Further clinical and molecular characterization of an XLID syndrome associated with BRWD3 variants, a gene implicated in the leukemia-related JAK-STAT pathway.
BRWD3
Intellectual disability
Macrocephaly
Obesity
Journal
European journal of medical genetics
ISSN: 1878-0849
Titre abrégé: Eur J Med Genet
Pays: Netherlands
ID NLM: 101247089
Informations de publication
Date de publication:
Jan 2023
Jan 2023
Historique:
received:
07
07
2022
revised:
13
10
2022
accepted:
11
11
2022
pubmed:
23
11
2022
medline:
22
12
2022
entrez:
22
11
2022
Statut:
ppublish
Résumé
Since the first description of a BRWD3-associated nonsydromic intellectual disability (ID) disorder in 2007, 21 additional families have been reported in the literature. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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
CONCLUSIONS
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.
Identifiants
pubmed: 36414205
pii: S1769-7212(22)00251-8
doi: 10.1016/j.ejmg.2022.104670
pii:
doi:
Substances chimiques
Janus Kinases
EC 2.7.10.2
STAT Transcription Factors
0
BRWD3 protein, human
0
Transcription Factors
0
Types de publication
Review
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
104670Informations de copyright
Copyright © 2022. Published by Elsevier Masson SAS.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare no conflict of interest.