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. 2020 Mar 26;11(4):355. doi: 10.3390/genes11040355

Table 1.

Description of DNA methylation abnormalities in mono/oligogenic diseases.

Disease (OMIM) Chromosome DNA Methylation Defects Frequency of Methylation Defects Associated Genetic Defects Mosaicism Recurrence Risk Methods Refs.
Fragile X syndrome (300624) Xq27.3 FMR1 GOM 100% Expansion of CGG repeat (>200) in the FMR1 5′-UTR Yes 50% for PM and FM mothers MS-MLPA [16,17,18,19,20,21,22,23,24,25]
Claes–Jensen syndrome (300534) Multiple chromosomes LOM of 1769 CpGs
(9 regions)		 100% KDM5C variants Yes 50% from female carriers to sons Illumina Infinium BeadChip [15,26,27,28,29]
Sotos syndrome (117550) Multiple chromosomes LOM of >7000 CpGs
(1300 regions)		 100% NSD1 variants Yes 50% Illumina Infinium BeadChip [15,29,30,31]
Kabuki syndrome (147920, 300867) Multiple chromosomes LOM of 856 CpGs, GOM of 648 CpGs 100% KMT2D and KDM6A variants Yes 50% Illumina Infinium BeadChip [15,29,32,33]
CHARGE syndrome (214800) Multiple chromosomes 1320 CpGs 100% CHD7 variants Yes 50% Illumina Infinium BeadChip [15,29,33]
Alpha thalassemia/mental retardation X-linked syndrome (301040) Multiple chromosomes 1112 CpGs
GOM of 11 regions
LOM of 5 regions		 100% ATRX variants Yes 50% from female carriers to sons Illumina Infinium BeadChip [15,29,34]
Floating–Harbor syndrome (136140) Multiple chromosomes 1078 CpGs
GOM of 19 regions
LOM of 9 regions		 100% SRCAP variants Yes 50% in dominant cases Illumina Infinium BeadChip [15,29,35]
BAFopathies (Coffin–Siris (135900, 614608, 614609), Nicolaides–Baraitser (601358) and 6q25 microdeletion (612863) syndromes) Multiple chromosomes 135–146 CpGs
(20–30 regions)		 100% ARID1B, SMARCB1, SMARCA4, SMARCA2 variants, ARID1B deletions Yes 50% Illumina Infinium BeadChip [15,36]
ADNP syndrome (615873) Multiple chromosomes LOM of ~6000 CpGs
GOM of ~1000 CpGs		 100% ADNP variants Yes 50% Illumina Infinium BeadChip [37]
Autosomal dominant cerebellar ataxia with deafness and narcolepsy (604121) Multiple chromosomes 3562 CpGs (mostly LOM)
GOM of 82 regions		 100% DNMT1 variants Yes 50% Illumina Infinium BeadChip [15,29,38]
Hereditary sensory and autonomic neuropathy type 1 with dementia and hearing loss (614116) Multiple chromosomes LOM of 5649 regions
GOM of 1872 regions		 100% DNMT1 variants Yes 50% Illumina Infinium BeadChip [39]
Tatton-Brown–Rahman syndrome (615879) Multiple chromosomes LOM of 388 regions
GOM of 1 region		 100% DNMT3A variants Yes 50% Illumina Infinium BeadChip [40]
Heyn–Sproul–Jackson syndrome (618724) Multiple chromosomes GOM of 1140 regions
LOM of 738 region		 100% DNMT3A variants Yes 50% Illumina Infinium BeadChip [41]
Immunodeficiency-centromeric instability-facial anomalies syndrome 1 (242860) Multiple chromosomes LOM of 6942 CpGs
GOM of 1921 CpGs		 100% DNMT3B variants Yes 25% Illumina Infinium BeadChip [42,43]
Immunodeficiency-centromeric instability-facial anomalies syndrome 2 (614069) Multiple chromosomes LOM of 8414 CpGs
GOM of 2661 CpGs		 100% ZBTB24 variants Yes 25% Illumina Infinium BeadChip [42]
Immunodeficiency-centromeric instability-facial anomalies syndrome 3 (616910) Multiple chromosomes LOM of 9623 CpGs
GOM of 2166 CpGs		 100% CDCA7 variants Yes 25% Illumina Infinium BeadChip
Immunodeficiency-centromeric instability-facial anomalies syndrome 4 (616911) Multiple chromosomes LOM of 8708 CpGs
GOM of 4120 CpGs		 100% HELLS variants Yes 25% Illumina Infinium BeadChip
Genitopatellar syndrome (606170) Multiple chromosomes ~700 CpGs 100% KAT6B variants Yes 50% Illumina Infinium BeadChip [15,29]
Say–Barber–Biesecker–Young–Simpson syndrome (603736) Multiple chromosomes ~800 CpGs 100% KAT6B variants Yes 50% Illumina Infinium BeadChip [15,29]
Werner syndrome (277700) Multiple chromosomes LOM of 614 CpGs
GOM of 511 CpGs		 100% WRN variants Yes 25% Illumina Infinium BeadChip [15]
Williams syndrome (194050) Multiple chromosomes 1413 CpGs
(mostly GOM)		 100% 7q11.23 deletions Yes 50% Illumina Infinium BeadChip [15]
7q11.23 duplication syndrome (609757) Multiple chromosomes 508 CpGs
(mostly LOM)		 100% 7q11.23 duplications Yes 50% Illumina Infinium BeadChip [15]
Progressive supranuclear palsy (601104) Multiple chromosomes GOM of 6110 CpGs
LOM of 2818 CpGs		 100% MAPT variants Yes 50% Illumina Infinium BeadChip [15]
Frontotemporal dementia (600274) Multiple chromosomes LOM of 387 CpGs
GOM of 142 CpGs		 100% MAPT variants Yes 50% Illumina Infinium BeadChip [15]
Cornelia de Lange syndrome (122470, 300590, 610759) Multiple chromosomes GOM of 563 CpGs
LOM of 361 CpGs		 100% NIPBL, SMC1A, SMC3 variants Yes 50% Illumina Infinium BeadChip [44]
SETD1B-related syndrome Multiple chromosomes 3340 CpGs
(mostly GOM)		 100% 12q31.24 deletions/SETD1B variants Yes 50% Illumina Infinium BeadChip [45]
Prader–Willi syndrome (176270) 15q11.2 SNURF GOM 99%

  • pat deletion of 15q11q13

  • UPD(15)mat

 Yes <1% for primary epimutations or UPD,
50% for pat deletions		 MS-MLPA
MS-pyrosequencing		 [46,47,48,49,50]
Angelman syndrome (601623) 15q11.2 SNURF LOM 80%

  • mat deletion of 15q11q13

  • UPD(15)pat

 Yes <1% for primary epimutations or UPD,
50% for mat deletions		 MS-MLPA
MS-pyrosequencing		 [47,49,51,52,53,54,55]
Temple syndrome (616222) 14q32 MEG3/DLK1 LOM 100%

  • UPD(14)mat

  • pat deletion of MEG3/DLK1 IG-DMR

  • chromosomal rearrangements

 Yes <1% for primary epimutations or UPD,
50% for pat deletions		 MS-MLPA [56,57,58,59,60]
Kagami–Ogata Syndrome (608149) 14q32 MEG3/DLK1
and/or
MEG3 GOM		 100%

  • UPD(14)pat

  • mat deletion of MEG3/DLK1 IG-DMR

  • chromosomal rearrangements

 Yes <1% for primary epimutations or UPD,
50% for mat deletions		 MS-MLPA [60,61,62,63]
Beckwith–Wiedemann syndrome (130630) 11p15.5–11p15.4 IC2 LOM 80%

  • UPD(11)pat (up to 10% with whole genome pat UPD)

  • mat IC1 deletion or SNVs

  • mat SCMC SNVs (see MLID)

  • chromosomal rearrangements

 Yes <1% for primary epimutations or UPD,
50% for mat IC1 deletions or SNVs,
increased for mat SCMC SNVs		 MS-MLPA
MS-pyrosequencing		 [64,65,66,67,68,69]
IC2 LOM
+
IC1 GOM
IC1 GOM
Silver–Russell syndrome (1800860) 11p15.5 IC1 LOM 50%

  • pat deletion of IC1

  • UPD(11)mat (rarely whole genome mat UPD)

  • mat SCMC variants (see MLID)

  • chromosomal rearrangements

 Yes <1% for primary epimutations or UPD,
50% for pat IC1 deletions,
increased for mat SCMC SNVs		 MS-MLPA
MS-pyrosequencing		 [66,70,71,72,73,74,75,76,77,78,79,80,81,82]
IC2 GOM
+
IC1 LOM
7 MEST GOM
+
GRB10 GOM		 4–10% UPD(7)mat (rarely whole genome mat UPD) <1%
Pseudohypoparathyroidism 1b (603233) 20q13.32 GNAS LOM 100%

  • mat deletions/duplications of GNAS DMRs

  • UPD(20)pat

 Not reported <1% for primary epimutations or UPD,
50% for mat deletions/duplications		 MS-MLPA [83,84,85,86,87,88,89,90,91]
Transient neonatal diabetes mellitus (601410) 6q24 PLAGL1 LOM 70%

  • UPD(6)pat

  • chromosomal rearrangements

  • ZFP57 variants (see MLID)

 unknown <1% for primary epimutations or UPD,
25% with parents carrying ZFP57 variants		 MS-MLPA [92,93,94]
MLID Multiple chromosomes LOM of multiple DMRs

  • 50%–75% of TNDM cases with PLAGL1 LOM

  • 20%–50% of BWS cases with IC2 LOM

  • 9.5%–30% of SRS cases with IC1 LOM

  • 0%–6.3% of PHP-1b cases with GNAS LOM

  • Maternal-effect SCMC variants

  • Zygotic ZFP57 variants

 Yes <1% for primary epimutations,
Increased in case of maternal-effect SCMC variants or zygotic ZFP57 variants		 MS-MLPA [95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118]
Retinoblastoma (180200) 13q14 RB1 GOM 13% Not reported Yes <1% MS-MLPA [119,120,121,122,123,124]
Lynch syndrome (609310) 3p22.2 MLH1/EPM2AIP1 GOM up to 3% deletions or c.-27C>A and c.85G>T substitutions Yes <1% for primary epimutations,
50% in case of genetic alterations		 MS-MLPA [125,126,127,128,129,130,131,132,133,134]
Lynch syndrome (120435) 2p21-p16 MSH2 GOM 1%–3% EPCAM 3′ deletions Yes, limited to epithelial tissues 50% MS-MLPA
Myotonic dystrophy type 1 (160900) 19q13.3 DMPK GOM

  • 100% in the congenital forms

  • 16%–50% in non-congenital forms

 Expansion of CTG repeat (>50) in the DMPK 3′-UTR Yes 50% for FM and PM mothers MS-HRMA
bisulphite sequencing		 [135,136,137,138,139,140]
Amyotrophic Lateral Sclerosis (105550) 9p21.2 C9orf72 GOM 10%–30% Expansion of GGGGCC repeat in the C9orf72 5′UTR Yes 50% bisulphite sequencing [141,142,143,144]
Facioscapulohumeral Muscular Dystrophy (158900, 158901) 4q35 D4Z4 LOM 100%

  • Deletion of D4Z4 repeats (FSHD1)

  • SMCHD1 and DNMT3B variants (FSHD2)

 Yes 50% for FSHD1,
lower for FSHD2		 bisulphite sequencing [145,146,147,148,149,150,151,152,153,154]

Loss of methylation (LOM); gain of methylation (GOM); uniparental disomy (UPD); full mutation (FM); premutation (PM); methylation-specific (MS); multiplex ligation probe-dependent amplification (MLPA); paternal (Pat); maternal (Mat); Beckwith–Wiedemann syndrome (BWS); Silver–Russell syndrome (SRS); Transient Neonatal Diabetes Mellitus (TNDM); pseudohypoparathyroidism 1b (PHP1b); Multi-Locus Imprinting Disturbances (MLID); Facioscapulohumeral Muscular Dystrophy (FSHD).