Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome

Clinical Epigenetics

Table 2 Classification of uncertain cases suspected of having ADNP syndrome

ID	ADNP variant	In silico assessment ^d	Population allele frequency (%)^e	Classification (score)	Support for prediction
ADNP_18 ^a	Not known	N/A	N/A	ADNP-2 (0.90)	^f
ADNP_26 ^b	c.201G>C (p.Gln67His)	Deleterious	0	ADNP-1 (0.95)	^g
ADNP_01 ^b	c.1039A>G (p.Met347Val)	Tolerated	0.008	None (0.96)	^h
ADNP_06 ^b	c.2963C>T (p.Thr988Ile)	Conflicting	0.0004	None (0.97)	^{h, i}
ADNP_19 ^b	c.356A>G (p.Lys119Arg)	Conflicting	0.007	None (0.96)	^h
ADNP_27 ^{b, c}	c.1855G>T (p.Val619Phe)	Deleterious	0.003	None (0.95)	^h, j
ADNP_28 ^{b, c}	c.1855G>T (p.Val619Phe)	Deleterious	0.003	None (0.95)	^h, j

^aThis patient was a confirmed case of ADNP syndrome, but the mutation was not known at the time of the study. ^bReason for assessment was reporting of a variant of unknown clinical significance in ADNP. ^cSubjects ADNP_27 and ADNP_28 are fraternal twins sharing a missense change with an unknown mode of inheritance. ^dIn Silico assessment for the suspected variant was performed using three tools: SIFT, PolyPhen, and MutationTaster. A “tolerated” or “deleterious” decision was assigned only if all three tools were in agreement with regard to the variant. ^eAllele frequency was obtained from the gnomAD database (v2.1) and represents the combined frequencies of different subpopulations; ^fADNP sequencing later identified a nonsense variant in the expected ADNP-2 region: c.2156dupA (p.Tyr719*). ^gVariant is absent from the general population and was classified as likely pathogenic according to the ACMG guidelines. ^hPopulation minor allele frequency is too high for a dominant condition. ⁱVariant is inherited from an unaffected mother. ^jNo further data is available for assessment. N/A not applicable. ADNP transcript, NM_015339.4. Photographs of some of these subjects are provided in Additional file 1: Figure S1

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