Table 2.
Resolved 13 families- summary of main US findings, WES results and final molecular diagnosis.
| Family number | Main US findings (according to fetuses) | WES type | Gene | Causative variants | Inheritance and zygosity | Diagnosis (relevant phenotype MIM number) |
|---|---|---|---|---|---|---|
| 1 | 1st: Shortening of long bones (femur, humerus, tibia), IUFD 2nd: Narrow thorax, bowed femur, shortening of long bones (mostly fibula) | Quatro | EVC2 | NM_147127.4: c.572A>T, p.Asn191Ile; NM_147127.4: c.3265C>T, p.Gln1089∗ | AR (compound het) | Ellis-van Creveld syndrome (MIM: 225500) |
| 2 | 1st: Encephalocele, large multicystic kidneys, oligohydrmanios, suspected polydactyly, lack of urinary bladder and stomach demonstration | Trio | TCTN2 | NM_024809.4: c.1506-2A>G | AR (hom) | Meckel syndrome type 8 (MIM: 613885) |
| 2nd: Posterior fossa abnormality (suspected dandy-walker malformation), short and malformed corpus callosum, IUGR, SUA, small dysgenetic kidneys, urinary bladder was not visualized, oligohydramnios, hypertelorism | ||||||
| 3 | 1st: Fetal akinesia, mild polyhydramnios, small stomach, suspected right clubfoot, extended lower limbs, clenched hands, neck hyper-extension | Trio | LMOD3 | NM_198271.4: c.723_733del, p.Asp242Glufs∗4; NM_198271.4: c.360dupA, p.Glu121Argfs∗5 | AR (compound het) | Nemaline Myopathy 10 (MIM: 616165) |
| 2nd: Arthrogryposis, hypotonic features, abnormal posture | ||||||
| 4 | 1st: Abnormal spine and chest, unusual skull shape, echogenic cystic and horseshoe like kidneys | Single | BMPER | NM_133468.5: c.410T>A, p.Val137Asp | AR (hom) | Diaphanospondylodysostosis (MIM: 608022) |
| 2nd: Increased NT (8 mm), generalized edema, spine distortion, bilateral clubfoot, absent nasal bone | ||||||
| 3rd: Reduced/lack ossification in the skull, ribs and vertebrae, protruding abdomen, short trunk | ||||||
| 5 | 1st: Distal arthrogryposis (hands), probably unilateral clubfoot, IUFD 2nd: Bilateral clubfoot |
Quatro | FKBP14 | NM_017946.3: c.568_570del, p.Lys190del | AR (hom) | Ehlers-Danlos syndrome, kyphoscoliotic type, 2 (MIM: 614557) |
| 6 | 1st: Posterior urethral valve, cystic finding in kidney, suspected omphalocele 2nd: Increased NT (10 mm), cystic lesion near umbilical cord insertion site 3rd: Septated cystic hygroma, partial vermian agenesis, ARSA, omphalocele, echogenic and multicystic kidneys 4th: Increased NT (4.5 mm), facial dysmorphism (hypoplastic nasal bridge and micrognathia), echogenic kidneys, omphalocele, postaxial polydactyly, clubfoot, complex heart malformation (VSD, double outlet right ventricle, tricuspid valve regurgitation) |
Quatro | PIGN | NM_176787.5: c.163C>T, p.Arg55∗; NM_176787.5: c.2283G>C, p.Lys761Asn | AR (compound het) | Multiple congenital anomalies-hypotonia-seizures syndrome 1 (MIM: 614080) |
| 7 | 1st: large polycystic kidneys, oligohydramnios, moderate bilateral ventriculomegaly | Quatro | CPT2 | NM_001330589.1: c.1239_1240del, p.Lys414Thrfs∗7 | AR (hom) | CPT II deficiency, lethal neonatal (MIM: 608836) |
| 2nd: Polycystic kidneys, hydrocephalus, mega cysterna magna, macrocephaly | ||||||
| 3rd: Enlarged echogenic kidneys, severe oligohydramnios, hydrocephalus, mega cysterna magna, thin corpus callosum | ||||||
| 8 | 1st: Occipital encephalocele, ventriculomegaly, mild to moderate hydronephrosis 2nd: Occipital encephalocele, ventriculomegaly, microphthalmia, cataract |
Trio | B3GALNT2 | NM_001277155.2: c.236-1G>C | AR (hom) | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 11) (MIM: 615181) |
| 9 | Short corpus callosum, suspected unilateral cataract and coloboma, IUGR (∗) | Single | MED12 | NM_005120.3; c.6388C>T, p.Gln2130∗ | XL hemizygous (maternally inherited) | Opitz-Kaveggia syndrome (MIM: 305450); Ohdo syndrome, X-linked (MIM: 300895) |
| 10 | Preaxial polydactyly of foot, syndactyly of hands (∗∗) | Trio | GLI3 | NM_000168.6: c.1445G>A, p.Cys482Tyr | AD het (maternally inherited) | Greig cephalosyndactyly (MIM: 175700); Polydactyly, preaxial, type IV (MIM: 174700) |
| 11 | Shortening and bowing of long bones, poor bone mineralization, reduced skull ossification, small/narrow thorax | Trio | COL1A2 | NM_000089.3: c.1829G>T, p.Gly610Val | de novo het | Osteogenesis imperfecta type 2-3 (MIM: 166210, 259420) |
| 12 | Poor ossification of skull, tibial bowing, fractures of femur, shortening of long bones | Trio | COL1A2 | NM_000089.3: c.2260G>T, p.Gly754Cys | de novo het | Osteogenesis imperfecta type 2-3 (MIM: 166210, 259420) |
| 13 | Increased NT (5.7 mm), bilateral mild hypoplastic 5th finger, bilateral pyelectasis/hydronephrosis, short and thick corpus callosum, bulbous nose, mild polyhydramnios | Trio | TCF4 | NM_001243226.2: c.2032C>T, p.Arg678∗ | de novo het | Pitt-Hopkins syndrome (MIM: 610954) |
All fetuses had abnormal US findings. Cases 1–8 refer to families with two or more affected fetuses, 9–10 to families with single fetus and relevant family medical history (affected parent) and 11–13 to families with single fetus and lack of relevant family history. Cases 3 and 4 were previously reported by Berkenstadt et al. (2018) and Greenbaum et al. (2019), respectively.
∗Mother – Prominent facial dysmorphism (synophrys, small mouth and ears, mid-facial hypoplasia, prominent philtrum, dental crowding), head circumference in 10th percentile, hirsutism, menstural abnormalities and Intact cognition. She is probably a manifesting carrier. The fetus was male.
∗∗Mother – syndactyly (hands), hypotonia at infancy.
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; ARSA, aberrant right subclavian artery; het, heterozygous; hom, homozygous. IUFD, intrauterine fetal death; IUGR, intrauterine growth restriction; MIM, Mendelian inheritance in man; NT, nuchal translucency, SUA, single umbilical artery; VSD, ventricular septal defect; XL, X-linked.