Table 2 Comparison of clinical features of the cohort of individuals heterozygous for the NF1 p.Met992del pathogenic variant with the cohorts of individuals with the NF1 missense pathogenic variants affecting codons 1809 and 844–848 as well as with large-scale previously reported cohorts of individuals with “classic” NF1

From: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

NF1 feature

N (%)

P value (2-tailed Fisher’s exact test)

p.Met992dela

p.Arg1809b

aa 844–848c

Previously reported NF1 cohortsd

p.Met992del vs. p.Arg1809

p.Met992del vs. aa 844–848

p.Met992del vs. “classic” NF1

>5 CALMs

165/182 (90.7)

157/169 (92.9)

130/157 (82.8)

1537/1728 (89)16

 

0.0357 ↗

 

Skinfold freckling

105/171 (61.4)

95/161 (59)

104/144 (72.2)

1403/1667 (84.2)16

  

<0.0001p ↘

Lisch nodules

16/139 (11.5)

12/120 (10)

42/98 (42.9)

729/1237 (58.9)16

 

<0.0001p ↘

<0.0001p ↘

Major external plexiform neurofibromase

0/125 (0)

0/105 (0)

36/92 (39.1)

120/648 (18.5)11,18

 

<0.0001p ↘

<0.0001p ↘

Cutaneous neurofibromasf

0–1/57 (0–1.8)g

0/57 (0)

47/69 (68.1)

656/723 (90.7)12,13,18,22,23

 

<0.0001p ↘

<0.0001p ↘

Subcutaneous neurofibromasf

0–3/36 (0–8.3)g

0–5/57 (0–8.8)g

33/65 (50.8)

297/515 (57.7)18,22,23

 

<0.0001p ↘

<0.0001p ↘

Symptomatic spinal neurofibromas

1/165 (0.6)

0/76 (0)

13/127 (10.2)

36/2058 (1.8)11,18,19

 

0.0001p ↘

 

Symptomatic OPGsh

0/170 (0)

0/139 (0)

12/136 (8.8)

64/1650 (3.9)16

 

<0.0001p ↘

0.0033o ↘

Asymptomatic OPGsi

1/41 (2.4)

0/38 (0)

18/63 (28.6)

70/519 (13.5)14,21,24

 

0.0005p ↘

0.0473 ↘

Brain tumors

6/126 (4.8)j

1/129 (0.8)k

4/139 (2.9)l

    

Skeletal abnormalities

30/172 (17.4)

21/126 (16.7)

48/144 (33.3)

144/948 (15.2)11,17,18,23

 

0.0016o ↘

 

Scoliosisf

7/57 (12.3)

6/48 (12.5)

20/64 (31.3)

51/236 (21.6)12,13,23

 

0.0159 ↘

 

Cognitive impairment and/or learning disabilities

58/176 (33)

80/159 (50.3)

56/138 (40.6)

190/424 (44.8)11,18

0.0018o ↘

 

0.0082o ↘

Noonan-like featuresm

19/166 (11.5)

46/148 (31.1)

10/134 (7.5)

57/1683 (3.4)16

<0.0001p ↘

 

<0.0001p ↗

Short staturen

16/118 (13.6)

32/111 (28.8)

15/91 (16.5)

109/684 (15.9)11,22

0.0056o ↘

  

Macrocephaly

30/132 (22.7)

31/107 (29)

36/98 (36.7)

239/704 (33.9)11,22

 

0.0267 ↘

0.0111 ↘

Pulmonic stenosis

8/160 (5)

14/132 (10.6)

2/113 (1.8)

25/2322 (1.1)20

  

0.0009p ↗

  1. CALMs, café-au-lait macules; NF1, neurofibromatosis type 1; OPG, optic pathway glioma.
  2. aBased on data from this study and Upadhyaya et al.4
  3. bBased on data from Pinna et al.,5 Rojnueangnit et al.,6 Ekvall et al.,8 Nyström et al.,9 and Santoro et al.10
  4. cBased on data from Koczkowska et al.7
  5. dBased on data from Huson et al.,11,12,13 Listernick et al.,14 Van Es et al.,15 Friedman and Birch,16 Cnossen et al.,17 McGaughran et al.,18 Thakkar et al.,19 Lin et al.,20 Blazo et al.,21 Khosrotehrani et al.,22 Plotkin et al.,23 and/or Blanchard et al.24
  6. eIn individuals ≥9 years old.
  7. fIn individuals ≥19 years old.
  8. gIndividuals with few (2–6) cutaneous or subcutaneous “neurofibromas”; none were biopsied and therefore none have been histologically confirmed.
  9. hThe absence of symptomatic OPGs was determined by ophthalmological examination and/or by magnetic resonance imaging (MRI).
  10. iIncluding only individuals without signs of symptomatic OPGs who underwent MRI examination.
  11. jOnly brain tumors, not including OPGs and neurofibromas, included, that is, astrocytoma (n = 1), oligodendroglioma (n = 1), hypothalamic glioma (n = 1), craniopharyngioma (n = 1), brain tumor with hamartomatous aspect by MRI of the encephalon (n = 1), and astrocytoma/dysembryoplastic neuroepithelial tumor (DNET) (n = 1).
  12. kOnly brain tumors, not including OPGs and neurofibromas, included, that is, astrocytoma (n = 1).
  13. lOnly brain tumors, not including OPGs and neurofibromas, included, that is, hypothalamic glioma (n = 1) and cerebral tumors (n = 3).
  14. mAn individual was classified as having Noonan-like phenotype when at least two of the following features were present: short stature, low-set ears, hypertelorism, midface hypoplasia, webbed neck, and/or pulmonic stenosis.
  15. nAs no specific growth curves are available for the Hispanic and Asian populations, Hispanic and Asian individuals were excluded as having short or normal stature.
  16. Statistically significant P values with false discovery rates (FDR) of 0.05 (indicated by o) and 0.01 (indicated by p) after correction for multiple testing using Benjamini–Hochberg procedure (see details in Table  S2 ). After applying the Benjamini–Hochberg correction, P ≤ 0.0082 and P ≤ 0.0009 remained statistically significant at FDR of 0.05 and 0.01, respectively. The black arrows indicate the statistically significant differences of the NF1 clinical features prevalence between the p.Met992del group and the cohort(s) used for the comparison, with the up and down arrows representing an increase and a decrease of the prevalence in the p.Met992del group, respectively.
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