Further clinical and molecular characterization of an XLID syndrome associated with BRWD3 variants, a gene implicated in the leukemia-related JAK-STAT pathway

Julian Delanne*, Magaly Lecat, Patrick R. Blackburn, Eric W. Klee, Constance T.R.M. Stumpel, Sander Stegmann, Servi J.C. Stevens, Caroline Nava, Delphine Heron, Boris Keren, Sonal Mahida, Sakkubai Naidu, Dusica Babovic-Vuksanovic, Johanna C. Herkert, Pernille M. Torring, Maria Kibæk, Isabelle De Bie, Rolph Pfundt, Yvonne M.C. Hendriks, Lilian Bomme OusagerRenee Bend, Hannah Warren, Steven A. Skinner, Michael J. Lyons, Charlotte Pöe, Martin Chevarin, Thibaud Jouan, Aurore Garde, Quentin Thomas, Paul Kuentz, Emilie Tisserant, Yannis Duffourd, Christophe Philippe, Laurence Faivre, Christel Thauvin-Robinet

*Kontaktforfatter

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Abstract

Background: Since the first description of a BRWD3-associated nonsydromic intellectual disability (ID) disorder in 2007, 21 additional families have been reported in the literature. Methods: Using exome sequencing (ES) and international data sharing, we identified 14 additional unrelated individuals with pathogenic BRWD3 variants (12 males and 2 females, including one with skewed X-inactivation). We reviewed the 31 previously published cases in the literature with clinical data available, and describe the collective phenotypes of 43 males and 2 females, with 33 different BRWD3 variants. Results: The most common features in males (excluding one patient with a mosaic variant) included ID (39/39 males), speech delay (24/25 males), postnatal macrocephaly (28/35 males) with prominent forehead (18/25 males) and large ears (14/26 males), and obesity (12/27 males). Both females presented with macrocephaly, speech delay, and epilepsy, while epilepsy was only observed in 4/41 males. Among the 28 variants with available segregation reported, 19 were inherited from unaffected mothers and 9 were de novo. Conclusion: This study demonstrates that the BRWD3-related phenotypes are largely non-specific, leading to difficulty in clinical recognition of this disorder. A genotype-first approach, however, allows for the more efficient diagnosis of the BRWD3-related nonsyndromic ID. The refined clinical features presented here may provide additional diagnostic assistance for reverse phenotyping efforts.

OriginalsprogEngelsk
Artikelnummer104670
TidsskriftEuropean Journal of Medical Genetics
Vol/bind66
Udgave nummer1
Antal sider7
ISSN1769-7212
DOI
StatusUdgivet - jan. 2023

Bibliografisk note

Funding Information:
We thank the families for their participation. This work is supported by the European Union through the FEDER Bourgogne PERSONALISE 2019/2022 programs. Several authors are part of the ERN ITHACA. We thank Dr Mulhern and Mrs Lippa from the Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA for their participation to this study.

Funding Information:
We thank the families for their participation. This work is supported by the European Union through the FEDER Bourgogne PERSONALISE 2019/2022 programs. Several authors are part of the ERN ITHACA.

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