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 |