Summary of clinical, genetic and epigenetic features in families with maternal effect variants
| Family | Gene | Maternal effect variant* | Hypomethylated loci† | Maternal reproductive history of note | Family history of note | Clinical features of note in proband | Mutation previously reported | Family 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 child | Mother of proband has one healthy sister with three healthy sons | Son: 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 monozygotic | NR | SRS (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 child | Sister with three abortions, no live births | BW 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 disorder | BW 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 miscarriage | NR | SRS: NH-CSS 4/6; also bilateral radial anomalies, abnormalities of thumbs, single kidney | 19 | |
| 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 | NR | NR | BW 91st centile, exomphalos, macroglossia, neonatal diabetes, feeding difficulties in infancy, motor/speech delay, duplex kidneys, hemihypertrophy, scoliosis | 20 | |
| 8 | NLRP7 | NM_001127255.1:c.[2156C>T];[=], p.[(Ala719Val)];[=] (M het; P het) | H19, IGF1R, IGF2R | NR, two additional healthy children | NR | SRS: NH-CSS 5/6 | 5, 20 | |
| 9 | PADI6 | NM_207421.3:c.[902G>A(;)1298C>T], p.[(Arg301Gln)(;)(Pro433Leu)] (M compound het; P not tested) | H19, MEG3 | NR, only child | Maternal grandpaternal family history of pregnancy loss: one healthy child, one with low birth weight, four stillbirths including a twin pair | BW 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 child | NR | BW 90th–97th centile, macrosomia, macroglossia, asymmetry, naevus flammeus, ear creases, developmental delay | 3 (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 term | NR | Referred 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 child | NR | SRS: 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 | NR | NR | BW <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 pair | NR | Discordant 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 miscarriage | NR | BW >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.