Coffin-Siris syndrome and the BAF complex: genotype-phenotype study in 63 patients.
De novo germline variants in several components of the SWI/SNF-like BAF complex can cause Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NCBRS), and nonsyndromic intellectual disability. We screened 63 patients with a clinical diagnosis of CSS for these genes (ARID1A, ARID1B, SMARCA2, SMARCA4, SMARCB1, and SMARCE1) and identified pathogenic variants in 45 (71%) patients. We found a high proportion of variants in ARID1B (68%). All four pathogenic variants in ARID1A appeared to be mosaic. By using all variants from the Exome Variant Server as test data, we were able to classify variants in ARID1A, ARID1B, and SMARCB1 reliably as being pathogenic or nonpathogenic. For SMARCA2, SMARCA4, and SMARCE1 several variants in the EVS remained unclassified, underlining the importance of parental testing. We have entered all variant and clinical information in LOVD-powered databases to facilitate further genotype-phenotype correlations, as these will become increasingly important because of the uptake of targeted and untargeted next generation sequencing in diagnostics. The emerging phenotype-genotype correlation is that SMARCB1 patients have the most marked physical phenotype and severe cognitive and growth delay. The variability in phenotype seems most marked in ARID1A and ARID1B patients. Distal limbs anomalies are most marked in ARID1A patients and least in SMARCB1 patients. Numbers are small however, and larger series are needed to confirm this correlation.
Center for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
Gijs W E
GW
Santen
Emmelien
E
Aten
Anneke T
AT
Vulto-van Silfhout
Caroline
C
Pottinger
Bregje W M
BW
van Bon
Ivonne J H M
IJ
van Minderhout
Ronelle
R
Snowdowne
Christian A C
CA
van der Lans
Merel
M
Boogaard
Margot M L
MM
Linssen
Linda
L
Vijfhuizen
Michiel J R
MJ
van der Wielen
M J Ellen
MJ
Vollebregt
Martijn H
MH
Breuning
Marjolein
M
Kriek
Arie
A
van Haeringen
Johan T
JT
den Dunnen
Alexander
A
Hoischen
Jill
J
Clayton-Smith
Bert B A
BB
de Vries
Raoul C M
RC
Hennekam
Martine J
MJ
van Belzen
D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005091:Exons; D005145:Face / Q000002:abnormalities*; D019066:Facies; D023061:Gene Order; D056726:Genetic Association Studies; D006228:Hand Deformities, Congenital / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics*; D008844:Micrognathism / Q000175:diagnosis* / Q000235:genetics*; D046912:Multiprotein Complexes / Q000235:genetics*; D009333:Neck / Q000002:abnormalities*; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D000071796:SMARCB1 Protein; D014157:Transcription Factors / Q000235:genetics
C112476:ARID1A protein, human; C497837:ARID1B protein, human; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; C084011:SMARCA2 protein, human; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases
ARID1A; ARID1B; BAF; CSS; Coffin-Siris; NBS; Nicolaides-Baraitser; SMARCA2; SMARCA4; SMARCB1; SMARCE1; SWI/SNF; genotype-phenotype; mosaicism