Table 1.
Summary of clinical information and results in the affected pregnancies where a genetic diagnosis was obtained
| Case | Phenotype (HPO TERMS) | Affected Pregnancies | Consanguinity | Gene | HGVS Nomenclature | Variant Classification on Clinical Diagnostic Report | OMIM Diagnosis |
|---|---|---|---|---|---|---|---|
| 015 | Hydrops fetalis, multiple joint contractures, pulmonary hypoplasia | ≥2 | N | RYR1 | NM_000540.2 p.[(Ser3074Phe)];[?] c.[9221C>T];[14130‐2A>G] | Pathogenic | Fetal akinesia OMIM No.180901 |
| 025 | Arthrogryposis multiplex congenita, multiple pterygia | ≥2 | N | GLE1 | NM_001003722.1 p.[(Arg569His)];[(Val617Met)] c.[1706G>A];[1849G>A] | p.(Arg569His)11 Likely pathogenic p.(Val617Met)11 Likely pathogenic | Lethal congenital contracture syndrome 1/lethal arthrogryposis with anterior horn cell disease OMIM no 603371 |
| 03 | Hydrops fetalis, agenesis of corpus callosum, hypertrophic cardiomyopathy, pulmonary hypoplasia, low‐set ears, increased nuchal translucency, ventriculomegaly, wide anterior fontanel | ≥2 | N | MRPS22 | NM_020191.2 p.[(Arg170His)];[?] c.[509G>A];[878+1G>T] | p.(Arg170His)12 Likely pathogenic c.878+1G>T Pathogenic | Combined oxidative phosphorylation deficiency 5 OMIM no 605810 |
| 04 | Congenital microcephaly | 1 | N | CENPJ | NM_018451.4 p.[(Glu9Ter)];[(Gln971Ter)] c.[25G>T];[2911C>T] | Pathogenic | Autosomal recessive primary microcephaly 6 OMIM no 609279 |
| 07 | Postaxial hand polydactyly, postaxial foot polydactyly, fibular aplasia, downslanted palpebral fissures, low‐set ears, cleft palate, intestinal malrotation, abnormality of pancreas morphology, absent tibia, preaxial foot polydactyly | ≥2 | N | IFT122 | NM_052985.3 p.[(Ala688_Asp694delinsGlyVal)];[(?)] c.[2063_2082delinsGCGTG];[3039+4A>G] | Likely Pathogenic | Cranioectodermal dysplasia‐1 (CED1) OMIM no 218330 |
| 09 | Absent hand (bilateral), absent toes, gastroschisis, intestinal malrotation, bilateral renal agenesis, ventriculomegaly, sex reversal | ≥2 | N | LRP4 | NM_002334.3 p.[(Asp606Asn)];[(Gly629Glu)] c.[1816G>A];[1886G>A] | Likely Pathogenic | Cenani‐Lenz syndrome OMIM no 604270 |
| 11 | Ambiguous genitalia, arthrogryposis multiplex congenita | ≥2 | N | ATRX | NM_000489.4 p.[(Asp2177Ala)];[0] c.[6530A>C];[0] | Likely Pathogenic | Mental retardation‐hypotonic facies syndrome, X‐linked OMIM no 309580 |
| 12 | Hyperechogenic kidneys, polydactyly | ≥2 | N | BBS10 | NM_024685.3 p.[(Cys91fs)];[(Cys91fs)] c.271[dup];[dup] | Pathogenic13, 14 | Bardet‐Biedl syndrome 10 OMIM no 610148 |
| 13 | Polyhydramnios, decreased fetal movement, arthrogryposis multiplex congenita, micrognathia, high palate, congenital hip dislocation, poor suck, focal seizures, increased serum lactate, hypoglycemia | ≥2 | N | GLE1 | NM_001003722.1 p.[(Ser194Asn)];[(Arg670Leu)] c.[581G>A];[2009G>T] | Likely Pathogenic | Lethal congenital contracture syndrome 1/lethal arthrogryposis with anterior horn cell disease OMIM no 603371 |
| 14 | Congenital microcephaly, agenesis of corpus callosum, cerebellar hypoplasia, 11 pairs of ribs | ≥2 | Y | SASS6 | NM_194292.1 p.[(Glu412Gln)];[(Glu412Gln)] c.1235[A>G];[A>G] | Likely Pathogenic | Autosomal recessive primary microcephaly 14 OMIM no 609321 |
| 16 | Arthrogryposis multiplex congenita, hydrops fetalis | ≥2 | N | RYR1 | NM_000540.2 p.[(?)];[(Gly4782Arg)] c.[12013‐2A>G];[14344G>A] | p.(Gly4782Arg)15 Likely Pathogenic c.12013‐2A>G Pathogenic | Fetal akinesia OMIM no 180901 |
| 17 | Hand polydactyly, foot polydactyly, multiple renal cysts , enlarged kidneys, hyperechogenic kidneys | 1 | Y | BBS9 | NM_198428.2 p.[(Asn254Ser)];[(Gly306Glu)] c.[761A>G];[917G>A] | Likely Pathogenic | Bardet‐Biedl syndrome 9 OMIM no 615986 |
| 18 | Short long bones, neonatal respiratory distress, short ribs, anterior rib cupping, thoracic hypoplasia, abnormality of the clavicle | 1 | N | DYNC2H1 | NM_001080463.1 p.[(Thr1696Met)];[(Ser3281Asn)] c.[5087C>T];[9842G>A] | Likely Pathogenic | Short rib polydactyly type III OMIM no 603297 |
| 19 | Bilateral renal agenesis, oligohydramnios, pulmonary hypoplasia, hypertrophic cardiomyopathy, anal atresia, aplasia of the uterus, aplasia/Hypoplasia of the fallopian tube | ≥2 | N | FRAS1 | NM_025074.6 p.[?];[(Gly2004Ser)] c.[5530‐2A>C];[6010G>A] | c.5530‐2A>C Pathogenic p.(Gly2004Ser) Pathogenic | Fraser syndrome OMIM no 607830 |
| 20 | Bilateral renal agenesis, oligohydramnios | ≥2 | Y | ITGA8 | NM_003638.1 p.[(Val489fs)];[(Val489fs)] c.1466_1470[del];[del] | Pathogenic | Renal hypoplasia/aplasia 1 OMIM no 604063 |
| 21 | Intrauterine growth retardation, hypertelorism, low‐set ears, megalencephaly, ventriculomegaly | ≥2 | N | B3GLCT | NM_194318.3 p.[?];[?] c.660+1[G>A];[G>A] | c.660+1G>A Pathogenic16, 17 | Peters‐plus syndrome OMIM no 261540 |
| 27 | Occipital meningoencephalocele, cystic renal dysplasia, polydactyly, 2‐3 toe syndactyly, low‐set ears, female external genitalia in individual with 46,XY karyotype, pulmonary hypoplasia | 1 | N | MKS1 | NM_017777.3 p.[?];[?] c.1408‐34_1408‐6[del];[del] | c.1408‐34_1408‐6del18, 19 Pathogenic | Meckel syndrome 1 OMIM no 249000 |
| 28 | Ventriculomegaly | ≥2 | N | POMGNT1 | NM_001243766.1 p.[(Arg497Gln)];[(Arg497Gln)] c.1490[G>A];[G>A] | Likely Pathogenic | Muscular dystrophy‐dystroglycanopathy type A3 OMIM No. 253280 |
| 29 | Arthrogryposis multiplex congenita | 1 | Y | ERCC5 | NM_000123.3 p.[(Gln622Ter)];[(Gln622Ter)] c.1864[C>T];[C>T] | Pathogenic | Cerebrooculofacioskeletal syndrome 3 OMIM no 616570 |
| 31 | Cerebellar hypoplasia | 1 | N | EXOSC3 | NM_016042.3 p.[(Gly31Ala)];[(Gly31Ala)] c.92[G>C];[G>C] | p.(Gly31Ala)20, 21, 22 Pathogenic | Pontocerebellar hypoplasia, type 1B OMIM no 614678 |
| 34 | Bilateral renal dysplasia, multiple renal cysts | ≥2 | N | ETFA | NM_000126.3 p.[(Arg223Ter)];[?] c.[667C>T];[(882+1_883‐1)_(963+1_964‐1)del] | p.(Arg223Ter) Pathogenic Exon 11 deletion Likely Pathogenic | Glutaric acidemia IIA OMIM no 231680 |
| 37 | Tetraamelia, kyphoscoliosis, absent septum pellucidum, abnormal cortical gyration | ≥2 | N | TRIP11 | NM_004239.4 p.[(Arg225Ter)];[(Val671fs)] c.[673C>T];[2010del] | Pathogenic | Achondrogenesis, type IA OMIM no 200600 |
| 39 | Arthrogryposis multiplex congenita, fetal akinesia sequence | ≥2 | Y | NEK9 | NM_033116.5 p.[(Glu500fs)];[(Glu500fs)] c.1498[del];[del] | Pathogenic | Lethal contracture syndrome type 10 OMIM no 617022 |
| 41 | Hypertrophic cardiomyopathy, cerebellar hypoplasia, cryptorchidism, opacification of the corneal stroma, neonatal asphyxia, neonatal hypotonia | ≥2 | N | ATAD3A | NM_001170535.1 p.[(Phe50Leu)];[?] c.[150C>G];[(282+1_283‐1)_(444+1_445‐1)del] | p.(Phe50Leu) Likely pathogenic Exon 3‐4 deletion Likely pathogenic | Harel‐Yoon syndrome OMIM no 617183 |
| 47 | Cerebellar hypoplasia, ventriculomegaly, enlarged kidneys, decreased fetal movements, abnormality of the amniotic fluid | 1 | N | TMEM67 | NM_153704.5 p.[(Arg74Ter)];[(Trp346Cys)] c.[220C>T];[1038G>T] | p.(Arg74Ter) Pathogenic p.(Trp346Cys) Likely pathogenic | Meckel syndrome type 3 OMIM no 607361 |
| 48 | Microcephaly, flat forehead, proptosis | 1 | Y | ASPM | NM_018136.4 p.[(Gln421fs)];[(Gln421fs)] c.1260_1266[del];[del] | p.(Gln421fs)23 Pathogenic | Primary Microcephaly type 5 OMIM no 608716 |
Cases 1 and 2 have been described previously.5
†For ACMG classification see Table S1. The reference is included for variants previously reported in the literature.