See Table A. Genes and Databases for chromosome locus and protein.

The estimated frequencies represent a compilation of unique cases in reports of cohorts of clinically ascertained individuals with CSS [Tsurusaki et al 2012, Santen et al 2013, Wieczorek et al 2013, Tsurusaki et al 2014b] except as indicated with a footnote.

See Molecular Genetics for information on allelic variants detected in these genes.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Mosaic pathogenic variants have been noted for ARID1A [Santen et al 2013, Wieczorek et al 2013].

No data on detection rate of gene-targeted deletion/duplication analysis are available.

Small deletions of chromosome 6q25.3 that include ARID1B have been reported in: (a) children with CSS ascertained prior to the understanding of the molecular basis of CSS [Tsurusaki et al 2012]; (b) children ascertained with a small deletion containing ARID1B and secondarily noted to have features similar to CSS [Santen et al 2012]; and (c) individuals with mildly or variably syndromic intellectual disability [Nagamani et al 2009, Halgren et al 2012, Hoyer et al 2012, Michelson et al 2012] for whom available clinical information is insufficient to determine the similarity to CSS. Of note, these individuals may have complex clinical findings due to the involvement of additional genes surrounding the ARID1B locus.

Only seven individuals with pathogenic variants in this gene have been reported [Gazdagh et al 2019].

Fewer than ten affected individuals have been identified with mutation in this gene [Milone et al 2020].

Individuals initially ascertained with CSS when younger have been found to have pathogenic variants in PHF6. Most of these have acquired facial features more consistent with Borjeson-Forssman-Lehmann syndrome as they age [Wieczorek et al 2013]. See Differential Diagnosis.

Only two affected individuals with a CCS phenotype have been reported to have mutation in this gene [Wieczorek et al 2013].

Reevaluation of an individual initially thought to have CSS concluded that findings were more consistent with Nicolaides-Baraitser syndrome [Tsurusaki et al 2012, Van Houdt et al 2012]; however, since a number of individuals with SMARCA2 pathogenic variants were initially ascertained with CSS, the authors have included them. See Differential Diagnosis.

Evidence indicates that pathogenic variants in SMARCA4, SMARCB1, and SMARCE1 act through a gain-of-function mechanism, suggesting that large pathogenic deletions or duplications are unlikely to occur; however, in-frame deletions or duplications of relevant domains may be pathogenic; one such deletion in SMARCA4 has been reported (see Molecular Genetics).

Approximately 15 individuals have been found to have mutation of this gene and features that could be consistent with CSS; however, only four had classic features [Machol et al 2019].

Only four individuals with a CCS phenotype have been reported to have mutation in this gene [Zawerton et al 2019].

Tsurusaki et al [2014a]

Tsurusaki et al [2014a], Hempel et al [2016]

Hempel et al [2016]

Approximately 40% of individuals with CSS did not have a pathogenic variant in one of the known genes [Tsurusaki et al 2012, Santen et al 2013, Wieczorek et al 2013, Tsurusaki et al 2014b].