Table 1

Summary of clinical, genetic and epigenetic features in families with maternal effect variants

FamilyGeneMaternal effect variant*Hypomethylated loci†Maternal reproductive history of noteFamily history of noteClinical features of note in probandMutation previously reportedFamily previously reported: ref (patient)
1 NLRP2 NM_017852.4:c.
[1479_1480del];[1479_1480del], p.[(Arg493SerfsTer32)];[(Arg493SerfsTer32)]
M hom; P1 het; P2 het
PLAGL1, GRB10, MEST, KCNQ1OT1, GNAS Two children affected by MLID, one early abortion (gw 8), two late miscarriages (gw 24 and gw 36), one healthy childMother of proband has one healthy sister with three healthy sonsSon: omphalocele, macroglossia, neonatal hypoglycaemia, heart defect, developmental delay. Daughter: macroglossia, dysmorphisms, prominent eyes, developmental delay.4
2 NLRP2 NM_017852.4:c.[2237del];[=], p.[(Asn746ThrfsTer4)];[=]
M, P het
KCNQ1OT1, H19, MEST In vitro Fertilisation, triplet, not monozygoticNRSRS (NH-CSS: 6/6)20 (patient 2)
3 (patient 31)
3 NLRP2 NM_017852.4:c.[2860_2861del];[=], p.[(Cys954GlnfsTer18)];[=]
M het
GRB10, MEST, H19, KCNQ1OT1, MEG3,GNAS-AS, GNAS NR, only childSister with three abortions, no live birthsBW at 27 wg 465 g, OFC 32 cm. PNGR, respiratory support for 2 months, gastric tube feeding for first year. Microcephaly, precocious puberty, dysmorphism. Developmental delay. 47,XXY
4 NLRP2 NM_017852.4:c.[314C>T];[=], p.[(Pro105Leu);[=]
M het
PLAGL1, MEST, DIRAS3, IGF1R, IGF2R One further child, at least two miscarriages.Sibling of proband has anxiety disorderBW 9th centile, neonatal hyperglycaemia, remission at 3 months, childhood height and weight >99th centile, autistic spectrum disorder, speech and language delay
5 NLRP2 NM_017852.4:c.[1885T>C(;)2401G>A], p.[(Ser629Pro)(;)(Ala801Thr)]
M, P het both variants
H19, IGF2R One subsequent healthy child, one miscarriageNRSRS: NH-CSS 4/6; also bilateral radial anomalies, abnormalities of thumbs, single kidney19
6 NLRP7 NM_001127255.1:c.[2161C>T];[2573T>C]; NP_001120727.1:p.[(Arg721Trp)];[(Ile858Thr)]
M het both variants; P not tested
GRB10, MEST, KCNQ1OT1 Two early abortions (gw 4 and gw 4)
1 induced abortion (gw 19)
Sister of proband’s mother was also compound heterozygous; one healthy child (born at gw 26), three early abortions (gw 4, gw 6, gw 7); one ongoing pregnancy, ultrasound  normal, no MLID, p.(Ile858Thr)Induced abortion at 19 gw. Omphalocele, shortened humeri. Mesenchymal placenta.21,22
7 NLRP7 NM_001127255.1:c.[749T>G];[1104T>G]; p.[(Phe250Cys)];[(Ile368Met)] (M compound het; (P Ile368Met het) KCNQ1OT1, PLAGL1, IGF2R, MEST, DIRAS3, IGF1R NRNRBW 91st centile, exomphalos, macroglossia, neonatal diabetes, feeding difficulties in infancy, motor/speech delay, duplex kidneys, hemihypertrophy, scoliosis20
8 NLRP7 NM_001127255.1:c.[2156C>T];[=], p.[(Ala719Val)];[=] (M het; P het) H19, IGF1R, IGF2R NR, two additional healthy childrenNRSRS: NH-CSS 5/65, 20
9 PADI6 NM_207421.3:c.[902G>A(;)1298C>T], p.[(Arg301Gln)(;)(Pro433Leu)] (M compound het; P not tested) H19, MEG3 NR, only childMaternal grandpaternal family history of pregnancy loss: one healthy child, one with low birth weight, four stillbirths including a twin pairBW 2nd centile, preserved OFC, micrognathia, hypotonia and feeding difficulties in infancy. In childhood, facial asymmetry, regrognathia, broad fleshy nasal tip, height 10th–25th centile, weight 90th centile.19
10 PADI6 NM_207421.3:c.[1124T>C];[1639G>A], p.[Leu375Ser)];[(Asp547Asn)] (M compound het; P Asp547Asn het) KCNQ1OT1, GRB10, H19, MEST, IGF2R, IGF1R NR, only childNRBW 90th–97th centile, macrosomia, macroglossia, asymmetry, naevus flammeus, ear creases, developmental delay3 (patient 31)
11 PADI6 NM_207421.3:c.[1046A>G];[=], p.[(Asp349Gly)];[=] (M het) H19, IGF2R, GRB10, MEST, MEG3, SNRPN, GNAS-AS, GNAS Two healthy children, patient born at termNRReferred for testing as SRS, but NH-CSS negative (3/6): no relative macrocephaly, no feeding difficulties, no protruding forehead; developmental delay
12 PADI6 NM_207421.3:c.[433A>G];[=], p.[(Lys145Glu)];[=] (M het) H19, IGF2R, MEG3 NR, only childNRSRS: NH-CSS 4/6: no feeding difficulties, no asymmetry
13 OOEP NM_001080507.2:c.[109C>T];[109C>T], p.[(Arg37Trp)];[(Arg37Trp)] (M hom, P het) PLAGL1, IGF2R, DIRAS3, GRB10, SNRPN, IGF1R NRNRBW <0.4th centile. Hyperglycaemia 1–3.5 months, pelvic renal dilatation, developmental delay
14 UHRF1 NM_013282.4:c.[514G>A];[=], p.[(Val172Met)];[=] (M het, P het) H19, PLAGL1, IGF2R, KCNQ1OT1, IGF1R, PEG3, GNAS-AS Proband is one of discordant monozygotic twin pairNRDiscordant monozygotic twin. SRS: NH-CSS 5/6; also kidney failure in infancy, bilateral renal dysplasia
15 ZAR1 NM_175619.2:c.[130G>T];[=], p.[(Glu44Cys)];[=] (M het, P het) KCNQ1OT1, GNAS, DIRAS3, IGF1R Two healthy siblings, one miscarriageNRBW >98th centile, mild macroglossia, consistently high weight (>98th centile)
  • 47The table summarises clinical, genetic and epigenetic features in families with maternal-effect variants. gw: gestational week; NR: not reported; BW: birth weight; OFC: occipitofrontal circumference; PNGR: postnatal growth restriction; NH-CSS: Netchine-Harbison Clinical Scoring System47 (Netchine-Harbison score from 6 parameters: intrauterine growth restriction, postnatal growth restriction, relative macrocephaly, feeding difficulties, asymmetry, protruding forehead). *M: variant detected in mother (by definition); P: variant detected in proband; hom: homozygous; het: heterozygous.

  • †All loci were tested, but the table lists only loci at which hypomethylation was detected.