PURPOSE: 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. METHODS: 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. RESULTS: 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 nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification. CONCLUSION: We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.

• Klíčová slova
• BIS, Nicolaides–Baraitser syndrome, SMARCA2, intellectual disability, neurodevelopmental disorder,
• MeSH
• blefarofimóza * MeSH
• faciální stigmatizace MeSH
• fenotyp MeSH
• hypotrichóza * MeSH
• lidé MeSH
• mentální retardace * genetika   MeSH
• transkripční faktory genetika   MeSH
• vrozené deformity nohy (od hlezna dolů) MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• SMARCA2 protein, human MeSH Prohlížeč
• transkripční faktory MeSH

Lenz-Majewski syndrome (LMS) is a syndrome of intellectual disability and multiple congenital anomalies that features generalized craniotubular hyperostosis. By using whole-exome sequencing and selecting variants consistent with the predicted dominant de novo etiology of LMS, we identified causative heterozygous missense mutations in PTDSS1, which encodes phosphatidylserine synthase 1 (PSS1). PSS1 is one of two enzymes involved in the production of phosphatidylserine. Phosphatidylserine synthesis was increased in intact fibroblasts from affected individuals, and end-product inhibition of PSS1 by phosphatidylserine was markedly reduced. Therefore, these mutations cause a gain-of-function effect associated with regulatory dysfunction of PSS1. We have identified LMS as the first human disease, to our knowledge, caused by disrupted phosphatidylserine metabolism. Our results point to an unexplored link between phosphatidylserine synthesis and bone metabolism.

• MeSH
• dánio pruhované embryologie   genetika   MeSH
• dítě MeSH
• embryo nesavčí MeSH
• fibroblasty metabolismus   MeSH
• fosfatidylseriny biosyntéza   genetika   MeSH
• hyperostóza MeSH
• kultivované buňky MeSH
• lidé MeSH
• mladiství MeSH
• mnohočetné abnormality genetika   MeSH
• molekulární sekvence - údaje MeSH
• mutace * MeSH
• nanismus MeSH
• syndrom MeSH
• transferasy dusíkatých skupin genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• fosfatidylseriny MeSH
• phospholipid serine base exchange enzyme MeSH Prohlížeč
• transferasy dusíkatých skupin MeSH