TAR syndrome: Clinical and molecular characterization of a cohort of 26 patients and description of novel noncoding variants of RBM8A.

Simon Boussion, Fabienne Escande, Anne‐Sophie Jourdain, Thomas Smol, Perrine Brunelle, Céline Duhamel, Yves Alembik, Tania Attié‐Bitach, Geneviève Baujat, Anne Bazin, Maryse Bonnière, Philippe Carassou, Dominique Carles, Louise Devisme, Cyril Goizet, Alice Goldenberg, Sarah Grotto, Agnès Guichet, Pierre‐Simon Jouk, Laurence Loeuillet, Charlotte Mechler, Caroline Michot, Fanny Pelluard, Audrey Putoux, Sandra Whalen, Jamal Ghoumid, Sylvie Manouvrier‐Hanu, Florence Petit
Human Mutation. 2020-04-06; 41(7): 1220-1225
DOI: 10.1002/humu.24021

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1. Hum Mutat. 2020 Jul;41(7):1220-1225. doi: 10.1002/humu.24021. Epub 2020 Apr 6.

TAR syndrome: Clinical and molecular characterization of a cohort of 26 patients
and description of novel noncoding variants of RBM8A.

Boussion S(1)(2), Escande F(2)(3), Jourdain AS(2)(3), Smol T(2)(4), Brunelle
P(2)(3), Duhamel C(2), Alembik Y(5), Attié-Bitach T(6), Baujat G(7), Bazin A(8),
Bonnière M(6), Carassou P(9), Carles D(10), Devisme L(2)(11), Goizet C(12),
Goldenberg A(13), Grotto S(14), Guichet A(15), Jouk PS(16), Loeuillet L(17),
Mechler C(18), Michot C(7), Pelluard F(19), Putoux A(20)(21), Whalen S(22),
Ghoumid J(1)(2), Manouvrier-Hanu S(1)(2), Petit F(1)(2).

Author information:
(1)Clinical Genetics Department, Reference Center for Developmental Anomalies,
CHU Lille, Lille, France.
(2)EA7364-RADEME, Lille University, Lille, France.
(3)Biochemistry and Molecular Oncology Laboratory, CHU Lille, Lille, France.
(4)Medical Genetics Department, CHU Lille, Lille, France.
(5)Medical Genetics Department, CHU Strasbourg, Strasbourg, France.
(6)Histology, Embryology and Cytogenetics Department, Necker-Enfants Malades
Hospital, AP-HP, Paris, France.
(7)Clinical Genetics Department, Necker-Enfants Malades Hospital, AP-HP, INSERM
UMR, IMAGINE Institute, Paris, France.
(8)Antenatal Diagnosis Department, René Dubois Hospital, Pontoise, France.
(9)Hematology Department, CHR Metz-Thionville, Metz, France.
(10)Anatomo-Pathology Department, CHU Bordeaux, Bordeaux, France.
(11)Anatomo-Pathology Institute, CHU Lille, Lille, France.
(12)Medical Genetics Department, CHU Bordeaux, MRGM Laboratory, INSERM, Bordeaux
University, Bordeaux, France.
(13)Genetics Department, Reference Center for Developmental Anomalies, CHU Rouen,
Rouen, France.
(14)Genetics Department, Robert Debré Hospital, AP-HP, Paris, France.
(15)Genetics Department, CHU Angers, Angers, France.
(16)Genetics Department, CHU Grenoble-Alpes, Grenoble, France.
(17)Anatomo-Cytopathology Department, Cochin Hospital, AP-HP, Paris, France.
(18)Foetopathology Department, Robert Debré Hospital, AP-HP, Paris, France.
(19)INSERM U1053-UMR BaRITOn, Foetopathology Department, Pellegrin Hospital, CHU
Bordeaux, Bordeaux, France.
(20)Genetics Department, Hospices Civils de Lyon, Lyon, France.
(21)GENDEV Team, CRNL, INSERM U1028, CNRS UMR 5292, UCBL1, Lyon, France.
(22)Clinical Genetics, Reference Center for Developmental Anomalies, Armand
Trousseau Hospital, AP-HP, Paris, France.

Thrombocytopenia-absent radius (TAR) syndrome is characterized by radial defect
and neonatal thrombocytopenia. It is caused by biallelic variants of RBM8A gene
(1q21.1) with the association of a null allele and a hypomorphic noncoding
variant. RBM8A encodes Y14, a core protein of the exon junction complex involved
in messenger RNA maturation. To date, only two hypomorphic variants have been
identified. We report on a cohort of 26 patients affected with TAR syndrome and
carrying biallelic variants in RBM8A. Half patients carried a 1q21.1 deletion and
one of the two known hypomorphic variants. Four novel noncoding variants of RBM8A
were identified in the remaining patients. We developed experimental models
enabling their functional characterization in vitro. Two variants, located
respectively in the 5′-untranslated region (5′-UTR) and 3′-UTR regions, are
responsible for a diminished expression whereas two intronic variants alter
splicing. Our results bring new insights into the molecular knowledge of TAR
syndrome and enabled us to propose genetic counseling for patients’ families.

© 2020 Wiley Periodicals, Inc.

DOI: 10.1002/humu.24021
PMID: 32227665 [Indexed for MEDLINE]

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