Introduction
Subjects and methods
Subjects
Whole-exome sequencing and variants interpretation
Results
Clinical manifestations of seven Chinese patients with KS
Patient | 1 | 2 | 3 | 4 | 5 | 6 | 7 | Literature (N = 40) | Chinese cohort (N = 47) | Non-Chinese cohort (N = 86) (Ref. 17) |
---|---|---|---|---|---|---|---|---|---|---|
Gender | Female | Female | Male | Female | Male | Male | Female | |||
Age of diagnosis | 1.3 yrs | 11 Months | 5 Months | 7d | 7 yrs | 2.6 Months | 3.2 yrs | |||
Growth | ||||||||||
Short stature | + | – | – | – | + | + | + | 23 | 57.4% | 57% |
Neurological abnormalities | ||||||||||
Intellectual disability | + | – | + | NA | + | + | + | 32 | 80.4% | 90% |
Seizures | – | – | – | – | – | – | – | 4 | 8.5% | 15% |
Cerebellar vermis dysplasia | – | – | – | – | – | – | – | 1 | 2.1% | |
Corpus callosum hypoplasia | – | – | – | – | – | – | – | 1 | 2.1% | |
Dany-Walker malformation | – | – | – | – | – | – | – | 1 | 2.1% | |
Thinning of pituitary | – | – | – | – | + | – | – | 0 | 2.1% | |
Delay myelination of cerebral | – | – | + | – | – | – | – | 0 | 2.1% | |
Hydrocephalus | – | – | – | – | – | – | – | 1 | 2.1% | |
Craniofacial features | ||||||||||
Microcephaly | – | + | + | – | – | – | – | 3 | 10.6% | 41% |
Micrognathia | – | – | – | – | – | – | – | 3 | 6.3% | 39% |
High forehead and hairline | + | – | – | – | – | – | – | 0 | 2.1% | |
Low hairline | + | – | – | – | – | – | – | 2 | 6.3% | |
Hypertelorism | – | – | + | – | – | + | – | 8 | 21.2% | |
Epicanthus | – | – | – | – | + | – | – | 8 | 19.1% | |
Long palpebral fissures | – | + | + | – | – | – | + | 15 | 38.2% | 99% |
Strabismus | – | – | – | – | – | – | – | 1 | 2.1% | 37% |
Eversion of lateral third of lower eyelids | + | – | + | – | + | – | + | 14 | 38.2% | 87% |
Long eyelashes | + | – | – | – | – | – | + | 9 | 23.9% | |
Arched eyebrows | + | – | – | – | – | + | – | 2 | 8.7% | |
Sparse eyebrows | – | – | – | – | + | + | – | 18 | 42.5% | |
Depressed nasal tip | + | + | – | – | – | + | + | 29 | 70.2% | 80% |
Wide nasal bridge | + | + | – | – | – | + | – | 7 | 21.9% | |
A displastic ear | – | + | – | – | – | – | – | 3 | 8.7% | |
Large ears | – | + | – | – | + | + | – | 29 | 68.0% | 79% |
High-arched/cleft palate | – | + | + | – | – | – | + | 24 | 57.4% | 66% |
Thin upper vermillion | + | – | – | – | + | – | + | 2 | 10.6% | 76% |
Abnormal dentition | – | – | – | – | – | – | – | 5 | 10.6% | 51% |
Congenital heart defect | + | + | + | + | – | + | + | 14 | 42.6% | 42% |
Aortic coartation | – | + | – | – | – | – | – | 1 | 4.3% | |
Atrial septal defect | + | – | + | + | – | + | – | 6 | 21.7% | |
Ventricular septal defects | + | – | + | + | – | – | + | 6 | 21.7% | |
Patent ductus arteriosus | – | – | – | + | – | + | – | 1 | 6.5% | |
Patent foramen ovale | + | + | + | + | – | – | + | 5 | 21.7% | |
Aortic arch dysplasia | – | – | – | + | – | – | – | 0 | 2.2% | |
Internal organ problem | ||||||||||
Feeding difficulties | + | – | – | – | – | – | – | 3 | 8.5% | |
Anal atresia | – | – | – | – | – | + | – | 3 | 8.5% | |
Bilateral inguinal hernia | – | – | – | – | – | – | – | 2 | 4.2% | |
Splenomegaly | – | – | – | – | – | + | – | 1 | 4.2% | |
Cryptorchidism | – | – | – | – | – | – | – | 1 | 2.% | |
Hearing impairment | – | + | + | – | – | + | – | 13 | 34.0% | 25% |
Otitis media | – | – | – | – | – | + | – | 12 | 27.6% | |
Cholesteatoma | – | – | – | – | + | – | – | 2 | 6.4% | |
Cochlear dysplasia | – | – | – | – | – | + | – | 0 | 2.1% | |
Renal/ureter malformation | – | – | – | + | + | + | – | 2 | 10.6% | 40% |
Musculoskeletal features | ||||||||||
Hip joint dislocation | – | – | – | – | + | – | + | 9 | 23.4% | 26% |
Right diaphyseal femoral fracture | – | – | – | – | – | – | + | 0 | 2.1% | |
Fifth finger clinodactyly | + | – | – | – | – | – | – | 22 | 48.9% | 84% |
Absent palmer transverse crease | – | – | + | – | – | – | – | 5 | 12.7% | |
Fingertip pads | + | – | – | – | – | – | – | 24 | 53.2% | 89% |
Endocrine | ||||||||||
Hypoglycemia | – | + | + | – | – | – | – | 2 | 8.5% | 7–8% |
Early breast development | – | – | – | – | – | + | 1 | 4.2% | 28% |
Pathogenic variants in KMT2D and KDM6A
Phenotypic spectrum of 47 Chinese KS patients
Discussion
Case ID | Literature | Genes involve | Mutation | Preticted protein changes | Type of mutation | Inheritance | Exon | Pathogenic classification |
---|---|---|---|---|---|---|---|---|
1 | This study | KMT2D | c.5845delC | p.Q1949Sfs*98 | Frameshift del | De novo | 27 | Pathogenic |
2 | KMT2D | c.16294C > T | p.R5432W | Missense | NA | 51 | Likely Pathogenic | |
3 | KDM6A | c.2668-2671del | p.N891Vfs*27 | Frameshift del | De novo | 18 | Pathogenic | |
4 | KMT2D | c.6595delT | p.Y2199Ifs*65 | Frameshift del | NA | 31 | Pathogenic | |
5 | KMT2D | c.16442delG | p.C5481Lfs*6 | Frameshift del | NA | 52 | Pathogenic | |
6 | KMT2D | c.3926delC | p.P1309Qfs*21 | Frameshift del | NA | 12 | Pathogenic | |
7 | KMT2D | c.12630delG | p.Q4210fs*5 | Frameshift del | De novo | 39 | Pathogenic | |
8 | [7] Liu S, et al. BMC Med Genet. 2015, 16:26. | KMT2D | c.12199C > T | p.P4067Sr | Missense | De novo | 39 | Likely Pathogenic |
c.16295G > A | p.R5432Q | Missense | De novo | 51 | Likely Pathogenic | |||
9 | KMT2D | c.4664C > T | p.S1555F | Missense | De novo | 17 | Likely Pathogenic | |
10 | KMT2D | c.8639 T > C | p.L2880P | Missense | De novo | 34 | Likely Pathogenic | |
11 | KMT2D | c.3095delT | p.L1032Rfs24X | Frameshift del | NA | 11 | Pathogenic | |
12 | KMT2D | c.96C > G | p.D32E | Missense | De novo | 2 | Likely Pathogenic | |
13 | KMT2D | c.4395dupC | p.K1466Qfs25X | Frameshift del | NA | 15 | Pathogenic | |
14 | KMT2D | c.11638C > Aa | p.L3880 M | Missense | NA | 39 | Uncertain significance | |
15 | KMT2D | c.4140 T > A | p.C1370X | Nonsense | NA | 14 | Pathogenic | |
c.11718-11723delGCAACA | Non-Frameshift indel | NA | 39 | Likely Pathogenic | ||||
16 | [8] Yang P, et al. Am J Med Genet A. 2016, 170 (6): 1613–21. | KDM6A | exon1-2del | Frameshift del | De novo | Pathogenic | ||
17 | [9] Wu BB, et al. Chin J Evid Based Pediatr. 2017, 12 (2):135–9. | KMT2D | c.12697C > T | p.Q4233X | Nonsense | De novo | 39 | Pathogenic |
c.12696C > T | p.Q4232H | Missense | De novo | 39 | Pathogenic | |||
18 | KMT2D | c.3495delC | p.P1165Lfs*47 | Frameshift del | De novo | 11 | Pathogenic | |
19 | KMT2D | c.10881delT | p.L3627Rfs*31 | Frameshift del | De novo | 39 | Pathogenic | |
20 | KMT2D | c.16498C > T | p.R5500W | Missense | NA | 53 | Likely Pathogenic | |
21 | KMT2D | c.12560G > A | p.G4187E | Missense | NA | 39 | Likely Pathogenic | |
22 | KMT2D | c.16273G > A | p.E5425K | Missense | NA | 51 | Likely Pathogenic | |
23 | [10] JUN LU, et al. MOLECULAR MEDICINE REPORTS. 2016, 14: 3641–3645. | KMT2D | c.4485C > A | p.Y1495S | Missense | De novo | 16 | Pathogenic |
24 | [11] Chengqi Xin, BMC Medical Genetics. 2018, 19:31 | KMT2D | c.5235delA | p.A1746Lfs*39 | Frameshift del | De novo | 22 | Pathogenic |
25 | KMT2D | c.7048G > A | p.Q2350* | Frameshift del | De novo | 31 | Pathogenic | |
26 | [12] Ju-Li Lin, et al. Clinical Genetics, 2015, 88 (3): 255–260. | KMT2D | c.12307C > T | p.Q4013X | Nonsense | De novo | 38 | Pathogenic |
27 | KMT2D | c.3754C > T | p.R1252X | Nonsense | De novo | 11 | Pathogenic | |
28 | KMT2D | c.16294C > T | p.R5432W | Nonsense | De novo | 51 | Likely Pathogenic | |
29 | KMT2D | c.5993A > G | p.Y1998C | Missense | De novo | 28 | Likely Pathogenic | |
30 | KMT2D | c.16273G > A | p. E5425K | Missense | Father | 51 | Likely Pathogenic | |
31 | KMT2D | c.16273G > A | p. E5425K | Missense | Father | 51 | Likely Pathogenic | |
32 | KMT2D | c.16273G > A | p. E5425K | Missense | Father | 51 | Likely Pathogenic | |
33 | KMT2D | c.8743C > T | p.R2915X | Nonsense | De novo | 34 | Pathogenic | |
34 | KMT2D | c.5269C > T | p.R1757X | Nonsense | De novo | 22 | Pathogenic | |
35 | KMT2D | c.16273G > A | p.E5425K | Missense | De novo | 51 | Likely Pathogenic | |
36 | KMT2D | c.7650-1delCT | p.P2550Rfs2604X | Frameshift del | De novo | 31 | Pathogenic | |
37 | KMT2D | c.16135C > T | p.Q5379X | Nonsense | De novo | 51 | Pathogenic | |
38 | KMT2D | c.15326G > T | p.C5109F | Missense | De novo | 48 | Pathogenic | |
39 | KMT2D | c.16498C > T | p.R5500W | Missense | De novo | 53 | Pathogenic | |
40 | [13] LI Jieling, ea. al. J Clin Pediatr. 2018, 1 (36): 53–56. | KMT2D | c.7130C > Ta | p.P2377L | Missense | Father | 31 | Uncertain significance |
41 | KMT2D | IVS9 + 2 T > G | Splice mutation | De novo | Pathogenic | |||
42 | [14] Wang Hongmei, et al. Chin J Pediatr. 2018, 56 (11): 846–849. | KMT2D | c.11770C > T | p.Q3924X | Nonsense | De novo | 39 | Pathogenic |
43 | KMT2D | c.13033A > T | p.K4345X | Nonsense | De novo | 39 | Pathogenic | |
44 | KMT2D | c.1763C > G | p.S588X | Nonsense | De novo | 10 | Pathogenic | |
45 | KMT2D | c.5848delT | p.S1950Pfs*97 | Frameshift | De novo | 27 | Pathogenic | |
46 | KMT2D | c.16294C > T | p.R5432W | Missense | De novo | 51 | Likely Pathogenic | |
47 | [15] Guo Z,et al. BMC Med. Genet. 2018, 12 03;19 (1). | KDM6A | c.335-1G > T | Splice site mutation | mother | Likely Pathogenic |