TABLE 1.
Summary of cases: fetal phenotypes at the time of invasive sampling and the syndromic disorders detected by various molecular tests in the presented cohort
| Indication for prenatal testing | Gene |
Molecular diagnosis Phenotypic MIM number |
Indication for prenatal testing | Gene |
Diagnosis Phenotypic MIM number |
|---|---|---|---|---|---|
| Musculoskeletal (17) | Hydrops (7) | ||||
| Short long bones with restrained curvature | DYNC2H1 | Jeune syndrome (short‐rib thoracic dysplasia 3 with or without polydactyly) #613091 | Six cases of hydrops fetalis | PTPN11, RAF1, SOS1 | Noonan syndrome #163950 |
| Signs of skeletal dysplasia | DYNC2H1 | Jeune syndrome (asphyxiating thoracic dystrophy 3) #613091 | Hydrops fetalis | UNC13D | Hemophagocytic lymphohistiocytosis type 3 #608898 |
| Short limbs | DYNC2H1 | Jeune syndrome (asphyxiating thoracic dystrophy 3) #613091 | IUGR (3) | ||
| Short long bones, rocker bottom foot right | LEPRE1 ( P3H1) | Osteogenesis imperfecta type 8 #610915 | IUGR | BRCA2 | Fanconi anemia #605724 |
| Signs of skeletal dysplasia | COL1A1 | Osteogenesis imperfecta type 2 #166210 | IUGR | H19 | Silver‐Russell syndrome #180680 |
| Signs of skeletal dysplasia, short ribcage, short long bones with restrained curvature | COL1A1 | Osteogenesis imperfecta type 2 #166200 | IUGR | DDX11 | Warsaw breakage syndrome #613398 |
| Signs of skeletal dysplasia, sacral agenesis, rocker bottom feet | COL2A1 | Spondyloepiphyseal dysplasia congenital (SEDC) #183900 | Genitourinary (4) | ||
| Short long bones | COL2A1 | Spondyloepiphyseal dysplasia congenital (SEDC) #183900 | Unilateral multicystic renal dysplasia and pyelectasis with echogenic cortex left | HNF1B | Renal cysts and diabetes syndrome (RCAD) #137920 |
| Contracture of the hands (flexion of the wrists), short long bones | B3GALT6 | Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures #271640 | Ambiguous genitalia | CYP21A2 | Adrenal hyperplasia, congenital, due to 21‐ hydroxylase deficiency #201910 |
| Short long bones | COL2A1 | Achondrogenesis, type II #200610 | Polycystic renal dysplasia | ANKS6 | Nephronophthisis 16 #615382 |
| Short long bones | FGFR3 | Achondroplasia #100800 | LUTO/hydronephrosis, anhydramnios | FRAS1 | Fraser syndrome #219000 |
| Micrognathia | COL1A1 | Marshall syndrome #154780 | CNS (4) | ||
| Micro‐retrognathia | COL2A1 | Stickler syndrome type 1 #108300 | Macrocephaly, frontal bossing | PIK3CA | Megalencephaly‐capillary malformation syndrome (M‐CAP) #602501 |
| Signs of arthrogryposis | ECEL1 | Distal arthrogryposis type 5D #615065 | Dysgenesis of corpus callosum | FLNA | Periventricular nodular heterotopia and corpus callosum hypoplasia #300049 |
| Unilateral reduction defect of the upper extremity | DOCK6 | Adams/Oliver syndrome #614219 | Ventriculomegaly and hypoplastic cerebellum | ISPD | Walker‐Warburg syndrome (congenital muscular dystrophy‐dystroglycanopathy with brain and eye anomalies type A) #614643 |
| Signs of skeletal dysplasia, hand and foot anomalies, polydactyly, short long bones and short ribs | EVC | Ellis van Creveld syndrome #225500 | Lissencephaly | DCX | Subcortical laminar heterotopia, X‐linked, included double cortex syndrome #300067 |
| Short long bones, bell‐shaped thorax | FGFR3 | Thanatophoric dysplasia type I #187600 | NT ≥ 3.5 mm (3) | ||
| Major anomaly accompanied by a soft marker in another system (6) | 3 cases: NT 3.6 mm, NT 8.3 mm, NT 8.0 mm | PTPN11 | Noonan syndrome #163950 | ||
| Hydrops fetalis, ascites, echogenic bowel | CFTR | Cystic fibrosis #602421 | Multiple system anomalies | ||
| Ventriculomegaly, echogenic bowel | SOX2 | Microphthalmia, syndromic 3 #206900 | NT 9.3 mm, cardiac anomalies | PTPN11 | Noonan syndrome #163950 |
| IUGR, echogenic bowel, short femoral bones | SKIV2L |
Trichohepatoenteric syndrome (THES) type 2 #614602 |
Hydrops fetalis, complex cardiac anomalies, abnormal intracranial anatomy | PTPN11 | Noonan syndrome #163950 |
| Short long bones and bilateral pyelectasis | H19 | Silver‐Russell syndrome #180680 | NT 8.0 mm and unilateral talipes | RAF1 | Noonan syndrome #611553 |
| SUA, pyelectasis, asymmetric ventriculomegaly | ZEB2 | Mowat‐Wilson syndrome #235730 | Dandy Walker malformation, polycystic renal disease, oligohydramios | CEP290 | Joubert syndrome type 5 #610188 |
| Bilateral talipes, varix vena umbilicalis | PTEN | Cowden syndrome PTEN hamartoma tumor syndrome (PHTS) #158350 | Vermis hypoplasia, ventriculomegaly, severe dysplastic renal disease, anhydramnios, ascites | CEP290 | Joubert syndrome #610188 |
| Cardiovascular (2) | Craniofacial defect, semi‐lobar holoprosencephaly, encephalocele, retrognathia, bilateral (multiple) renal cysts, deformity of the hands and feet. | CC2D2A | Joubert syndrome 9 #612284 or Meckel Gruber syndrome 6 #612284) | ||
| Complex cardiac anomaly | MASP1 | 3MC syndrome 1 #257920 | NT 4.6 mm, AVSD, absence cavum septi pellucidi, severe vermian defect, | ARID1A | Coffin‐ Siris syndrome #614607 |
| AVSD | PTPN11 | Noonan syndrome #163950 | VSD, corpus callosum dysgenesis, ventriculomegaly | ARID1A | Coffin‐Siris syndrome #614607 |
| Mild ventriculomegaly, dysgenesis of corpus callosum, rocker bottom foot, SUA | SMARCB1 | Coffin‐Siris syndrome #614608 | |||
| Gastrointestinal (2) | Spina bifida, oligohydramnios and IUGR | MANBA | β‐Mannosidosis #248510 | ||
| Echogenic bowel, dilated intestinal loop | CFTR | Cystic fibrosis #602421 | Encephalocele, ventriculomegaly, micrognathia, palatoschisis, polydactyly, pes equinovarus, bilateral clubhand and clubfeet, VSD | HSPG2 | Dyssegmental dysplasia, type Silverman‐Handmaker #224410 |
| Omphalocele | CDKN1C | Beckwith‐Wiedemann syndrome #130650 | IUGR, microcephaly, porencephaly, hypotelorism, micrognathia | RNU4ATAC | Microcephalic osteodysplastic primordial dwarfism type 1 #210710 |
| Soft markers (1) | Arthrogryposis, midline defect | MYH3 | Freeman‐Sheldon syndrome (distal arthrogryposis type 2A) #193700 | ||
| SUA, echogenic bowel | CFTR | Cystic fibrosis #602421 | VSD, short femur, pyelectasis, and urinary bladder cyst | CREBBP | Rubinstein‐ Taybi syndrome #180849 |
| Multiple system anomalies (27) | Cleft hand/foot malformation, small abdominal circumference | H19 | Silver‐Russell syndrome #180680 | ||
| SUA, AVSD, small abdominal circumference < P1 | SETD5 | Mental retardation (MRD) type 23 #615761 | Hydrops fetalis, severe short extremities and retained curvature of the bones | COL1A1 | Osteogenesis imperfecta type 2A #166210 |
| Hydrops fetalis, complex cardiac anomalies | KMT2D | Kabuki syndrome 1 #147920 | Microcephaly, IUGR | DHCR7 | Smith‐Lemli‐Opitz syndrome #270400 |
| CL, tetralogy of Fallot, hypertelorism, hypospadias | MID1 | Opitz G/BBB syndrome #300000 | Nuchal fold, possible syndactyly, craniosynostosis (sutura coronalis sinistra) | FGFR2 | Apert syndrome #101200 |
| NT 7 mm, SUA, echogenic bowel, dilated LV abnormal mitralis valve, aortic valve with high PSV, cardiomegaly | NOTCH1 | Adams‐Oliver syndrome #616028 | Exencephaly, bilateral enlarged cystic renal disease with no filling of the urinary bladder, bilateral talipes | CC2D2A | Meckel syndrome type 6 #612284 |
| Bilateral enlarged kidneys, enlarged cisterna magna, ascites, pes equinovarus and oligohydramnios | BBS2 | Bardet‐Biedl syndrome #209900 | complex cardiac anomalies, abnormal fossa posterior, abdominal cyst | CHD7 | CHARGE syndrome #214800 |
|
Bilateral cleft palate and lip, polydactyly, nuchal fold thickening, echogenic focus within heart, stenosis of the arteria pulmonalis, mild tricuspid valve insufficiency and stenosis |
CEP164 | Nephronophthisis 15 #614845 | Prefrontal edema, ascites, hypoplastic nose, kyphoscoliosis thoraco‐lumbar, bilateral rocker bottom feet, bilateral clenched hands, short long bones < p5, bell‐shaped thorax | COG5 | Congenital disorder of glycosylation type IIi (CDG2i) #613612 |
Abbreviations: AVSD, atrioventricular septal defect; CL, cleft lip; CNS, central nervous system; IUGR, intrauterine growth restriction; LUTO, lower urinary tract obstruction; LV, left ventricle; NT, nuchal translucency; PSV, persistent sciatic vein; SUA, single umbilical artery; VSD, ventricular septal defect.