JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome

Eline A. Verberne; Shuxiang Goh; Jade England; Manon van Ginkel; Louise Rafael-Croes; Saskia Maas; Abeltje Polstra; Yuri A. Zarate; Katherine A. Bosanko; Kieran B. Pechter; Emma Bedoukian; Kosuke Izumi; Ayeshah Chaudhry; Nathaniel H. Robin; Megan Boothe; Natalie C. Lippa; Vimla Aggarwal; Darryl C. De Vivo; Anna Lehman; Causes Study; Sylvia Stockler; Ange Line Bruel; Bertrand Isidor; Jennifer Lemons; David F. Rodriguez-Buritica; Christopher M. Richmond; Zornitza Stark; Pankaj B. Agrawal; R. Frank Kooy; Marije E.C. Meuwissen; David A. Koolen; Rolf Pfundt; Agne Lieden; Britt Marie Anderlid; Dagmar Glatz; Marcel M.A.M. Mannens; Madhura Bakshi; Frédérick A. Mallette; Mieke M. van Haelst; Philippe M. Campeau

doi:10.1038/s41436-020-00992-z

JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome

Eline A. Verberne
, Shuxiang Goh
, Jade England
, Manon van Ginkel
, Louise Rafael-Croes
, Saskia Maas
, Abeltje Polstra
, Yuri A. Zarate
, Katherine A. Bosanko
, Kieran B. Pechter
, Emma Bedoukian
, Kosuke Izumi
, Ayeshah Chaudhry
, Nathaniel H. Robin
, Megan Boothe
, Natalie C. Lippa
, Vimla Aggarwal
, Darryl C. De Vivo
, Anna Lehman
, Causes Study

Sylvia Stockler, Ange Line Bruel, Bertrand Isidor, Jennifer Lemons, David F. Rodriguez-Buritica, Christopher M. Richmond, Zornitza Stark, Pankaj B. Agrawal, R. Frank Kooy, Marije E.C. Meuwissen, David A. Koolen, Rolf Pfundt, Agne Lieden, Britt Marie Anderlid, Dagmar Glatz, Marcel M.A.M. Mannens, Madhura Bakshi, Frédérick A. Mallette, Mieke M. van Haelst, Philippe M. Campeau

Pediatrics

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

Purpose: JARID2, located on chromosome 6p22.3, is a regulator of histone methyltransferase complexes that is expressed in human neurons. So far, 13 individuals sharing clinical features including intellectual disability (ID) were reported with de novo heterozygous deletions in 6p22–p24 encompassing the full length JARID2 gene (OMIM 601594). However, all published individuals to date have a deletion of at least one other adjoining gene, making it difficult to determine if JARID2 is the critical gene responsible for the shared features. We aim to confirm JARID2 as a human disease gene and further elucidate the associated clinical phenotype. Methods: Chromosome microarray analysis, exome sequencing, and an online matching platform (GeneMatcher) were used to identify individuals with single-nucleotide variants or deletions involving JARID2. Results: We report 16 individuals in 15 families with a deletion or single-nucleotide variant in JARID2. Several of these variants are likely to result in haploinsufficiency due to nonsense-mediated messenger RNA (mRNA) decay. All individuals have developmental delay and/or ID and share some overlapping clinical characteristics such as facial features with those who have larger deletions involving JARID2. Conclusion: We report that JARID2 haploinsufficiency leads to a clinically distinct neurodevelopmental syndrome, thus establishing gene–disease validity for the purpose of diagnostic reporting.

Original language	English
Pages (from-to)	374-383
Number of pages	10
Journal	Genetics in Medicine
Volume	23
Issue number	2
DOIs	https://doi.org/10.1038/s41436-020-00992-z
State	Published - Feb 2021

Bibliographical note

Publisher Copyright:
© 2020, American College of Medical Genetics and Genomics.

Funding

We thank the families described in this study. Individual 12 was enrolled in the CAUSES Study; investigators include Shelin Adam, Christele Du Souich, Alison Elliott, Anna Lehman, Jill Mweni-fumbo, Tanya Nelson, Clara Van Karnebeek, and Jan Friedman; it is funded by Mining for Miracles, British Columbia Children’s Hospital Foundation (grant number F15-01355) and Genome British Columbia (grant number F16-02276). P.M.C. is supported by awards from the Canadian Institutes of Health Research and the Fonds de la Recherche du Quebec–Santé.

Funders	Funder number
Fonds de la Recherche du Quebec–Santé
Mining for Miracles
BC Children’s Hospital Foundation	F15-01355
Canadian Institutes of Health Research
Genome British Columbia	F16-02276

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

JARID2
developmental delay
intellectual disability
neurodevelopment

ASJC Scopus subject areas

Genetics(clinical)

Access to Document

10.1038/s41436-020-00992-z

Cite this

Verberne, E. A., Goh, S., England, J., van Ginkel, M., Rafael-Croes, L., Maas, S., Polstra, A., Zarate, Y. A., Bosanko, K. A., Pechter, K. B., Bedoukian, E., Izumi, K., Chaudhry, A., Robin, N. H., Boothe, M., Lippa, N. C., Aggarwal, V., De Vivo, D. C., Lehman, A., ... Campeau, P. M. (2021). JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome. Genetics in Medicine, 23(2), 374-383. https://doi.org/10.1038/s41436-020-00992-z

@article{1bb78bd76edd43eb84f7ddfbda684213,

title = "JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome",

abstract = "Purpose: JARID2, located on chromosome 6p22.3, is a regulator of histone methyltransferase complexes that is expressed in human neurons. So far, 13 individuals sharing clinical features including intellectual disability (ID) were reported with de novo heterozygous deletions in 6p22{\textendash}p24 encompassing the full length JARID2 gene (OMIM 601594). However, all published individuals to date have a deletion of at least one other adjoining gene, making it difficult to determine if JARID2 is the critical gene responsible for the shared features. We aim to confirm JARID2 as a human disease gene and further elucidate the associated clinical phenotype. Methods: Chromosome microarray analysis, exome sequencing, and an online matching platform (GeneMatcher) were used to identify individuals with single-nucleotide variants or deletions involving JARID2. Results: We report 16 individuals in 15 families with a deletion or single-nucleotide variant in JARID2. Several of these variants are likely to result in haploinsufficiency due to nonsense-mediated messenger RNA (mRNA) decay. All individuals have developmental delay and/or ID and share some overlapping clinical characteristics such as facial features with those who have larger deletions involving JARID2. Conclusion: We report that JARID2 haploinsufficiency leads to a clinically distinct neurodevelopmental syndrome, thus establishing gene{\textendash}disease validity for the purpose of diagnostic reporting.",

keywords = "JARID2, developmental delay, intellectual disability, neurodevelopment",

author = "Verberne, \{Eline A.\} and Shuxiang Goh and Jade England and \{van Ginkel\}, Manon and Louise Rafael-Croes and Saskia Maas and Abeltje Polstra and Zarate, \{Yuri A.\} and Bosanko, \{Katherine A.\} and Pechter, \{Kieran B.\} and Emma Bedoukian and Kosuke Izumi and Ayeshah Chaudhry and Robin, \{Nathaniel H.\} and Megan Boothe and Lippa, \{Natalie C.\} and Vimla Aggarwal and \{De Vivo\}, \{Darryl C.\} and Anna Lehman and Causes Study and Sylvia Stockler and Bruel, \{Ange Line\} and Bertrand Isidor and Jennifer Lemons and Rodriguez-Buritica, \{David F.\} and Richmond, \{Christopher M.\} and Zornitza Stark and Agrawal, \{Pankaj B.\} and Kooy, \{R. Frank\} and Meuwissen, \{Marije E.C.\} and Koolen, \{David A.\} and Rolf Pfundt and Agne Lieden and Anderlid, \{Britt Marie\} and Dagmar Glatz and Mannens, \{Marcel M.A.M.\} and Madhura Bakshi and Mallette, \{Fr{\'e}d{\'e}rick A.\} and \{van Haelst\}, \{Mieke M.\} and Campeau, \{Philippe M.\}",

note = "Publisher Copyright: {\textcopyright} 2020, American College of Medical Genetics and Genomics.",

year = "2021",

month = feb,

doi = "10.1038/s41436-020-00992-z",

language = "English",

volume = "23",

pages = "374--383",

number = "2",

}

Verberne, EA, Goh, S, England, J, van Ginkel, M, Rafael-Croes, L, Maas, S, Polstra, A, Zarate, YA, Bosanko, KA, Pechter, KB, Bedoukian, E, Izumi, K, Chaudhry, A, Robin, NH, Boothe, M, Lippa, NC, Aggarwal, V, De Vivo, DC, Lehman, A, Study, C, Stockler, S, Bruel, AL, Isidor, B, Lemons, J, Rodriguez-Buritica, DF, Richmond, CM, Stark, Z, Agrawal, PB, Kooy, RF, Meuwissen, MEC, Koolen, DA, Pfundt, R, Lieden, A, Anderlid, BM, Glatz, D, Mannens, MMAM, Bakshi, M, Mallette, FA, van Haelst, MM & Campeau, PM 2021, 'JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome', Genetics in Medicine, vol. 23, no. 2, pp. 374-383. https://doi.org/10.1038/s41436-020-00992-z

TY - JOUR

T1 - JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome

AU - Verberne, Eline A.

AU - Goh, Shuxiang

AU - England, Jade

AU - van Ginkel, Manon

AU - Rafael-Croes, Louise

AU - Maas, Saskia

AU - Polstra, Abeltje

AU - Zarate, Yuri A.

AU - Bosanko, Katherine A.

AU - Pechter, Kieran B.

AU - Bedoukian, Emma

AU - Izumi, Kosuke

AU - Chaudhry, Ayeshah

AU - Robin, Nathaniel H.

AU - Boothe, Megan

AU - Lippa, Natalie C.

AU - Aggarwal, Vimla

AU - De Vivo, Darryl C.

AU - Lehman, Anna

AU - Study, Causes

AU - Stockler, Sylvia

AU - Bruel, Ange Line

AU - Isidor, Bertrand

AU - Lemons, Jennifer

AU - Rodriguez-Buritica, David F.

AU - Richmond, Christopher M.

AU - Stark, Zornitza

AU - Agrawal, Pankaj B.

AU - Kooy, R. Frank

AU - Meuwissen, Marije E.C.

AU - Koolen, David A.

AU - Pfundt, Rolf

AU - Lieden, Agne

AU - Anderlid, Britt Marie

AU - Glatz, Dagmar

AU - Mannens, Marcel M.A.M.

AU - Bakshi, Madhura

AU - Mallette, Frédérick A.

AU - van Haelst, Mieke M.

AU - Campeau, Philippe M.

PY - 2021/2

Y1 - 2021/2

N2 - Purpose: JARID2, located on chromosome 6p22.3, is a regulator of histone methyltransferase complexes that is expressed in human neurons. So far, 13 individuals sharing clinical features including intellectual disability (ID) were reported with de novo heterozygous deletions in 6p22–p24 encompassing the full length JARID2 gene (OMIM 601594). However, all published individuals to date have a deletion of at least one other adjoining gene, making it difficult to determine if JARID2 is the critical gene responsible for the shared features. We aim to confirm JARID2 as a human disease gene and further elucidate the associated clinical phenotype. Methods: Chromosome microarray analysis, exome sequencing, and an online matching platform (GeneMatcher) were used to identify individuals with single-nucleotide variants or deletions involving JARID2. Results: We report 16 individuals in 15 families with a deletion or single-nucleotide variant in JARID2. Several of these variants are likely to result in haploinsufficiency due to nonsense-mediated messenger RNA (mRNA) decay. All individuals have developmental delay and/or ID and share some overlapping clinical characteristics such as facial features with those who have larger deletions involving JARID2. Conclusion: We report that JARID2 haploinsufficiency leads to a clinically distinct neurodevelopmental syndrome, thus establishing gene–disease validity for the purpose of diagnostic reporting.

AB - Purpose: JARID2, located on chromosome 6p22.3, is a regulator of histone methyltransferase complexes that is expressed in human neurons. So far, 13 individuals sharing clinical features including intellectual disability (ID) were reported with de novo heterozygous deletions in 6p22–p24 encompassing the full length JARID2 gene (OMIM 601594). However, all published individuals to date have a deletion of at least one other adjoining gene, making it difficult to determine if JARID2 is the critical gene responsible for the shared features. We aim to confirm JARID2 as a human disease gene and further elucidate the associated clinical phenotype. Methods: Chromosome microarray analysis, exome sequencing, and an online matching platform (GeneMatcher) were used to identify individuals with single-nucleotide variants or deletions involving JARID2. Results: We report 16 individuals in 15 families with a deletion or single-nucleotide variant in JARID2. Several of these variants are likely to result in haploinsufficiency due to nonsense-mediated messenger RNA (mRNA) decay. All individuals have developmental delay and/or ID and share some overlapping clinical characteristics such as facial features with those who have larger deletions involving JARID2. Conclusion: We report that JARID2 haploinsufficiency leads to a clinically distinct neurodevelopmental syndrome, thus establishing gene–disease validity for the purpose of diagnostic reporting.

KW - JARID2

KW - developmental delay

KW - intellectual disability

KW - neurodevelopment

UR - https://www.scopus.com/pages/publications/85092694932

UR - https://www.scopus.com/pages/publications/85092694932#tab=citedBy

U2 - 10.1038/s41436-020-00992-z

DO - 10.1038/s41436-020-00992-z

M3 - Article

C2 - 33077894

AN - SCOPUS:85092694932

SN - 1098-3600

VL - 23

SP - 374

EP - 383

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 2

ER -

JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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