Table 3.
aList of Prenatal Cases with Available DNA from the Fetus
| ID | Result | Gene | Variant(s) | Zygosity | LOF | Observed Fetal Phenotype | Phenotype Category |
|---|---|---|---|---|---|---|---|
| 17-0422 | Solved | ALG9 | GenBank: NM_001077690.1:c.430T>C:p.Cys144Arg | Hom | – | Cardiomegaly, pericardial effusion, a thick nuchal fold, oligohydramnios, hydronephrosis, and a small bladder | Typical |
| 17-6079 | Solved | ATP11C | GenBank: NM_173694.4:c.1675+2T>C | Hemi | y | Fetus with hydrops fetalis. | Distinct prenatal presentation |
| 17-3514 | Solved | BBS1 | GenBank: NM_024649.4:c.830+2T>C | Hom | y | Severe oligohydramnios and enlarged echogenic kidney with cyst bilaterally, most likely ARPKD | Typical |
| 17-1195 | Ambiguous (candidate gene) | BRAP | GenBank: NM_006768.4:c.199C>T:p.Arg67Ter | Hom | y | Non-immune hydrops fetalis | NA (first case) |
| 16-3155 | Solved | CANT1 | GenBank: NM_138793.3:c.902_906dup:(p.Ser303AlafsTer21) | Hom | y | Skeletal dysplasia | Typical |
| REQ18-1150 | Solved | CC2D2A | GenBank: NM_001080522.2:c.4531T>C:p.Trp1511Arg | Hom | – | Enlarged kidneys and occipital encephalocele | Typical |
| 18-2311 | Solved | CEP55 | GenBank: NM_001127182.1:c.807T>G:p.Tyr269Ter | Hom | y | Renal dysplasia, anhydraminos, and hydranencephaly | Typical |
| 17-2713 | Ambiguous (VUS) | CHRNA1 | GenBank: NM_000079.3:c.254T>C:p.Leu85Pro | Hom | – | Non-immune hydrops fetalis | Typical |
| 17-0633 | Ambiguous (VUS) | CHRNG | GenBank: NM_005199.5:c.1180C>G:p.Pro394Ala | Hom | – | Club foot, oligohydramnios, cystic hygroma and/or increased nuchal thickness, skin edema, and fixed flexion in an upper limb | Typical |
| 17-5074 | Solved | CNTNAP1 | GenBank: NM_003632.2:c.1903C>T:p.Arg635Ter | Hom | y | Polyhydramnios, absent stomach, and a mother with history of IUFDs | Typical |
| 17-3078 | Solved | COL1A1 | GenBank: NM_000088.3:c.2399G>A:p.Gly800Glu | De novo | – | Skeletal dysplasia | Typical |
| REQ18-4214 | Solved | ECHS1 | GenBank: NM_004092.3:c.88+5G>A: | Het (carrier) | y | Normal (tested with the parents, who had a history of neonatal deaths with severe lactic acidosis but no available DNA. See “Molecular Autopsy by Proxy” for details.) | NA |
| 17-3698 | Solved | ERCC5 | GenBank: NM_001204425.1:c.3789delT:p.Asp1263GlufsTer24 | Hom | y | Fetus with a dilated third ventricle, dilated cisternae magna, hypertelorism, micrognathia, generalized skin edema, moderately enlarged heart, hydrothorax, bilateral talipes, bilateral clenched hands, and fixed position (hip flexed and upper limbs flexed) | Distinct prenatal presentation |
| 17-5348 | Solved | ETFA | GenBank: NM_000126.3:c.883-1_885delGACA | Hom | y | Pericardial effusion, echogenic kidney, hydrocephalus, and a small chest | Distinct prenatal presentation |
| 18-1181 | Solved | FLVCR2 | GenBank: NM_001195283.1:c.596T>A:p.Val199Glu | Hom | – | Hydrocephalus, dilated cisterna magna, hypoplastic cerebellum, and brain atrophy | Typical |
| 17-3511 | Ambiguous (candidate gene) | FRMD6 | GenBank: NM_001267046.1:c.262G>A:p.Ala88Thr | De novo | – | IUGR and microcephaly. | N/A (first case) |
| 17-0224 | Solved | FTO | GenBank: NM_001080432.3:c.871C>T:p.Gln291Ter | Hom | y | Dandy-Walker malformation, IUGR, and polyhydramnios | Typical |
| 18-2474 | Solved | GUSB | GenBank: NM_000181.4:c.307C>T:p.Arg103Trp | Hom | – | Fetus with non-immune hydrops | Typical |
| 18-2404 | Solved | HSPG2 | GenBank: NM_001291860.1:c.12462delT:p.Leu4155CysfsTer30 | Hom | y | Skeletal dysplasia | Typical |
| 17-0425 | Ambiguous (candidate gene) | IL6ST | GenBank: NM_001190981.1:c.841C>T:p.Arg281Ter | Hom | y | Brain malformation, short long bones, kidney malformation, and unilateral MCDK | NA (first case) |
| 17-0409 | Solved | KIF19 | GenBank: NM_153209.3:c.788G>A:p.Arg263His; NM_153209.3:c.1906T>G:p.Tyr636Asp | Het (CMP) | – | abnormal “strawberry” head shape, absent corpus callosum, and brain ventriculomegaly | NA (first case; see PMID: 28749478) |
| 17-0807 | Solved | MYH11 | GenBank: NM_022844.2:c.1033+1G>A | Hom | y | Megacystis | Distinct prenatal presentation |
| 17-5309 | Solved | MYH11 | GenBank: NM_002474.2:c.3424C>T:p.Arg1142Ter | Hom | y | Megacystis, bilateral hydronephrosis, absent stomach, borderline polyhydramnios, microcolon, and intestinal hypoperistalsis | Distinct prenatal presentation |
| 17-2355 | Solved | MYO9A | GenBank: NM_006901.4:c.1537C>T:p.Arg513Ter | Hom | y | Hydrocephalus | Distinct prenatal presentation |
| 17-4600 | Solved | MYSM1 | GenBank: NM_001085487.2:c.1168G>T:p.Glu390Ter | Hom | y | Non-immune hydrops fetalis | Distinct prenatal presentation |
| 17-2505 | Solved | NDUFB10 | GenBank: NM_004548.2:c.373_375delCAG:p.Gln125del | Hom | – | Non-immune hydrops fetalis and died after birth | Distinct prenatal presentation |
| 17-4671 | Solved | PEX5 | GenBank: NM_000319.4:c.1554T>G:p.Asn518Lys | Hom | – | Multicystic kidney, dilated cisterna magna, ventriculomegaly, and a positive family history | Distinct prenatal presentation |
| 17-6282 | Solved | PHGDH | GenBank: NM_006623.3:c.1030C>T:p.Arg344Ter | Hom | y | Non-immune hydrops fetalis | Phenotypic expansion |
| 17-5922 | Solved | PIEZO1 | GenBank: NM_001142864.4:c.5013_5016delGGCG:p.Ala1672CysfsTer59 | Hom | y | Non-immune hydrops | Typical |
| 17-2819 | Solved | PIEZO1 | GenBank: NM_001142864.4:c.6372G>C:p.Trp2124Cys | Hom | – | Hydrops fetalis | Typical |
| 17-4408 | Ambiguous (VUS) | POLG | GenBank: NM_001126131.1:c.2606G>A:p.Arg869Gln | Hom | – | Polyhydramnios, contractures, scoliosis, and kyphosis | Distinct prenatal presentation |
| 18-1761 | Solved | POMT1 | GenBank: NM_001077366.1:c.118+1G>T | Hom | y | Fetus with severe ventriculomegaly | Typical |
| 17-5897-B | Solved | PTPN11 | GenBank: NM_002834.4:c.781C>T:p.Leu261Phe | De novo | – | Non-immune hydrops fetalis | Phenotypic expansion |
| 17-1571 | Ambiguous (VUS) | RTEL1 | GenBank: NM_001283009.1:c.3730T>C:p.Cys1244Arg | Hom | – | Fetus with severe IUGR and oligohydramnios | Phenotypic expansion |
| REQ18-3059 | Ambiguous (VUS) | SMAD6 | GenBank: NM_005585.4:c.818A>G:p.Glu273Gly | Hom | – | Severe non-immune hydrops fetalis with a family history of a previously affected pregnancy | Distinct prenatal presentation |
| 17-3980 | Ambiguous (candidate gene) | SMPD4 | GenBank: NM_001171083.2:c.1471-28_1477del | Hom | y | Bilateral clenched hands and talipes, IUGR, partial absence of the corpus callosum, and a family history of three neonatal deaths with similar features | NA (first case) |
| 17-4710 | Solved | STRA6 | GenBank: NM_001142617.1:c.1594C>T:p.Arg532Ter | Hom | y | Hypoplastic left heart syndrome | Distinct prenatal presentation |
| 17-3069-A | Ambiguous (candidate gene) | STXBP3 | GenBank: NM_007269.4:c.622G>A:p.Ala208Thr | Hom | – | Arthrogryposis multiplex congenita | NA (first case) |
| 17-0889 | Solved | TBC1D32 | GenBank: NM_152730.6:c.1372+1G>T | Hom | y | Previous termination of 15/32 with holoprosencephaly, cyclops, cleft lip, ventricular septal defect, agenesis of the corpus callosum, club foot, and a sandal gap (no sample) | Phenotypic expansion |
| 17-0286 | Solved | TMEM130 | GenBank: NM_001134450.1:c.23G>A:p.Arg8His | Hom | – | Pericardial effusion, enlarged kidney, occipital encephalocele, and suspected to have Meckel-Gruber syndrome | Typical |
| 17-4015 | Ambiguous (VUS) | WDR34 | GenBank: NM_052844.3:c.1061C>T:p.Thr354Met | Hom | – | Fetus with IUGR and skeletal dysplasia | Typical |
Abbreviations are as follows: LOF = loss of function, y = yes, Hom = homozygous, Het = heterozygous, Hemi = hemizygous, IUGR = intrauterine growth restriction, ARKPD = autosomal-recessive polycystic kidney disease, VUS = variant of unknown significance, IUFD = intrauterine fetal death, NA = not applicable, MCDK = multicystic dysplastic kidney, and CMP = compound.
a
Negative instances can be found in Table S7.