Table 2.
Clinical features of validation cohort cases with Pathogenic/Likely Pathogenic NF1 or SPRED1 Variants
| ID | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age | 4M | 25Y | 18Y | 2Y | 1Y | 4Y | 9M | 4Y | 5.5M | 7Y | 3Y |
| Sex | F | F | M | M | F | F | F | M | M | M | F |
| Gene | NF1 | NF1 | NF1 | NF1 | NF1 | NF1 | NF1 | NF1 | NF1 | NF1 | SPRED1 |
| cDNA change | c.204+1G>T | c.2288T>C | c.2970_2972delAAT | c.3827G>A | c.3827G>A | c.3827G>A | c.4330A>G | c.5305C>T | c.6854_6855insA | c.(?_−50)_(*68_?)del | c.423+2T>C |
| Amino acid change | p.? | p.(Leu763Pro) | p.(Met992del) | p.(Arg1276Gln) | p.(Arg1276Gln) | p.(Arg1276Gln) | p.(Lys1444Glu) | p.(Arg1769*) | p.(Tyr2285*) | Whole gene deletion | p.? |
| Classification | Pathogenic | Likely Pathogenic | Pathogenic | Pathogenic | Pathogenic | Pathogenic | Pathogenic | Pathogenic | Pathogenic | Pathogenic | Pathogenic |
| Clinical Diagnosis/Suspicion | NFNS | NS | Legius or NFNS | Unspecified | NS | NS | NFNS or CFC | NF1 + other features | NFNS | NFNS | NF1 |
| Skin | |||||||||||
| Café au lait spots (n) | Y (multiple) | N | Y (11) | N | Y (7) | N | Y (15) | Y (multiple?) | Y (5) | Y (many) | Y (>6) |
| Lentigines | N | N | N | N | N | N | N | Y | N | N | N |
| Inguinal/Axillary freckling | N | N | N | N | N | N | N | Y | N | N | Y |
| Lisch Nodules | N | N | N | N | N | N | N | N | N | N | N |
| Wide‐spaced nipples | N | N | N | N | N | Y | N | N | N | N | N |
| Heart Defect | |||||||||||
| Pulmonic valve stenosis | Y | N | N | N | Y | Y | N | N | N | N | N |
| Other | Heart murmur | MVP | Vasculopathy | N | N | N | PFO | N | N | MVP | N |
| Facial Dysmorphism | |||||||||||
| Epicanthal Folds | N | N | N | N | Y | N | Y | Y | N | Y | N |
| Ptosis | N | N | N | N | N | Y | N | N | Y | N | N |
| Low Nasal Bridge | N | N | N | N | Y | Y | Y | N | N | N | wide nasal bridge |
| Macrocephaly | N | N | N | N | Y | N | Y | Microcephaly | N | Y | N |
| Hypertelorism | N | N | N | N | Y | Y | Y | N | N | N | N |
| Downward eye slant | N | N | N | N | N | N | Y | N | Y | N | N |
|
Low set/ posteriorly rotated ears |
N | Y | N | N | N | Y | Y | N | Y | N | N |
| Papillomas | N | N | N | N | N | N | N | N | N | N | N |
| Coarseness | N | N | N | N | N | N | Y | N | N | Y | Y (prominent lips) |
| Short/Thick neck | N | Y | N | N | N | Y | N | N | N | N | N |
| Short Stature | N | Y | Y | N | Y (1%ile) | N | N | N | N | N | Y (3%ile) |
| Neurological Features | |||||||||||
| Developmental Delay | Y | N | N | N | Y | Y | Y | Y | N | N | N |
| Learning Disabilities | N | N | Y | N | N | Y | N | Y | N | N | N |
| Intellectual Disability | N | N | N | N | N | Y | N | Y | N | N | Y |
| Seizures | N | N | Y | N | N | N | N | N | N | N | N |
| Other | N | N | N | N | N | N | N | N | N | ADHD | N |
| Skeletal Features | |||||||||||
| Pectus excavatum | N | N | N | N | N | Y | Y | N | N | Y | N |
| Pectus carinatum | N | N | N | N | N | N | N | N | N | N | N |
| Scoliosis | N | N | Y | N | N | Y | N | N | N | N | N |
| Neurofibromas | N | N | N | N | N | N | N | N | N | N | N |
| Other | Plagiocephaly | N | Possible malignancies | Hearing loss | Hepatomegaly | N | Hypotonia, Laryngomalacia | Hemangioma 6mo, encephalopathy | Tall forehead, cryptorchidism | Decreased hair pigmentation at midline frontal area | Bilateral vesicoureteral reflux, Short hands and broad fingers, similar feet |
| Family History | Mother has hypothyroidism, maternal cousin has HLHS | Patient is 22 weeks pregnant, fetus has cardiomegaly | Father has CALMs | None | None | Mother has learning disabilities, AFIB, and CALs, sister has NF1 and is carrier | Mother has wide‐spaced eyes, tall stature. Mother had 3 SABs. | Multiple maternal relatives have CALs and developmental problems | Maternal uncle died near term, was very small, soft head; additional uncle died at 1 yr | Multiple maternal relatives have 2–3 CALs | None |
Abbreviations: CALs, Cafe au lait macules; HLHS, Hypoplastic left heart syndrome; MVP, Mitral Valve Prolapse; PFO, patent foramen ovale; SAB, Spontaneous abortion
*
Transcripts: NF1 (NM_000267.3) and SPRED1 (NM_152594.3)