EpiSign targeted

EpiSign Targeted is a targeted review of the methylation data intended to resolve variants of uncertain clinical significance in genes with a known epigenetic signature (see list below).
Pathogenic variants in these genes have an established unique signature. When present, this signature can be used to provide supporting evidence during variant classification of a VUS.

Episignatures:
Alpha-thalassemia mental retardation syndrome (ATRX)
Arboleda-Tham syndrome (KAT6A)
Autism, susceptibility to, 18 (CHD8)
BAFopathies: Coffin-Siris 1-4 & Nicolaides-Baraitser syndromes ¹ (BAFopathy) (ARID1B, ARID1A, SMARCB1, SMARCA4, SMARCA2)
Beck-Fahrner syndrome ^2,3 (TET3)
Blepharophimosis Intellectual disability SMARCA2 syndrome (SMARCA2)
Börjeson-Forssman-Lehmann syndrome (PHF6)
CHARGE syndrome (CHD7)
Chr1p36 deletion syndrome, distal (Chr1p36 deletion)
BAFopathies: Coffin-Siris syndrome 1 and 2 ⁴ (ARID1B, ARID1A)
Coffin-Siris syndrome-1 ⁵ (ARID1B)
Coffin-Siris syndrome-2 ⁵ (ARID1A)
Coffin-Siris syndrome-3 ⁵ (SMARCB1)
Coffin-Siris syndrome-4 ⁵ (SMARCA4)
Coffin-Siris syndrome-4 ⁶ (CSS4_c.2656) (SMARCA4)
Coffin-Siris syndrome-9 (SOX11)
Congenital Heart Defects, Dysmorphic Facial Features, and Intellectual Developmental Disorder (CDK13, CCNK)
Cornelia de Lange syndromes 1-4 ⁷ (NIPBL, SMC1A, SMC3, RAD21)
Down syndrome (Chr21 trisomy)
Dystonia 28 (KMT2B)
Epileptic encephalopathy, childhood-onset (CHD2)
Floating Harbour syndrome (SRCAP)
Gabriele-de Vries syndrome (YY1)
Genitopatellar syndrome (see also Ohdo syndrome) ⁸ (KAT6B)
Helsmoortel-van der Aa syndrome ⁹ (ADNP)
Hunter McAlpine craniosynostosis syndrome (Chr5q35-qter duplication)
Immunodeficiency-centromeric instabilityfacial anomalies syndromes 1-4 ¹⁰ (DNMT3B, CDCA7, ZBTB24, HELLS (242860, 614069, 616910, 616911)
Intellectual developmental disorder with seizures and language delay (SETD1B)
Intellectual developmental disorder, X-linked 93 ² (BRWD3)
Intellectual developmental disorder, X-linked 97 (ZNF711)
Intellectual developmental disorder, X-linked, syndromic, Armfield type (FAM50A)
Intellectual developmental disorder, X-linked, syndromic, Claes-Jensen type ^2,11 (KDM5C)
Intellectual developmental disorder, X-linked syndromic, Nascimento-type ¹² (UBE2A)
Intellectual developmental disorder, X-linked, Snyder-Robinson type (SMS)
Kabuki syndrome 1 and 2 (KMT2D, KDM6A)
Kabuki syndrome 1 ¹³ (KMT2D)
Kabuki syndrome 2 ¹³ (KDM6A)
KBG Syndrome ¹⁴ (ANKRD11)
KDM2B-related syndrome (KDM2B)
Kleefstra syndrome 1 (EHMT1)
Klinefelter Syndrome (XXY)
Koolen de Vreis syndrome (KANSL1)
Luscan-Lumish syndrome (SETD2)
Menke-Hennekam syndrome 1 and 2 ¹⁵ (CREBBP, EP300) ID4 domains
Mental retardation, autosomal dominant 23 ¹⁴ (SETD5)
Mental retardation, autosomal dominant 51 ² (KMT5B)
Nicolaides-Baraitser syndrome ⁵ (SMARCA2)
Ohdo syndrome, SBBYSS variant (see also Genitopatellar syndrome) ⁸ (KAT6B)
Phelan-McDermid syndrome ¹⁶ (Chr22q13.3 deletion)
Potocki-Lupski syndrome (Chr17p11.2 duplication)
PRC2 Complex (Weaver syndrome and Cohen-Gibson syndrome) ¹⁷ (EED, EZH2)
Rahman syndrome (HIST1H1E)
Renpenning syndrome (PQBP1)
Rubinstein-Taybi syndrome 1 and 2 (CREBBP, EP300)
Rubinstein-Taybi syndrome 1 ¹⁸ (CREBBP)
Rubinstein-Taybi syndrome 2 ¹⁸ (EP300)
Sifrim-Hitz-Weiss yndrome (CHD4)
SLC32A1 related disorder (SLC32A1)
Smith-Magenis syndrome ¹⁹ (Chr17p11.2 deletion)
Sotos syndrome 1 (NSD1)
Tatton-Brown-Rahman syndrome (DNMT3A)
Velocardiofacial syndrome (Chr22q11.2 deletion)
White-Sutton syndrome (POGZ)
Wieacker-Wolff Syndrome (ZC4H2)
Wiedemann-Steiner syndrome (KMT2A)
Williams-Beuren syndrome (Chr7q11.23 deletion)
Williams-Beuren region duplication syndrome (Chr7q11.23 duplication)
Witteveen-Kolk syndrome (SIN3A)
Wolf-Hirschhorn syndrome ²⁰ (Chr4p16.13 deletion, NSD2)

^1. Patients with other BAFopathy genes may be detected, but not confirmed in our experiments.
^2. Healthy carriers and those with incomplete penetrance are detectable.
^3. Patients with biallelic variants are distinguishable from those with monoallelic variants.
^4. Only for variants near c.6200. No separate episignature due small cohort size, however these samples cluster separately from other BAFopathy/CSS1&2 samples.
^5. This is a secondary signature; sample must also be positive for BAFopathy signature.
^6. Only for variants at c.2656. No separate episignature due small cohort size however these samples cluster separately from other BAFopathy/CSS4 samples.
^7. Male CdLS5 patients (HDAC8 mutations) may be detected, but not confirmed in our experiments.
^8. GTPTS and SBBYSS are both caused by KAT6B mutations. We will report both regardless of which one is requested.
^9. ADNP consists of two distinct episignatures dependent on variant location. HVDAS_T includes variants within the N- and C-terminus while HVDAS_C includes variants within the central region (approximately c.2054-2340).
^10. ICF1 exhibits a unique episignature while ICF 2, 3 and 4 exhibit a distinct, shared episignature.
^11. Heterozygotes have a distinct profile from hemizygotes
^12. Carriers have not been detected in our experiments.
^13. This is a secondary signature; sample must also be positive for combined Kabuki signature.
^14. KBGS and MRD23 share a common episignature. Separate KGBS and MRD23 episignatures will be used as secondary signatures, with sample positivity for the combined KBGS/MRD23 episignature required.
^15. Only for domain ID4. MKHK1/2 exhibit a shared ID4 domain episignature and therefore cannot distinguish between MKHK1 and MKHK2. Other domains of MKHK1/2 are not available for assessment.
^16. Only for copy number variants. Sequence variants in SHANK3 have been shown to not match the episignature.
^17. Shared episignatures between PRC2 complex syndromes WVS and COGIS.
^18. This is secondary signature; sample must also be positive for combined RSTS signature.
¹⁹. Only for copy number variants. Sequence variants in RAI1 have been shown to not match the episignature.
^20. WHS episignature can detect truncating variants in NSD2.

The following list of genes have been classified as having reduced sensitivity and more moderate episignatures based on
episignature strength, limited reference cohort size, or types of mutations that have been tested: ANKRD11, BRWD3,
CCNK, CDCA7, CDK13, CHD8, DNMT1, DNMT3A, DNMT3B, FAM50A, HELLS, KAT6A, KAT6B, KMT5B, PHF6, PQBP1, SETD5,
SIN3A, SLC32A1, SOX11, SMS, UBE2A, YY1, ZBTB24, ZC4H2, ZNF711, Chr1p36del, Chr17p11.2dup.

Pheripheral blood collected in an EDTA (lavender top) tube is the required specimen type. See Conditions application Genome Diagnostics.

Extracted DNA or banked is also accepted for this test given the original specimen was whole blood collected in an EDTA tube, minumun required amount 5 ug.

The sample should be stored at room temperature and shipped overnight.

If shipment is delayed by one or two days, the specimen should be refrigerated and shipped at room temperature.

Do not freeze the specimen. Samples collected on Friday can be safely designated for Monday delivery.