Coffin-Siris Syndrome Panel

Coffin-Siris syndrome (CSS) is a multi-systemic genetic disease characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and additional digits, variable developmental or cognitive delay/intellectual disability, distinctive facial features, hypotonia, hirsutism/hypertrichosis, and sparse scalp hair. Other variable findings include short stature, feeding difficulties, ophthalmologic abnormalities, cardiac anomalies and hearing loss (Schrier Vergano et al. 2021. PubMed ID: 23556151; Vergano and Deardorff. 2014. PubMed ID: 25169447).

To date, ~ 200 cases of molecularly confirmed CSS have been reported. The exact prevalence and incidence is not clear, but this disorder is probably underestimated as not all individuals may have come to medical attention. Molecular genetic testing is particularly useful to reach an accurate diagnosis (Schrier Vergano et al. 2021. PubMed ID: 23556151).

The majority of CSS is inherited in an autosomal dominant (AD) manner with high penetrance. Most patients reported to date have a de novo pathogenic variant. Pathogenic variants or genomic rearrangements in the following genes have been reported to be causative for CSS and other CSS-like conditions: ARID1A, ARID1B, ARID2, DPF2, PHF6, SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX4, and SOX11 (Santen et al. 2013. PubMed ID: 23929686; Kosho et al. 2014. PubMed ID: 25169878; Hempel et al. 2016. PubMed ID: 26543203; Vasileiou et al. 2018. PubMed ID: 29429572; Schrier Vergano et al. 2021. PubMed ID: 23556151). Most of these genes encode for subunit proteins of BAF complex, also known as the SWI/SNF complex, which is essential in chromatin remodeling (Watanabe et al. 2014. PubMed ID: 24788099; Vasko et al. 2021. PubMed ID: 34205270). Genotype-phenotype correlations have been observed in clinically diagnosed individuals with confirmed pathogenic variants in the above-mentioned genes (Schrier Vergano et al. 2021. PubMed ID: 23556151; Vasko et al. 2021. PubMed ID: 34205270).

Pathogenic variants in ARID1B are the most common cause of CSS, followed by variants in SMARCA4 (Wieczorek et al. 2013. PubMed ID: 23906836; Schrier Vergano et al. 2021. PubMed ID: 23556151; Vasko et al. 2021. PubMed ID: 34205270). Pathogenic variants in these genes include single nucleotide changes, small insertions/duplications, single or multiple exon deletions, as well as entire gene deletions (Human Gene Mutation Database). Pathogenic variants in SOX11 have also been reported to cause CSS. SOX11 is a transcription factor downstream of the BAF complex and plays an important role in neurogenesis during brain development (Tsurusaki et al. 2014. PubMed ID: 24886874; Hempel et al. 2016. PubMed ID: 26543203). Additionally, de novo missense variants in SOX4, another member of the family of SOX transcription factors, have been reported in individuals with clinical characteristics similar to CSS (Zawerton et al. 2019. PubMed ID: 30661772). 

Heterozygous pathogenic variants in SMARCA4 and SMARCB1 have also been reported to cause the rhabdoid tumor predisposition syndrome (Roberts and Biegel. 2009. PubMed ID: 19305156; Hasselblatt et al. 2011. PubMed ID: 21566516; Biegel et al. 2014. PubMed ID: 25169151). Heterozygous pathogenic variants in SMARCB1 cause schwannomatosis, a condition characterized by multiple cutaneous neurilemmomas and spinal schwannomas (Merker et al. 2012. PubMed ID: 22927469). Kidney malformations are more common in individuals with SMARCB1 and SMARCE1 variants (Vasko et al. 2021. PubMed ID: 34205270).

Pathogenic variants in PHF6 are mainly associated with X-linked Börjeson–Forssman–Lehmann syndrome, which is characterized by mild to moderately impaired intellectual disability, seizures, hypotonia, hypogonadism, obesity with marked gynecomastia, tapering fingers, and large, but not deformed, ears (Lower et al. 2002. PubMed ID: 12415272; Wieczorek et al. 2013. PubMed ID: 23906836; Schrier Vergano et al. 2021. PubMed ID: 23556151). In addition, relatively few cases have been reported to be associated with single exon or partial gene deletion involving the X-linked PHF6 gene (Di Donato et al. 2014. PubMed ID: 24380767; Zweier et al. 2013. PubMed ID: 24092917), and heterozygous missense or splicing variants in DPF2 (Vasileiou et al. 2018. PubMed ID: 29429572). 

Variants in SMARCA2 are mainly reported in patients with autosomal dominant Nicolaides-Baraitser syndrome characterized by sparse hair, distinctive facial morphology, distal-limb anomalies and intellectual disability, and most of these variants are de novo missense (Van Houdt et al. 2012. PubMed ID: 22366787).

See individual gene summaries for information about molecular biology of gene products and spectra of pathogenic variants.

This test is expected to detect causative variants in about 60% of patients with Coffin-Siris syndrome (Schrier Vergano et al. 2021. PubMed ID: 23556151).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).