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

Delanne, J.; Lecat, M.; Blackburn, P.R.; Klee, E.W.; Stumpel, C.T.R.M.; Stegmann, S.; Stevens, S.J.C.; Nava, C.; Heron, D.; Keren, B.; Mahida, S.; Naidu, S.; Babovic-Vuksanovic, D.; Herkert, J.C.; Torring, P.M.; Kibaek, M.; Bie, I. de; Pfundt, R.; Hendriks, Y.M.C.; Ousager, L.B.; Bend, R.; Warren, H.; Skinner, S.A.; Lyons, M.J.; Poe, C.; Chevarin, M.; Jouan, T.; Garde, A.; Thomas, Q.; Kuentz, P.; Tisserant, E.; Duffourd, Y.; Philippe, C.; Faivre, L.; Thauvin-Robinet, C.

doi:doi:10.1016/j.ejmg.2022.104670

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 -inactiva-tion). 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...Show moreBackground: 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 -inactiva-tion). 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 effi-cient diagnosis of the BRWD3-related nonsyndromic ID. The refined clinical features presented here may provide additional diagnostic assistance for reverse phenotyping efforts.Show less

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