TABLE 2.
Overview of diagnoses identified prenatally with the use of rWES
| Case description | Clinically relevant variants identified by rWES | Interpretation based on follow up | T | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Case ID | Clinical details¥ | Indication | Gene | Variant(s) | Protein effect(s) | Zygosity and inheritance | Variant classification based on ACMG guidelines 24 | Phenotype explained | rWES interpretation strategy that identified the pathogenic variant(s) | Follow‐up information | Phenotype explained | Disease (#OMIM; Inheritance pattern) | ||
| 7 | IUGR, short long bones (P0‐P1). Ear anomalies. Clenched hands. Rocker bottom feet. Kidney defect | MFCA | ERCC5 | NM_000123.3: c.1096C > T | p.(Arg366*) | Hom | Mat | P | PVS1, PM2, PM3 | Yes | Clinical Exome (tier 1) | n.a. | n.a. | COFS syndrome type 3 (#616570; AR) |
| 8 | Possible skeletal dysplasia. All long bones <P3, OFC P90 | SD | COL2A1 | NM_001844.4: c.1115G > A | p.(Gly372Glu) | Het | UK | LP | PM2,PM5, PP3, PP5 | Yes | In silico disease‐gene panel (tier 1) | n.a. | n.a. | Spondyloperipheral dysplasia with short ulna (#27100; AD) |
| 10 | Long bones <P3, sandal gap feet. Slight bowing in humeri and femora. Narrow thorax | SD | FGFR3 | NM_000142.4: c.742C > T | p.(Arg248Cys) | Het | DN | P | PS1, PM1,PM2,PP3, PP5 | Yes | In silico disease‐gene panel (tier 1) | n.a. | n.a. | Thanatophoric dysplasia (#187600; AD) or Achondroplasia (#100800; AD) |
| 11 | Unilateral bowed and short femur P10 | SD | COL1A2 | NM_000089.3: c.1009G > A | p.(Gly337Ser) | Het | Mat mosaic (27% of reads) | P | PS1, PM1, PM2, PP3, PP5 | Yes | In silico disease‐gene panel (tier 1) | n.a. | n.a. | Osteogenesis Imperfecta (Type 2, 3 or 4) (#166210; 259 420; 166 220; AD) |
| 12 | CDH, polyhydramnion, hydrothorax and ascites | MFCA | ANKRD11 | NM_001256182.1: c.6504del | p.(Ala2170fs) | Het | DN | P | PVS1, PS2 | Yes | Clinical Exome (tier 1) | n.a. | n.a. | KBG syndrome§ (#148050; AD) |
| 13 | Severe skeletal dysplasia | SD | SLC26A2 | NM_000112.3: c.532C > T NM_000112.3: c.835C > T | p.(Arg178*) p.(Arg279Trp) | CH | Pat Mat | P LP | PVS1, PS3, PM2 PM3, PP5 PS1, PM3, PP3, PP5 | Yes | In silico disease‐gene panel (tier 1) | n.a. | n.a. | Diastrophic dysplasia (#222600; AR) |
| 14 | Severe skeletal dysplasia: narrow and short thorax. Absence of ossification of sacrum. Brachycephaly. | SD | COL2A1 | NM_001844.4: c.1879G > C | p.(Gly627Arg) | Het | DN | LP | PS2, PM2, PP3 | Yes | In silico disease‐gene panel (tier 1) | n.a. | n.a. | Hypochrondogenesis (#200610; AD) |
| 15 | Turribrachycephaly, proptosis, lobar holoprosencephaly, vertebral anomalies | MFCA | FGFR2 | NM_000141.4: c.1052C > G | p.(Ser351Cys) | Het | DN | P | PS1, PS2, PM2, PP3 PP4 | Yes | In silico disease‐gene panel (tier 1) | n.a. | n.a. | Pfeiffer syndrome Antley‐Bixler syndrome (#101600; 207 410; AD) |
| 16 | Short long bones, bowed femur, clubfeet, deviation of hand, scoliosis, micrognathia, abnormal filling stomach | SD | NEK9 | NM_033116.5: c.1871A > G NM_033116.5: c.329_331del | p.(Asn624Ser) p.(Asn110del) | CH | Mat Pat | VUS VUS | PM2, PP3 PM2, PP3 | Unclear | In silico disease‐gene panel (tier 1) | Development of arthrogryposis in current pregnancy and in new pregnancy of fetus that also carried both NEK9 variants. | Yes | Arthrogryposis, Perthes disease, and upward gaze palsy (#614262; AR) |
| 17 | Progressive shortening of long bones, deviation of left foot, polyhydramnion. | SD | COL2A1 | NM_001844.4: c.905C > T | p.(Ala302Val) | Het | DN | P | PS1, PS2, PM2, PM2, PP3, PP5 | Yes | In silico disease‐gene panel (tier 1) | n.a. | n.a. | Kniest dysplasia (#156550; AD) |
| 25 | Short limbs, short ribs, hypertelorism, skull dysmorphism | SD | RUNX2 | NM_001024630.3: c.625C > T | p.(Gln209*) | Het | DN | P | PVS1, PS2, PM2, PP5 | Yes | In silico disease‐gene panel (tier 1) | n.a. | n.a. | Cleidocranial dysplasia (#119600; AD) |
| 26 | Short limbs (femur P0/P0,1), small stomach, plump hands, polyhydramnion. | SD | COL2A1 | NM_001844.4: c.1286G > A | p.(Gly429Asp) | Het | DN | LP | PS2, PM2, PP3, PP5 | Yes | In silico disease‐gene panel (tier 1) | n.a. | n.a. | Type II collagen disorders (range from mild to lethal skeletal dysplasia) (#120140; AD) |
| 30 | Microcephaly, abnormal development of sulci, possible neural migration disorder. | ICSA | TUBA1A | NM_001270399.1: c.1205G > A | p.(Arg402His) | Het | DN | P | PS2,PM1, PM2, PP3, PP5 | Yes | Clinical Exome (tier 1) | n.a. | n.a. | Lissencephaly type 3 (#611603; AD) |
| 33 | Hydrocephalus, dysplastic fourth ventricle. Vermis hypoplasia. Lissencephaly. Fold in brainstem. | ICSA | FKRP | NM_001039885.2: c.1181G > T | p.(Trp394Leu) | Hom | Pat + Mat | VUS | PM2, PP3, PP4 | Yes | Clinical Exome (tier 1) | n.a. | n.a. | FRKP‐related Walker‐Warburg syndrome or Muscle‐Eye‐Brain disease (#613153; AR) |
| 39 | Mild bowing of femoral bones with normal length. | SD | DYNC2H1 | NM_001080463.1: c.1151C > T NM_001080463.1: c.11488_11489del | p.(Ala384Val) p.(Gln3830fs) | CH | Pat Mat | P P | PS1, PM1, PM2, PM3, PP3, PP5 PVS1, PM2, PM3 | Yes | In silico disease‐gene panel (tier 1) | n.a. | n.a. | Short rib thoracic dysplasia type 3 with or without polydactyly (#613091; AR) |
| 40 | Mild ventriculomegaly, cerebellar hypoplasia, ACC, rotated vermis, delayed gyration. | ICSA | TUBA1A | NM_001270399.1: c.1285G > A | p.(Glu429Lys) | Het | DN | P | PS2, PM1, PM2, PM5, PP3 | Yes | Clinical Exome (tier 1) | n.a. | n.a. | Lissencephaly type 3 (#611603; AD) |
| 42 | Bowing of‐ and short long bones with unequal aspect of skeleton. | SD | COL1A2 | NM_000089.3: c.2152G > T | p.(Gly718Cys) | Het | DN | LP | PS2, PM2, PM5, PP3 | Yes | In silico disease‐gene panel (tier 1) | n.a. | n.a. | Osteogenesis Imperfecta (Type 2, 3 or 4) (#166210; 259 420; 166 220; AD) |
| 43 | Shortening of long bones and small thoracic cage. Possibly a congenital heart defect. | SD | NIPBL | NM_133433.3: c.5044C > T | p.(Arg1682*) | Het | DN | P | PVS1, PS2, PM2, PP3 | Unclear | Clinical Exome (tier 2) | Postmortem examination: phenotype fitting with Cornelia de Lange syndrome | Yes | Cornelia de Lange syndrome (122 470; AD) |
| 50 | Polyhydramnion. Thickened nuchal fold. Fetal hydrops, pleural effusion. Macrosomia. Brachycephaly. ADV, PRUV. | MFCA | SOS1 | NM_005633.3: c.508A > G | p.(Lys170Glu) | Het | DN | P | PS2, PM1, PM2, PP3, PP5 | Yes | Clinical Exome (tier 1) | n.a. | n.a. | Noonan syndrome 4 (#610733; AD) |
| 54 | Phocomelia: hands attached to shoulders. Micrognathia. Prenasal thickness. Adduction of lower legs. | SD | RBM8A | NM_005105.4: c.‐21G > A Microdeletion 1q21.1 | p.(?) haploinsufficient allele | CH | Mat Pat | P P | PS4, PS5, PM3, PP4, PP5 | Yes | In silico disease‐gene panel (tier 1) | n.a. | n.a. | Thrombocytopenia absent radius syndrome (TAR) (#274000; AR) |
Abbreviations: AD, autosomal dominant; AR, Autosomal recessive; MFCA, multiple fetal congenital anomalies; rWES, rapid whole exome sequencing.