[26] Care Natl Hosp, Dept Pediat, Riyadh, Saudi Arabia

[27] Birmingham Womens & Childrens Hosp, West Midlands Reg Genet Serv, Birmingham, W Midlands, England

[28] Aberdeen Royal Infirm, Clin Genet Serv, NHS Grampian, Aberdeen, Scotland

[29] Univ Perugia, Santa Maria Misericordia Hosp, Dept Med, Neurol Clin, Perugia, Italy

[30] Univ Perugia, Santa Maria Misericordia Hosp, Med Genet Unit, Perugia, Italy

[31] Mauro Baschirotto Inst Rare Dis BIRD, Genet Unit, Costozza Longare, Vicenza, Italy

[32] Geisinger, Autism & Dev Med Inst, Danville, PA USA

[33] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands

[34] Weill Cornell Med Coll, Dept Pediat, Div Med Genet, New York, NY USA

[35] Queens Univ, Dept Pediat, Div Med Genet, Kingston, ON, Canada

[36] Univ Bourgogne, GAD Genet Anomalies Dev, UFR Sci Sante, INSERM,FHU,TRANSLAD,UMR1231, Dijon, France

[37] Oxford Univ Hosp NHS Trust, Dept Clin Genet, Oxford, England

[38] King Faisal Specialist Hosp & Res Ctr, Ctr Genom Med, Dept Translat Genom, Riyadh, Saudi Arabia

[39] Univ Colorado, Denver, CO 80202 USA

[40] Childrens Hosp Colorado, Denver, CO USA

[41] Santa Casa Sao Paulo Sch Med Sci, Dept Pediat, Div Child Neurol, Sao Paulo, Brazil

[42] Sheffield Childrens NHS Fdn Trust, EDS Natl Diagnost Serv, Sheffield, S Yorkshire, England

[43] Welcome Trust Sanger Inst, Cambridge, England

[44] St Michaels Hosp, Bristol Reg Genet Serv, Bristol, Avon, England

[45] Temple St Childrens Hosp, Dept Clin Genet, Dublin, Ireland

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

[47] Univ Calif Los Angeles, David Geffen Sch Med, Harbor UCLA Med Ctr, Cedars Sinai Med Ctr, Los Angeles, CA 90095 USA

来源：

AMERICAN JOURNAL OF MEDICAL GENETICS PART A | 2021年 / 185卷 / 11期

关键词：

ASXL3; ASXL3-related syndrome; Bainbridge-Ropers syndrome; BRPS; intellectual disability; speech impairment; MUTATION; DISORDERS; EPILEPSY;

D O I：

10.1002/ajmg.a.62465

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.

引用

页码：3446 / 3458

页数：13

共 6 条

[1] ASXL3 De Novo Variant-Related Neurodevelopmental Disorder Presenting as Dystonic Cerebral Palsy
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NEUROPEDIATRICS, 2022, 53 (05) : 361 - 365
[2] Four heterozygous de novo variants in ASXL3 identified with Bainbridge-Ropers syndrome and further dissecting published genotype-phenotype spectrum
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FRONTIERS IN NEUROSCIENCE, 2024, 18
[3] Mosaicism in ASXL3-related syndrome: Description of five patients from three families
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EUROPEAN JOURNAL OF MEDICAL GENETICS, 2020, 63 (06)
[4] De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome
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Donna M Muzny
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Genome Medicine, 5
[5] Further expanding the clinical phenotype in Bainbridge-Ropers syndrome and dissecting genotype-phenotype correlation in the ASXL3 mutational cluster regions
Yu, Kris Pui-Tak
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EUROPEAN JOURNAL OF MEDICAL GENETICS, 2021, 64 (01)
[6] De novo nonsense variant in ASXL3 in a Chinese girl causing Bainbridge-Ropers syndrome: A case report and review of literature
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MOLECULAR GENETICS & GENOMIC MEDICINE, 2022, 10 (05):

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