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 - 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 -