TY - JOUR
T1 - Further clinical and molecular characterization of an XLID syndrome associated with BRWD3 variants, a gene implicated in the leukemia-related JAK-STAT pathway
AU - Delanne, Julian
AU - Lecat, Magaly
AU - Blackburn, Patrick R.
AU - Klee, Eric W.
AU - Stumpel, Constance T.R.M.
AU - Stegmann, Sander
AU - Stevens, Servi J.C.
AU - Nava, Caroline
AU - Heron, Delphine
AU - Keren, Boris
AU - Mahida, Sonal
AU - Naidu, Sakkubai
AU - Babovic-Vuksanovic, Dusica
AU - Herkert, Johanna C.
AU - Torring, Pernille M.
AU - Kibæk, Maria
AU - De Bie, Isabelle
AU - Pfundt, Rolph
AU - Hendriks, Yvonne M.C.
AU - Ousager, Lilian Bomme
AU - Bend, Renee
AU - Warren, Hannah
AU - Skinner, Steven A.
AU - Lyons, Michael J.
AU - Pöe, Charlotte
AU - Chevarin, Martin
AU - Jouan, Thibaud
AU - Garde, Aurore
AU - Thomas, Quentin
AU - Kuentz, Paul
AU - Tisserant, Emilie
AU - Duffourd, Yannis
AU - Philippe, Christophe
AU - Faivre, Laurence
AU - Thauvin-Robinet, Christel
N1 - 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.
Publisher Copyright:
© 2022
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
KW - BRWD3
KW - Intellectual disability
KW - Macrocephaly
KW - Obesity
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U2 - 10.1016/j.ejmg.2022.104670
DO - 10.1016/j.ejmg.2022.104670
M3 - Article
C2 - 36414205
AN - SCOPUS:85144054120
SN - 1769-7212
VL - 66
JO - European Journal of Medical Genetics
JF - European Journal of Medical Genetics
IS - 1
M1 - 104670
ER -