Table 1 Summary of the study cohorts and their molecular findings
ID | Phenotype | Analysis | Recurrence | Consanguinity | Variant | Zygosity | Mutation effect | Class | ACMG score | ACMG classification | Variant reference | Justification of candidacy (category III) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
14DG1255 | NIHF | Solo | No | Yes | GUSB:NM_000181:exon9:c.1429C>T:p.ARG477Trp | Homozygous | Missense (Polyphen=probably_damaging(1),SIFT=deleterious(0), CADD=35) | I | PS1,PM2,PP3 | Likely pathogenic | CM960803 | |
15DG1257 | NIHF | Duo | Yes | Yes | MOCS3:NM_014484:exon1:c.1027C>T:p.Arg343* | Homozygous | Protein truncation | III | VUS | VUS | This study | KO is lethal in yeast (PMID: 14551258) |
16DG0787 | NIHF | Solo | Yes | Yes | MYBPC3:NM_000256.3:c.2449C>T:p.Arg817Trp | Homozygous | Missense mutation (Polyphen=probably_damaging(1),SIFT=deleterious(0), CADD=34) | II | PS1,PM2,PP1,PP3 | Likely pathogenic | CM1516385 | |
15DG1390 | NIHF and CHD | Solo | Yes | Yes | MYBPHL:NM_001010985:exon2:c.212T>G:p.V71G, | Homozygous | Missense (Polyphen=possibly_damaging(0.7),SIFT=deleterious(0),CADD=26) | III | VUS | VUS | This study | KO mouse has defective cardiac function (http://circres.ahajournals.org/content/119/Suppl_1/A391) |
15DG1889 | NIHF | Solo | Yes | Yes | PRPF19:NM_014502:exon10:c.794A>G:p.Lys265Arg | Homozygous | Missense (Polyphen=probably_damaging(0.934),SIFT=deleterious(0.01),CADD=27.6) | III | VUS | VUS | This study | KO mouse is embryonic lethal (PMID: 27626380) |
15DG1117 | IUFD | Duo | Yes | Yes | VPS13D:NM_018156:exon17:c.2020C>G:p.Arg674Gly | Homozygous | Missense (Polyphen=probably_damaging (0.936),SIFT=deleterious(0.01),CADD=31) | III | VUS | VUS | This study | KO mouse is embryonic lethal (PMID: 27626380) |
KFMC-306 | Anhydramnios, cystic hygroma, bilateral renal agenesis, enlarged and cystic liver | Solo | Yes | Yes | TTC21B:NM_024753.4:c.1176_1185+1del | Homozygous | Splicing | II | PVS1,PM2 | likely pathogenic | This study | |
13DG0010 | Hydrocephalus and holoprosencephaly (terminated pregnancy) | Solo | Yes | Yes | WDR81:NM_001163809:c.845G>A:p.Gly282Glu | Homozygous | Missense (Polyphen=probably_damaging(1),SIFT=deleterious(0), CADD=26) | II | PM2,PP2,PP3,PP4,PP5 | likely pathogenic | HGMD CM150814 | |
12DG1901 | Holoprosencephaly (terminated pregnancy) | Solo | Yes | Yes | No obvious candidate | This study | ||||||
14DG1138 | Anhydramnios, bilateral echogenic kidneys, stillbirth | Solo | No | Yes | AGT:NM_000029:c.104G>A:p.Arg35Gln | Homozygous | Missense (PolyPhen=probably_damaging(0.999);SIFT=deleterious(0) | II | PM2,PP3,PP4 | VUS | This study | |
15DG0174 | IUFD, dilated 3rd and lateral ventricles, absent choroid plexus dilated posterior fossa, hypoplastic cerebellum, signs of hydrops fetalis | Solo | Yes | Yes | FKTN:NM_006731:c.78C>G:p.Tyr26* | Homozygous | Protein truncation | II | PVS1,PM2 | Likely pathogenic | This study | |
030hc | NIHF | Yes | Yes | FEN1:NM_004111.5:c.704G>A:p.Cys235Tyr | Homozygous | Missense (Polyphen=probably_damaging(0.97),deleterious(0), CADD=27) | III | VUS | VUS | This study | KO mouse is embryonic lethal (PMID: 27626380) | |
603hc | IUFD, unilateral renal agenesis, unilateral polycystic kidney, lung hypoplasia | Solo | Yes | Yes | HSPB11:NM_016126.2:c.183dup:p.(Leu62Alafs*14) | Homozygous | Protein truncation | III | VUS | VUS | This study | KO mouse is embryonic lethal (PMID: 27626380) |
15DG1840 | IUFD, hypoplastic cerebellum, absent choroid plexus, micrognathia, hydrops fetalis, fixed flexed deformities in upper and lower limbs | Solo | Yes | Yes | No obvious candidate | |||||||
15DG0610 | NIHF | Solo | Yes | Yes | CTSA:NM_000308:c.575T>C:p.Leu192Pro | Homozygous | Missense (Polyphen=probably_damaging(0.979),SIFT=deleterious(0), CADD=28.2) | I | PM1,PM2,PP1,PP3 | Likely pathogenic | This study | |
17-0409 | Recurrent lethal hydrocephalus | Trio | Yes | No | KIF19: NM_153209:c.788G>A: p.Arg263His.KIF19: NM_153209.3: c.1906T>G:p.Tyr636ASP | Comp het | Missense (Polyphen=possibly_damaging(0.80) deleterious(0), CADD=29/ Polyphen=possibly_damaging(0.60) deleterious(0.02), CADD=26.7) | III | VUS | VUS | This study | KO mouse is embryonic lethal (PMID: 27626380) |
15DG0877 | NIHF | Solo | Yes | Yes | SLC17A5:NM_012434:c.738_741del:p.246_247del | Homozygous | Protein truncation (partial) | I | PVS1,PM2 | Likely pathogenic | This study | |
15DG1315 | Micromelia, craniofacial dysmorphia | Solo | Yes | Yes | COL11A2:NM_080679:c.1550dupC:p.Pro517fSer | Homozygous | Protein truncation | II | PVS1,PM2 | Likely pathogenic | This study | |
14DG1950 | IUFD | Solo | Yes | No | MS4A7:NM_206939:c.305C>A:p.Ser102* | Homozygous | Protein truncation | III | VUS | VUS | This study | Gene depleted for deleterious homozygous variants |
15DG0599 | NIHF | Solo | Yes | Yes | SERPINA11:NM_001080451:c.643+1G>A | Homozygous | Splicing | III | VUS | VUS | This study | Gene depleted for deleterious homozygous variants |
16DG1276 | NIHF | Solo | Yes | Yes | LZTR1:NM_006767:c.2317G>A:p.Val773Met | Homozygous | Missense (Polyphen=probably_damaging(0.999),SIFT=deleterious(0),CADD=33) | II | PM2,PP2,PP3 | VUS | This study | |
15DG0933 | NIHF | Solo | Yes | Yes | SLC17A5:NM_012434:c.1111+1G>A | Homozygous | Splicing | I | PVS1,PM2 | Likely pathogenic | This study | |
13DG0259 | NIHF | Solo | Yes | Yes | FCRL4:NM_031282:c.847+1G>A | Homozygous | Splicing | III | VUS | VUS | This study | Gene depleted for deleterious homozygous variants |
15DG0934 | NIHF | Duo | Yes | Yes | No obvious candidate | |||||||
SC1319 | IUFD, fetal akinesia | Solo | Yes | Yes | ASCC1:NM_001198800:c.710+1G>A | Homozygous | Splicing | II | PVS1,PM2 | Likely pathogenic | This study | |
16DG0940 | Post fossa malformation (terminated pregnancy) | Solo | Yes | Yes | EXOC3L2:NM_138568:c.122T>A:p.Leu41Gln | Homozygous | Missense (Polyphen=eprobably_damaging(1) SIFT=deleterious(0), CADD=24) | III | PM2,PP1,PP2,PP3,PP4 | Likely pathogenic | This study | Previously reported candidate in lethal ciliopathy (PMID: 27894351) |
15DG1901 | NIHF | Solo | Yes | Yes | THSD1:NM_018676:c.617G>A:p.Cys206Tyr | Homozygous | Missense (Polyphen=probably_damaging(0.999),SIFT=deleterious(0).CADD=27) | I | PS1,PM2 | Likely pathogenic | HGMD CM155511 | |
16DG1603 | NIHF | Solo | Yes | Yes | NEB:NM_001164507:c.20974delA:p.Val6993Serfs*8 | Homozygous | Missense (Polyphen=benign(0.365), SIFT=deleterious(0.01),CADD=23) | II | PVS1,PM2 | Likely pathogenic | This study | |
15DG0986 | NIHF, very short long bones, partial agenesis of the corpus callosum | Duo | No | Yes | MRPS16:NM_016065::c.331C>T:p.Arg111*, | Homozygous | Protein truncation | I | PS1,PS3,PM2 | Pathogenic | HGMD CM043302 | |
15DG2390 | NIHF | Solo | Yes | Yes | KRIT1:NM_194455:c.992A>G:p.Tyr331Cys | Homozygous | Missense (Polyphen=possibly_damaging(0.907SIFT=deleterious(0.02),CADD=25.2) | II | PM1,PM2,PP1,PP3 | Likely pathogenic | This study | |
15DG1933 | Hydrocephalus, hypoplastic cerebellum, skin edema and bilateral talipes, two previous IUFDs at 6 months of pregnancy with similar presentation of severe hydrocephalus, spina bifida, and polyhydramnios | Solo | Yes | Yes | KIAA1109:NM_015312:c.12067G>T:p.Glu4023*, | Homozygous | Protein truncation | III | VUS | VUS | This study | Previously reported candidate in lethal hydrocephalus (PMID: 25558065) |
16DG0291 | NIHF | Solo | No | Yes | ASCC1:NM_001198800:c.871+1G>A | Homozygous | Splicing | II | PVS1,PM2 | Likely pathogenic | This study | |
16DG0493 | NIHF | Solo | No | Yes | PIEZO1:NM_001142864:c.1264C>T:p.Gln422* | Homozygous | Protein truncation | I | PVS1,PM2 | Likely pathogenic | This study | |
16DG0673 | IUFD, ventriculomegaly, ACC, hypoplastic vermis, thickened cardiac wall, and fixed flexion deformities of the extremities | Solo | Yes | No | No obvious candidate | |||||||
16DG1142 | NIHF | Solo | Yes | Yes | SVOPL:NM_174959:c.205delT:p.Phe69Leufs*28 | Homozygous | Protein truncation | III | VUS | VUS | This study | SV2 KO mouse is embryonic lethal |
15DG0595 | Hydrocephalus and limb malformations (terminated pregnancy) | Solo | Yes | Yes | KIAA1109:NM_015312:c.11250-1G>A | Homozygous | Splicing | III | VUS | VUS | This study | Previously reported candidate in lethal hydrocephalus (PMID: 25558065) |
15DG2472 | IUFD | Duo | Yes | Yes | No obvious candidate | |||||||
14DG1030 | Polyhydramnios, talipes, cerebellar hypoplasia (terminated pregnancy) | Solo | Yes | Yes | KLHL41:NM_006063::c.176G>C:p.Arg59Pro | Homozygous | Missense (Polyphen=probably_damaging(0.999),SIFT=deleterious(0),CADD=30) | II | PM1,PM2,PP2,PP3 | Likely pathogenic | This study | |
16DG1084 | NIHF | Solo | Yes | Yes | GUSB:NM_000181:c.1429C>T:p.Arg477Trp | Homozygous | Missense (Polyphen=probably_damaging(1),SIFT=deleterious(0), CADD=35 /CM960803). | I | PS1,PM2,PP3 | Likely pathogenic | HGMD CM960803 | |
12DG1042 | NIHF | Solo | Yes | Yes | INVS:NM_014425:c.753T>G:p.Try251* | Homozygous | Protein truncation | II | PVS1,PM2 | Likely pathogenic | This study | |
15DG2545 | IUFD | Duo | Yes | Yes | No obvious candidate | |||||||
15DG1281 | NIHF | Solo | Yes | No | No obvious candidate | |||||||
15DG1287 | Lethal skeletal dysplasia with severe hypomineralization | Solo | No | Yes | ALPL:NM_001177520:c.1195G>A:p.Glu399Lys | Homozygous | Missense (PolyPhen=probably_damaging(1), SIFT=deleterious(0),CADD=35) | I | PM1,PM2,PP3,PP4 | Likely pathogenic | This study | |
16DG1654 | Recurrent IUFD and two perinatal deaths with severe hypotonia and arthrogryposis | Duo | yes | Yes | GFPT1:NM_001244710:c.686-1G>A | Homozygous | Splicing | I | PVS1,PM2 | Likely pathogenic | This study |
