Table 1 Disorders detectable by EpiSign v2.

From: Clinical epigenomics: genome-wide DNA methylation analysis for the diagnosis of Mendelian disorders

Disease/disorder

Causative gene(s)/region

New in EpiSign V2

Validation cohort positives

Clinical cohort positives

É‘-thalassemia/mental retardation X-linked syndrome (ATR-X)

ATRX (301404)

No

2

4

Autism, susceptibility to, 18 (AUT18)

CHD8 (610528)

Yes

6

3

BAFopathies: Coffin–Siris (CSS1–4, and 8) and Nicolaides–Baraitser (NCBRS) syndromes

ARID1B (135900), ARID1A (614607), SMARCB1 (614608), SMARCA4 (614609), SMARCC2 (618362), SMARCA2 (601358)

ARID1A, SMARCC2

28

10

Blepharophimosis intellectual disability syndrome, SMARCA2 type

SMARCA2 (OMIM not available, PMID: 32694869)

Yes

2

 

Börjeson–Forssman–Lehmann syndrome (BFLS)

PHF6 (301900)

Yes

1

 

Cerebellar ataxia, deafness, and narcolepsy, autosomal dominant (ADCADN)

DNMT1 (604121)

No

  

CHARGE syndrome

CHD7 (214800)

No

6

4

Cornelia de Lange syndrome (CdLS)

NIPBL (122470), RAD21 (614701), SMC3 (610759), SMC1A (300590)

No

11

6

Down syndrome

Trisomy 21 (190685)

No

1

 

Epileptic encephalopathy, childhood-onset (EEOC)

CHD2 (615369)

Yes

1

 

Floating Harbor syndrome (FLHS)

SRCAP (136140)

No

  

Genitopatellar syndrome (GTPTS) and Ohdo syndrome, SBBYSS variant (SBBYSS)

KAT6B (606170; 603736)

No

3

2

Helsmoortel–van der Aa syndrome (HVDAS)a

ADNP (615873)

No

9

2

Hunter–McAlpine syndrome (HMA)

Chr5q35-qter duplication (601379)

Yes

  

Immunodeficiency–centromeric instability–facial anomalies syndrome (ICF)b

DNMT3B (242860), CDCA7 (616910), ZBTB24 (614069), HELLS (616911)

Yes

  

Kabuki syndrome

KMT2D (147920), KDM6A (300867)

KDM6A

12

5

Kleefstra syndrome

EHMT1 (610253)

Yes

2

2

Koolen–de Vries syndrome (KDVS)

KANSL1 (610443)

Yes

5

 

Mental retardation, autosomal dominant 23 (MRD23)

SETD5 (615761)

Yes

4

 

Mental retardation, autosomal dominant 51 (MRD51)

KMT5B (617788)

Yes

  

Mental retardation, X-linked 93 (MRD93)

BRWD3 (300659)

Yes

1

1

Mental retardation, X-linked 97 (MRD97)

ZNF711 (300803)

Yes

 

1

Mental retardation, X-linked syndromic, Nascimento-type (MRXSN)

UBE2A (300860)

Yes

1

 

Mental retardation, X-linked, Snyder–Robinson type (MRXSSR)

SMS (309583)

Yes

 

1

Mental retardation, X-linked, syndromic, Claes–Jensen syndrome (MRXSCJ)

KDM5C (300534)

No

6

1

PCR2 complex (Weaver (WVS) and Cohen–Gibson (COGIS)

EZH2 (277590), EED (617561)

Yes

  

Rahman syndrome (RMNS)

HIST1H1E (617537)

Yes

  

Rubinstein–Taybi syndrome (RSTS)

CREBBP (180849), EP300 (613684)

Yes

2

3

SETD1B-related syndrome

SETD1B (619000)

Yes

 

1

Sotos syndrome

NSD1 (117500)

No

8

4

Tatton–Brown–Rahman syndrome (TBRS)

DNMT3A (615879)

Yes

1

1

Wiedemann–Steiner syndrome (WDSTS)

KMT2A (605130)

Yes

3

2

Williams–Beuren deletion syndrome (WBS) and Williams–Beuren regions duplication syndrome (Dup7)c

7q11.23 deletion (194050)/duplication (609757)

No

2

 

Wolf–Hirschhorn syndrome (WHS)

Chr4p16.13 deletion (194190)

Yes

  

Fragile X syndrome (FXS)

TNR/FMR1 (300624)

No

6

 

Mental retardation, FRA12A type

TNR/DIP2B (136630)

No

 

1

Angelman syndrome (AS)

ID/UBE3A (105830)

No

6

1

Prader–Willi syndrome

ID/15q11 (SNRPN, NDN) (176270)

No

3

 

Silver–Russell syndrome 1 (SRS1)

ID/11p15.5 (180860)

No

5

1

Beckwith–Wiedemann syndrome (BWS)

ID/11p15 (ICR1, KCNQ1OT1, CDKN1C) (130650)

No

4

 

Silver–Russell syndrome 2 (SRS2)

ID/7p11.2 (180860)

No

  

Temple syndrome

ID/14q32 (616222)

No

  

Kagami–Ogatta syndrome (KOS)

ID/14q32 (608149)

No

2

 
  1. OMIM number listed in parentheses adjacent to disorder name. The following list of genes have been classified as having reduced sensitivity and more moderate signatures based on signature strength, limited reference cohort size, or types of variants that have been tested: CHD8, PHF6, DNMT3B, CDCA7, ZBTB24, HELLS, SETD5, KMT5B, BRWD3, ZNF711, KAT6B, SMS, DNMT3A.
  2. ID imprinting disorder, TNR trinucleotide repeat disorder.
  3. aADNP has two distinct signatures depending on where in the gene the variant occurs. HVDAS_T signature includes variants that occupy the N- and C-terminus of the gene and HVDAS_C includes variants in the central region of the gene including the nuclear localization signal of the protein.
  4. bICF1 exhibits one signature while ICF 2, 3, and 4 exhibit a separate, common signature.
  5. cThese two deletion/duplication syndromes exhibit symmetrical increased/decreased DNA methylation signatures, respectively.
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