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

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

doi:10.1016/j.ejmg.2022.104670

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND: Since the first description of a BRWD3-related phenotype in 2007, 21 additional families have been reported with intellectual disability (ID).

METHODS: Using exome sequencing (ES) and international datasharing, we identified 14 new unrelated individuals with a pathogenic BRWD3 variant (12 males and 2 females one with skewed X-inactivation). Including the 31 previously individuals published in the literature with clinical data available, we describe the phenotype of 43 males and 2 females, with 32 different BRWD3 variants.

RESULTS: Most common features in males (excluding the one with the mosaic variant) include 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 present 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 phenotype could be non-specific, leading to difficulty in clinical recognition of this disorder. A genotype-first approach however allows the diagnosis of the BRWD3-related disorder. The refined clinical features presented here will prove useful for reverse phenotyping.

Original language	English
Article number	104670
Number of pages	7
Journal	European Journal of Medical Genetics
Volume	66
Issue number	1
Early online date	19 Nov 2022
DOIs	https://doi.org/10.1016/j.ejmg.2022.104670
Publication status	Published - Jan 2023

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Delanne, J., Lecat, M., Blackburn, P. R., Klee, E., Stumpel, C., 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., Kibæk, M., De Bie, I., Pfundt, R., Hendriks, Y. M. C., ... Thauvin-Robinet, C. (2023). Further clinical and molecular characterization of an XLID syndrome associated with BRWD3 variants, a gene implicated in the leukemia-related JAK-STAT pathway. European Journal of Medical Genetics, 66(1), Article 104670. https://doi.org/10.1016/j.ejmg.2022.104670

@article{919edaf391644919b5f028440befd19c,

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

abstract = "BACKGROUND: Since the first description of a BRWD3-related phenotype in 2007, 21 additional families have been reported with intellectual disability (ID).METHODS: Using exome sequencing (ES) and international datasharing, we identified 14 new unrelated individuals with a pathogenic BRWD3 variant (12 males and 2 females one with skewed X-inactivation). Including the 31 previously individuals published in the literature with clinical data available, we describe the phenotype of 43 males and 2 females, with 32 different BRWD3 variants.RESULTS: Most common features in males (excluding the one with the mosaic variant) include 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 present 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 phenotype could be non-specific, leading to difficulty in clinical recognition of this disorder. A genotype-first approach however allows the diagnosis of the BRWD3-related disorder. The refined clinical features presented here will prove useful for reverse phenotyping.",

author = "J Delanne and M Lecat and Blackburn, {P R} and E Klee and C Stumpel and S Stegmann and Stevens, {S J C} and C Nava and D Heron and B Keren and S Mahida and S Naidu and D Babovic-Vuksanovic and Herkert, {J C} and Torring, {P M} and M Kib{\ae}k and {De Bie}, I and R Pfundt and Hendriks, {Y M C} and Ousager, {L B} and R Bend and H Warren and S Skinner and M Lyons and C Poe and M Chevarin and T Jouan and A Garde and Q Thomas and P Kuentz and E Tisserant and Y Duffourd and C Philippe and L Faivre and C Thauvin-Robinet",

note = "Copyright {\textcopyright} 2022. Published by Elsevier Masson SAS.",

year = "2023",

month = jan,

doi = "10.1016/j.ejmg.2022.104670",

language = "English",

volume = "66",

journal = "European Journal of Medical Genetics",

issn = "1769-7212",

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Delanne, J, Lecat, M, Blackburn, PR, Klee, E, Stumpel, C, Stegmann, S , Stevens, SJC, Nava, C, Heron, D, Keren, B, Mahida, S, Naidu, S, Babovic-Vuksanovic, D, Herkert, JC, Torring, PM, Kibæk, M, De Bie, I, Pfundt, R, Hendriks, YMC, Ousager, LB, Bend, R, Warren, H, Skinner, S, Lyons, M, Poe, C, Chevarin, M, Jouan, T, Garde, A, Thomas, Q, Kuentz, P, Tisserant, E, Duffourd, Y, Philippe, C, Faivre, L & Thauvin-Robinet, C 2023, 'Further clinical and molecular characterization of an XLID syndrome associated with BRWD3 variants, a gene implicated in the leukemia-related JAK-STAT pathway', European Journal of Medical Genetics, vol. 66, no. 1, 104670. https://doi.org/10.1016/j.ejmg.2022.104670

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, J

AU - Lecat, M

AU - Blackburn, P R

AU - Klee, E

AU - Stumpel, C

AU - Stegmann, S

AU - Stevens, S J C

AU - Nava, C

AU - Heron, D

AU - Keren, B

AU - Mahida, S

AU - Naidu, S

AU - Babovic-Vuksanovic, D

AU - Herkert, J C

AU - Torring, P M

AU - Kibæk, M

AU - De Bie, I

AU - Pfundt, R

AU - Hendriks, Y M C

AU - Ousager, L B

AU - Bend, R

AU - Warren, H

AU - Skinner, S

AU - Lyons, M

AU - Poe, C

AU - Chevarin, M

AU - Jouan, T

AU - Garde, A

AU - Thomas, Q

AU - Kuentz, P

AU - Tisserant, E

AU - Duffourd, Y

AU - Philippe, C

AU - Faivre, L

AU - Thauvin-Robinet, C

PY - 2023/1

Y1 - 2023/1

N2 - BACKGROUND: Since the first description of a BRWD3-related phenotype in 2007, 21 additional families have been reported with intellectual disability (ID).METHODS: Using exome sequencing (ES) and international datasharing, we identified 14 new unrelated individuals with a pathogenic BRWD3 variant (12 males and 2 females one with skewed X-inactivation). Including the 31 previously individuals published in the literature with clinical data available, we describe the phenotype of 43 males and 2 females, with 32 different BRWD3 variants.RESULTS: Most common features in males (excluding the one with the mosaic variant) include 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 present 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 phenotype could be non-specific, leading to difficulty in clinical recognition of this disorder. A genotype-first approach however allows the diagnosis of the BRWD3-related disorder. The refined clinical features presented here will prove useful for reverse phenotyping.

AB - BACKGROUND: Since the first description of a BRWD3-related phenotype in 2007, 21 additional families have been reported with intellectual disability (ID).METHODS: Using exome sequencing (ES) and international datasharing, we identified 14 new unrelated individuals with a pathogenic BRWD3 variant (12 males and 2 females one with skewed X-inactivation). Including the 31 previously individuals published in the literature with clinical data available, we describe the phenotype of 43 males and 2 females, with 32 different BRWD3 variants.RESULTS: Most common features in males (excluding the one with the mosaic variant) include 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 present 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 phenotype could be non-specific, leading to difficulty in clinical recognition of this disorder. A genotype-first approach however allows the diagnosis of the BRWD3-related disorder. The refined clinical features presented here will prove useful for reverse phenotyping.

U2 - 10.1016/j.ejmg.2022.104670

DO - 10.1016/j.ejmg.2022.104670

M3 - Article

C2 - 36414205

SN - 1769-7212

VL - 66

JO - European Journal of Medical Genetics

JF - European Journal of Medical Genetics

IS - 1

M1 - 104670

ER -