Cornelia de Lange Syndrome and Related Disorders Panel

This panel includes genes currently known to be associated with Cornelia de Lange syndrome, Adams-Oliver syndrome, Coffin-Siris syndrome, CHARGE syndrome, Floating-Harbor syndrome, Rubinstein-Taybi syndrome, Roberts syndrome, FG Syndrome (also known as Opitz-Kaveggia Syndrome), Wiedemann-Steiner syndrome, KDM1A –related cleft palate, psychomotor retardation, and distinctive facial features, as well as intellectual disability related to CTCF, TAF1 and WDR26. For detailed clinical and genetic information, please see individual gene test descriptions on our website.

Cornelia de Lange syndrome (CdLS): NIPBL, SMC3, RAD21, KMT2A, AFF4 and ANKRD11-related CdLS are all inherited in autosomal dominant manner, while SMC1A and HDAC8-related CdLS are inherited in an X-linked manner. Intragenic NIPBL deletions and a duplication were identified in 13 (2.5%) out of 510 CdLS cases (12 deletions and 1 duplication) (Cheng et al. 2014. PubMed ID: 24689074). In one study, a de novo KMT2A pathogenic variant was found in one out of 32 Turkish patients clinically diagnosed with Cornelia de Lange syndrome (Yuan et al. 2015. PubMed ID: 25574841). In another study, de novo KMT2A pathogenic variants were found in five of the six Wiedemann-Steiner syndrome patients (Jones et al. 2012. PubMed ID: 22795537). A de novo nonsense NAA50 variant was reported in a patient with clinically suspected CdLS (Aoi et al. 2019. PubMed ID: 31337854). Large deletion/duplications account for ~30% of reported pathogenic variants in the ANKRD11 gene (Human Gene Mutation Database). Large deletions and duplications account for 11% of reported SMC1A pathogenic variants (Gilissen et al. 2014. PubMed ID: 24896178; Baquero-Montoya et al. 2014. PubMed ID: 23683030). Female carriers of SMC1A and HDAC8 pathogenic variants may show variable symptoms depending on random X-inactivation. TAF6 variants were reported to cause autosomal recessive CdLS.

Adams-Oliver syndrome: Pathogenic variants in ARHGAP31, DLL4, NOTCH1 and RBPJ cause autosomal dominant Adams-Oliver syndrome, while pathogenic variants in DOCK6 and EOGT cause autosomal recessive Adams-Oliver syndrome. Only 4 truncating ARHGAP31 pathogenic variants were reported to segregate with disease in four unrelated families (Southgate et al. 2011. PubMed ID: 21565291; Isrie et al. 2014. PubMed ID: 24668619, Human Gene Mutation Database). DLL4 pathogenic variants were found in 9 of 91 families with Adams-Oliver syndrome, one occurred de novo (Meester et al. 2015. PubMed ID: 26299364). NOTCH1 pathogenic variants explain ~17% of patients with Adams-Oliver syndrome (Southgate et al. 2015. PubMed ID: 25963545). There are almost 80 documented NOTCH1 pathogenic variants: missense ~55%, truncating ~ 26%, splicing ~11% and ~6% large deletion (Human Gene Mutation Database; Stittrich et al. 2014. PubMed ID: 25132448; Southgate et al. 2015. PubMed ID: 25963545). A large deletion involving NOTCH1 accounts for ~6% of documented NOTCH1 pathogenic variants (Human Gene Mutation Database; Stittrich et al. 2014. PubMed ID: 25132448; Southgate et al. 2015. PubMed ID: 25963545).Only two missense variants in RBPJ were reported to segregate with disease in two families with with Adams-Oliver syndrome (Hassed et al. 2012. PubMed ID: 22883147). DOCK6 and EOGT pathogenic variants were identified in 2 and 3 of 5 families with autosomal recessive Adams-Oliver syndrome, respectively (Shaheen et al. 2013. PubMed ID: 23522784).

CHARGE syndrome is autosomal dominant condition caused by pathogenic variants in the CHD7 gene. Large pathogenic CHD7 deletions have been reported in less than 5% of patients with a clinical diagnosis of CHARGE syndrome (Bergman et al. 2008. PubMed ID: 18472328; Wincent et al. 2009. PubMed ID: 19248844; Blake et al. 2011. PubMed ID: 21407266).

Coffin-Siris syndrome: ARID1A, ARID1B, SMARCA4, SMARCB1, SMARCE1, and SOX11 related Coffin-Siris syndrome are inherited in an autosomal dominant manner. PHF6 pathogenic variants mainly cause X-linked Börjeson-Forssman-Lehmann syndrome. Large deletions/duplications account for ~20% documented pathogenic variants in the ARID1B gene (Human Gene Mutation Database). For example, different sized heterozygous large de novo deletions involving ARID1B were reported in 7 patients with clinical features of corpus callosum defects, intellectual disability, speech impairment, and autism (Halgren et al. 2012. PubMed ID: 21801163). A few pathogenic variants in SMARCB1 were found in patients with Coffin-Siris syndrome (Santen et al. 2013. PubMed ID: 23929686). In one study, a large deletion involving SOX11 was reported in 7 of 10 studied Coffin–Siris syndrome patients (Hempel et al. 2016. PubMed ID: 26543203). Recently, two large deletions involving part or whole PHF6 were reported to be causative for X-linked Coffin-Siris syndrome.

KDM1A–related cleft palate, psychomotor retardation, and distinctive facial features is inherited in an autosomal dominant manner. Only 3 de novo missense KDM1A variants were reported in patients with severe non-syndromic sporadic intellectual disability (Rauch et al. 2012. PubMed ID: 23020937) or Kabuki syndrome-like phenotype (Tunovic et al. 2014. PubMed ID: 24838796). One large multiple gene deletion including part of KDM1A was reported in one patient with Li-Fraumeni syndrome with brain tumour (Aury-Landas et al. 2013. PubMed ID: 23612572).

Floating-Harbor syndrome is inherited in an autosomal dominant manner caused by pathogenic variants in the SRCAP gene. SRCAP truncating de novo variants were found in 6 out of 9 patients with Floating-Harbor syndrome (Le Goff et al. 2013. PubMed ID: 22965468).

Lujan syndrome (also known as Lujan-Fryns Syndrome) and FG syndrome Type 1 (also known as Opitz-Kaveggia Syndrome) and Ohdo syndrome, MKB type are inherited in an X-linked recessive manner and are caused by pathogenic variants in the MED12 gene. The majority of unique MED12 pathogenic variants were found in patients with intellectual disability. The MED12 (2881C>T, p.Arg961Trp) variant was found in 13% (6/45) of studied unrelated FG Syndrome families (Risheg et al. 2007. PubMed ID: 17334363). Almost all documented MED12 pathogenic variants are missense, except for one truncating. No Large deletion/duplications have been reported (Human Gene Mutation Database).

Roberts syndrome is inherited in autosomal recessive manner caused by pathogenic variants in the ESCO2 gene. In one study, pathogenic variants in the ESCO2 gene were found in all 17 Roberts syndrome patients who were from 16 unrelated families (Gordillo et al. 2008. PubMed ID: 18411254).

Rubinstein-Taybi syndrome is inherited in an autosomal dominant manner caused by pathogenic variants in the CREBBP and EP300 genes. 16p13.3 microdeletions (ranging from 3.3kb to 3900kb) involving CREBBP were found in 17 out of 83 patients with typical features of Rubinstein–Taybi syndrome using array CGH and quantitative multiplex fluorescent-PCR (Stef et al. 2007. PubMed ID: 17473832). One large deletion in EP300 was found in 1 of 33 Rubinstein-Taybi syndrome patients (Negri et al. 2015. PubMed ID: 24476420).

Wiedemann-Steiner syndrome is inherited in an autosomal dominant manner and caused by pathogenic variants in the KMT2A gene.

Pathogenic variants in TAF1 were mainly found in male patients with X-linked dysmorphic features, intellectual disability & neurological manifestations (O'Rawe et al. 2015. PubMed ID: 26637982). To date, more than 10 unique TAF1 pathogenic variants were reported; almost all of them are missense, except for one splicing, and 2 large duplications involving TAF1, de novo variants were found in ~50% of the studied patients/families (O'Rawe et al. 2015. PubMed ID: 26637982).

Pathogenic variants in CTCF cause autosomal dominant intellectual disability. So far only four de novo unique CTCF pathogenic variants were reported (1 missense, 2 truncating, and 1 large multiple gene deletion involving CTCF) (Gregor et al. 2013. PubMed ID: 23746550; Human Gene Mutation Database).

WDR26 was reported to be associated with autism spectrum disorder. So far, only three rare missense variants (2 of them are de novo) in the WDR26 gene were reported in two patients with Long QT syndrome (Shigemizu et al. 2015. PubMed ID: 26132555) and one patient with autism spectrum disorder (Wang et al. 2016. PubMed ID: 27824329).

Truncating variants in ASXL1 have been mainly reported in patients with autosomal dominant Bohring-Opitz syndrome (Hoischen et al. 2011. PubMed ID: 21706002; Human Gene Mutation Database). Only one de novo splicing ASXL1 variant has been reported in one patient with Cornelia de Lange syndrome (Yuan et al. 2019. PubMed ID: 30158690). Large deletions involving ASXL1 have been reported in patients with Facial dysmorphism with ridging of the metopic suture, developmental delay and short hands (Avila et al. 2013. PubMed ID: 23704076).

A few pathogenic variants in BRD4 have been reported in patients with Cornelia de Lange-like syndrome (Olley et al. 2018. PubMed ID: 29379197).

A few rare variants in EHMT1, ESPL1, KMT2A, PHIP, SETD5, ZMYND11 (Aoi et al. 2019. PubMed ID: 31337854), STAG1 (Yuan et al. 2019. PubMed ID: 30158690), and PDGFRB (Yavarna et al. 2015. PubMed ID: 26077850) were reported to be associated with clinically suspected Cornelia de Lange syndrome.

Deletion/duplications were reported in the ANKRD11, ARID1A, ARID1B, CHD7, CTCF, CREBBP, EP300, KDM1A, KMT2A, NIPBL, NOTCH1, PHF6, SMARCA4, SMARCE1, SMC1A, SOX11, SRCAP, and TAF1 genes.

No large deletion/duplications have been reported in the following genes: ARHGAP31, ESCO2, MED12, NAA50, RBPJ, and SMC3.

See individual gene test descriptions for detailed clinical information and molecular biology of gene products.

Over 70% of all Cornelia de Lange Syndrome (CdLS) patients harbor a pathogenic variant in NIPBL, SMC3, RAD21, SMC1A, or HDAC8 (Boyle et al. 2015. PubMed ID: 25209348). Only a few patients have been reported with pathogenic variants in AFF4, ANKRD11 and KMT2A. Most CdLS patients reported to date had a de novo pathogenic variant.

This test is expected to detect causative variants in about 60% of patients with Coffin-Siris Syndrome. Most of the patients had a de novo variant in one of the ARID1A, ARID1B, SMARCA4, SMARCB1, SMARCE1, and SOX11 genes (Vergano et al. 2018. PubMed ID: 23556151).

Pathogenic variants in CHD7 were detected in 65% -70% of patients with clinically diagnosed CHARGE syndrome, and most patients had a de novo CHD7 pathogenic variant (Lalani et al. 2012. PubMed ID: 20301296).

Sequence analysis can detect CREBBP pathogenic variants in 40%-50% of Rubinstein-Taybi syndrome cases. Pathogenic variants in EP300 are identified in 8%-10% of patients with Rubinstein–Taybi syndrome (Stevens. 2019. PubMed ID: 20301699).

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

This panel typically provides 99.8% 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).