Table 1.

Summary of the clinical and molecular features of the probands and their families

Family	Proband sex and age (years)	Maternal effect variant	Genotype	Hypomethylated and hypermethylated loci	Maternal reproductive history	Family history of note	Clinical features of proband
1	Female, 24	KHDC3L novel NM_001017361: c.296C > G; p.Thr99Arg AF: - GF: - PolyPhen-2: Possibly damaging SIFT: Deleterious SDM: Destabilizing	M: hom P: het F: wt	Hypomethylated loci: KCNQ1OT1, ZDBF2/GPR1, NAP1L5,PLAGL1, GRB10, PEG10, MEST, ZNF597, GNAS-XLas, GNAS A/B, GNAS-AS1 Hypermethylated loci: DIRAS3:TSS, GNAS-NESP, ZNF331-DMR1, ZNF331-DMR2	None	None	Macroglossia, macrosomia, umbilical hernias, ear creases/pits, nevus flammeus (eyelid), mild neonatal hypoglycaemia, pre-eclampsia, prognathism, maxillary hypoplasia, seizures (once), strabismus BWS score: 7
2	Female, 39	PADI6 novel NM_207421: c.356 T > C; p.Leu119Pro AF: - GF: - PolyPhen-2: Probably damaging SIFT: Deleterious SDM: Destabilizing	M: het P: het S: het F: wt	Hypomethylated loci: KCNQ1OT1, PPIEL, NAP1L5, PLAGL1, ZNF331-DMR1, ZNF331-DMR2, GNAS-XLas, GNAS A/B, GNAS-AS1 Hypermethylated loci: ZNF597, GNAS-NESP	Two miscarriages	Second sister: three miscarriages and one healthy daughter Third sister: two healthy children	Macroglossia, polyhydramnios, diastasis recti, neonatal hypoglycaemia, ear creases/pits, nevus flammeus, nephromegaly, enlarged pancreas, facies grossolana, face asymmetry, maxillary hypoplasia, mild intellectual deficit, psychomotor retardation BWS score: 8
3	Female, 40	NLRP5 rs768443657 NM_153447.4: c.2615G > A; p.Arg872Lys AF: 8.95E-06 GF: 0 PolyPhen-2: Possibly damaging SIFT: Deleterious SDM: Destabilizing NLRP5 rs36118060 NM_153447.4: c.3584G > A; p.Arg1195Gln AF: 0.145 GF: 0.022 PolyPhen-2: Benign SIFT: Tolerated SDM: Destabilizing NLRP4 rs111284755 NM_134444.4: c.1279G > A; p.Ala427Thr AF: 0.006 GF: 2.00E-05 PolyPhen-2: Benign SIFT: Tolerated SDM: Destabilizing	M: het P: wt F: na M: het P: het F: na M: het P: het F: na	Hypomethylated loci: KCNQ1OT1, DIRAS3:TSS, PLAGL1, GRB10, ERLIN2, GNAS-XLas, GNAS A/B, GNAS-AS1 Hypermethylated loci: ZNF331-DMR1,ZNF331-DMR2, GNAS-NESP	Ovarian stimulation Two miscarriages. One triplet pregnancy: one miscarriage, two children born at 6 months of gestation and died few hours/days later. One healthy son	Proband: one healthy daughter one miscarriage, one healthy son	Macroglossia, macrosomia, lower limbs dysmetria, scoliosis, hypotonia BWS score: 5
4	Male, 15	NLRP5 rs34175666 NM_153447.4: c.1685G > A; p.Arg562His AF: 0.007 GF: 0 PolyPhen-2: Possibly damaging SIFT: Deleterious SDM: Destabilizing NLRP5 rs12462795 NM_153447.4: c.3323C > G; p.Ser1108Cys AF: 0.145 GF: 0.022 PolyPhen-2: Probably damaging SIFT: Deleterious SDM: Stabilizing NLRP5 rs36118060 NM_153447.4: c.3584G > A; p.Arg1195Gln AF: 0.145 GF: 0.022 PolyPhen-2: Benign SIFT: Tolerated SDM: Destabilizing	M: het P: wt F: wt M: hom P: het F: wt M: hom P: het F: wt	Hypomethylated loci: KCNQ1OT1, PLAGL1, IGF1R, GNAS-AS1 Hypermethylated loci: none	Proband born by in vitro fertilization	None	Macroglossia, mild asymmetry, macrosomia, neonatal hypoglycaemia, atopic eczema, gestational diabetes BWS score: 6
5	Female, 22	NLRP2 rs61735086 NM_017852.4: c.1681G > A; p.Ala561Thr AF: 0.000 GF: 0 PolyPhen-2: Benign SIFT: Tolerated SDM: Destabilizing NLRP2 rs17699678 NM_017852.4: c.662C > T; p.Thr221Met AF: 0.110 GF: 0.012 PolyPhen-2: Possibly damaging SIFT: Deleterious SDM: Stabilizing	M: het P: wt F: wt M: het P: het F: wt	Hypomethylated loci: KCNQ1OT1, NAP1L5, NNAT, GNAS-XLas, GNAS A/B, GNAS-AS Hypermethylated loci: ZNF331-DMR2, GNAS-NESP	One miscarriage	Two daughters	Macroglossia, hyperinsulinism, hypoglycaemia, hepato/splenomegaly, nevus flammeus (head, neck), maxillary hypoplasia, neonatal anaemia, respiratory distress, round face. BWS score: 6
6	Female, 14	NLRP2 rs17699678 NM_017852.4: c.662C > T; p.Thr221Met AF: 0.110 GF: 0.012 PolyPhen-2: Possibly damaging SIFT: Deleterious SDM: Stabilizing	M: het P: het F: wt	Hypomethylated loci: KCNQ1OT1, NAP1L5, PLAGL1, PEG10, MEST, GNAS-XLas, GNAS A/B, GNAS-AS1 Hypermethylated loci: GNAS-NESP	None	None	Macroglossia, exomphalos, perinatal hypoglycaemia, macrosomia, anterior creases in the ear, nevus flammeus (neck), round face, haemangioma. BWS score: 7
7	Male, 15	PADI6 rs74834315 NM_207421.4: c.775G > A; p.Val259Ile AF: 0.001 GF: 0 PolyPhen-2: Benign SIFT: Deleterious SDM: Destabilizing	M: het P: het	Hypomethylated loci: KCNQ1OT1, IGF1R, SNU13 Hypermethylated loci: none	None	None	Macroglossia, macrosomia, round and coarse face with prominent forehead, antimongoloid palpebral fissures and later on advanced bone age. BWS score: 3
8	Female, 4	NLRP2 rs147585490 NM_017852.4: c.1055 T > G; p.Ile352Ser AF: 0.002 GF: 0 PolyPhen-2: Possibly damaging SIFT: Deleterious SDM: Destabilizing	M: het P: wt	Hypomethylated loci: GNAS-XLas, GNAS A/B, GNAS-AS, DIRAS3:Ex2, PLAGL1, MEST, ERLIN2, PEG13, IGF1R, SNU13 Hypermethylated loci: GNAS-NESP, ZDBF2/GPR1	Proband born by in vitro fertilization	None	Early onset obesity, intellectual disability
9	Female, 35	NLRP2 rs61735077 NM_017852.4: c.1060A > G; p.Ile354Val AF: 0.008 GF: 0.000 PolyPhen-2: Benign SIFT: Tolerated SDM: Destabilizing	M: het P: wt	Hypomethylated loci: GNAS-XLas, GNAS A/B, GNAS-AS, DIRAS3, FAM50B, MEST, MCTS2P Hypermethylated loci: GNAS-NESP, NDN, ZNF597	None	None	Truncal obesity, hypothyroidism, hypercholesterolemia, occasional high PTH levels
10	Male, 8	NLRP2 rs4306647 NM_017852.4: c.1091G > A; p.Arg364Lys AF:0.041 GF: 0.001 PolyPhen-2: Possibly damaging SIFT: Tolerated SDM: Destabilizing	M: het P: wt	Hypomethylated loci: GNAS-XLas, GNAS A/B, GNAS-AS, PEG10, PEG13, ZNF331 Hypermethylated loci: GNAS-NESP	One miscarriage	None	Short stature, mild global developmental delay, PTH resistance with hypocalcaemia and hyperphosphataemia

In third column AF: Allele frequency in European population; GF: frequency of the homozygous genotype of the variant in European population. In fourth column: M = mother, P = Proband, S = Sister, F = Father, na: not available