Table 1. Clinical features ofs patients with NRAS variants.
| Patient ID | 1 | 2 | 3-1 | 3-2 | 3-3 | 4-1 | 4-2 | 5-1 | 5-2 | 5-3 | 6 | 7 | 8 | 9 | 10-1 | 10-2 | 11 | 12 | 13 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age at last follow-up | 5y | IUFD at 22+3 weeks | 13y8mo | 10y3mo | 36y | 6y8mo | 42y | 21y | 1 day | 50 | 2y5mo | 2y5mo | 7y1mo | 2y1mo | 18y4mo | 8y11mo | 11y3mo | 1y0mo | 1y0mo |
| Gender | f | m | m | m | f | f | f | m | f | m | f | f | f | m | m | m | f | f | m |
| Genotype | c.34G>A | c.35G>T | c.71T>A | c.71T>A | c.71T>A | c.149C>T | c.149C>T | c.179G>A | c.179G>A | c.179G>A | c.112-1_113dupGGA | c.173C>T | c.149C>T | c.179G>A | c.179G>A | c.149C>T | c.34G>C | c.35G>A | |
| p.(Gly12Ser) | p.(Gly12Val) | p.(Ile24Asn) | p.(Ile24Asn) | p.(Ile24Asn) | p.(Thr50Ile) | p.(Thr50Ile) | p.(Gly60Glu) | p.(Gly60Glu) | untested | p.(Gly60Glu) | p.(Glu37dup) | p.(Thr58Ile) | p.(Thr50Ile) | p.(Gly60Glu) | p.(Gly60Glu) | p.(Thr50Ile) | p.(Gly12Arg) | p.(Gly12Asp) | |
| Segregation | de novo | de novo | Maternally inherited | Maternally inherited | ? | Maternally inherited | Likely de novo | Likely paternally inherited | Likely paternally inherited | Possibly maternally inherited | de novo | Father untested, mother no mutation | Mosaicism in father | Parents untested | ? | Paternally inherited | ? | de novo | de novo |
| Mutation confirmed in non-hematopetic tissue | Finger nails, buccal cells | Saliva, urine | Finger nails | Skin fibroblasts | |||||||||||||||
| Phenotype | NS | ND | NS | NS | NS | NS | NS | NS | NS | NS | NS | CFCS | NS | NS | NS | NS | CFCS | CS | NS |
| Prenatal findings | − | NE, HF | PH | − | ND | PH, HD | ND | PH, PST | PE, FA | ND | NE, PE, mild VM, congenital chylothorax | NE, PH, intracerebral arachnoid cyst, bilateral hydronephrosis | ND | ND | − | PH | − | PH | PH, mild pyelocalyceal dilatation left kidney |
| Feeding difficulties | + | ND | − | − | ND | − | ND | ND | − | ND | + | + | − | + | − | − | − | + | − |
| Heart defects/ anomalies | VSD, ASD, HCM, PDA | ND | HCM | HCM | HCM | HCM | − | PST, VSD | HCM | − | − | ASD | − | AVS | − | − | MVP | PDA,HCM | − |
| Lymphedema | − | ND | − | − | − | − | − | − | nLE | − | nLE, nCT | nLE | − | − | − | − | − | − | − |
| Height SDS | −2.91 | ND | −2.60 | −1.91 | −1.41 | 0.13 | ND | 0.32 (at 12y) | ND | −1.81 | −2.44 | −2.69 | 0.17 | −1.43 | −3.60 | −1.35 | −1.47 | −0.80 | 1.03 |
| Developmental delay | MD | ND | ID (mild) | MD, ID (mild) | ID (mild) | − | − | ID (mild) | ND | − | − | MD, ID (severe) | MD | − | − | − | MD, ID (mild) | MD (mild) | − |
| Cryptorchidism | NA | ND | + | + | NA | NA | NA | + | NA | + | NA | NA | NA | + | − | − | NA | NA | − |
| Hair and skin | CH | ND | WH, MN | WH | CH, MN, HA | SH, CH, SE, KP | − | ML | ND | ML | − | SH, HA | KP | KP, HA | MN | − | KP, MN | SH, MN | MN, CalS |
| Skeletal | SN | ND | SN | SN | SN | TH, SN | SN | TH, SN | ND | TH, SN | − | TH, SN | TH, SN | SN | SN | SN | SN | TH, SN | SN |
| Bleeding diathesis | − | ND | + | + | − | − | − | − | ND | − | − | − | Willebrand disease | − | − | − | − | − | ND |
| Ocular abnormalities | PT | ND | PT | PT, RE | PT | PT | PT | PT | ND | PT | PT | RE, ST, optic nerve pallor, gaze deviation | PT, RE | ST | PT, RE | − | PT, RE, ST | PT | PT |
| Additional | Died on first day of life from severe hydrops; post mortem MRI: left ventricular hypertrophy | Mildly dilated ventricles and extra-axial spaces | 1.24 Mb gain from 22q11.23; hydronephrosis with duplex collecting system, recurrent UTIs, ureteroceles. | Right clubfoot | Bilateral clubfoot | Hydrocephalus; perinatal complications with asphyxia, sepsis, and portal vein thrombosis | upper airway obstruction required tracheostomy; hyperinsulinemic hypoglycaemia; hypothalamic tumor | minor renal anomalies, JMML, external hydrocephalus |
Abbreviations: +, present; −, absent; ASD, atrial septal defect; AVS, atrial valve stenosis; CalS, café au-lait spots; CFCS, cardio-facio-cutaneous syndrome; CH, curly hair; CS, Costello syndrome; f, female; FA, fetal ascites; HA, haemangioma; HCM, hypertrophic cardiomyopathy; HD, prenatal heart defect; HF, hydrops fetalis; ID, intellectual disability; IUFD, intrauterine fetal death; JMML, juvenile myelomonocytic leukemia; KP, keratosis pilaris; m, male; mo, month(s); MD, motor delay; ML, multiple lentigines; MN, multiple nevi; MVP, mitral valve prolapse; NA, not applicable; nCT, neonatal chylothorax; ND, no data; NE, fetal nuchal oedema; nLE, neonatal lymphatic oedema; NS, Noonan syndrome; PDA, persistent ductus arteriosus; PE, fetal pleural effusions; PH, polyhydramnios; PST, pulmonary stenosis; PT, ocular ptosis; RE, refractive error; SE, sparse eyebrows; SH, sparse hair; SN, short neck /webbed neck; ST, strabismus; TH, thorax anomaly; VSD, ventricular septal defect; VM, ventriculomegaly; WH, wooly hair; y, year(s).
NRAS variants are described in the three-letter code according to the isoform NP_002515.1.