De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome.

Genetics in Medicine : Official Journal of the American College of Medical Genetics
Gerarda CappuccioNicola Brunetti-Pierri

Abstract

Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown. By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes. Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecifi...Continue Reading

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Citations

Jan 28, 2021·International Journal of Molecular Sciences·Sadegheh HaghshenasCharles Schwartz
Dec 10, 2020·International Journal of Molecular Sciences·Sadegheh HaghshenasBekim Sadikovic
Feb 7, 2021·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Bekim SadikovicMarielle Alders
Jul 24, 2021·American Journal of Human Genetics·Eric Chater-DiehlRosanna Weksberg
Oct 16, 2021·American Journal of Medical Genetics. Part a·Eriko NishiNobuhiko Okamoto

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Methods Mentioned

BETA
exome sequencing
PCR
RNA-seq
methylation profiling

Software Mentioned

CAMERA

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