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Clinical and genetic features of cystic fibrosis in Japan

Kozawa, Yuka Yamamoto, Akiko Nakakuki, Miyuki Fujiki, Kotoyo Kondo, Shiho Okada, Takuto Fukuyasu, Tomoya Yamaguchi, Makoto Taniguchi, Itsuka Nomura, Nao Liu, Libin Higuchi, Mayuko Niwa, Erina Sohma, Yoshiro Naruse, Satoru Takeyama, Yoshifumi Ishiguro, Hiroshi 名古屋大学

2023.10

概要

Cystic fibrosis (CF) is an autosomal recessive disease caused by variants in CF
transmembrane conductance regulator (CFTR) gene. CFTR is expressed in the apical
membrane of various epithelia and functions as a cyclic AMP-regulated anion channel.
Loss of function due to severe pathogenic variants in both alleles causes dehydrated,
thick, and viscous luminal fluid in respiratory and gastrointestinal tract, pancreatic duct,
and vas deferens. CF typically involves chronic infection and progressive obstruction of
the respiratory tract, pancreatic exocrine insufficiency (PI), and male infertility. CFTR
mediates Cl- absorption by the sweat duct and elevated sweat Cl- is the gold standard for
CF diagnosis.
While CF is one of the most common hereditary diseases in Europeans with an
estimated incidence of one in 2,500-3,500 newborns1,2, CF is very rare in East Asia. The
incidence of CF in Japan is approximately 1 in 590,000 live births3. In China, 78
patients were reported during 2015-2019 (ref. 4). Sporadic cases and case series in
institutions were reported from Korea and Taiwan5,6. Meanwhile, it has been reported
that the presence of CFTR variants increases the risk of chronic pancreatitis,
bronchiectasis, and male infertility in Japan, Korea, and China7,8,9,10,11.
Clinical phenotype and prognosis of CF in East Asia are not well understood and only a
few studies are found in the literature. Asians with CF in UK had a worse clinical course
(lung function and nutritional status) compared to clinic-matched non-Asian patients
homozygous for F508del12. Impact of Asian ethnicity on the diagnosis of CF was
recently examined by using the data accumulated in CFTR2 (Clinical and Functional
Translation of CFTR; https://cftr2.org/) and the UK CF database13. Asians with CF did
not have a worse clinical phenotype (no difference in lung function), while pancreatic
exocrine sufficiency (PS) was more common and more patients had sweat chloride
values lower than 60 mmol/L.
More than 2,000 different variants have been reported to the Cystic Fibrosis Mutation
Database (CFMD, www.genet.sickkids.on.ca/cftr). ...

論文の公開元へ

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FIGURE LEGENDS

Figure 1. Phenotype of cystic fibrosis patients in Japan

A: Sweat Cl-, fecal pancreatic elastase, %FEV1, SD scores of height and weight, BMI

percentile (%ile), serum levels of albumin and total cholesterol, and blood hemoglobin

of definite patients of cystic fibrosis aged <18 years (n=30). B: Sweat Cl-, fecal

pancreatic elastase, %FEV1, and BMI %ile in patients who have at least one CFTRdele16-17a-17b (dele16-17a-17b +, n=14) and patients those who do not have CFTRdele16-17a-17b (dele16-17a-17b ‒, n=16). C: Sweat Cl-, fecal pancreatic

elastase, %FEV1, and BMI %ile in patients with 2 East Asian/Japanese-type alleles

(Japanese-Japanese, n=21) and patients with 2 European-type alleles (EuropeanEuropean, n=7). D: Sweat Cl-, %FEV1, and BMI %ile in PI (n=26) and PS (n=4)

patients. Dotted lines indicate averages.

A (mmol/L)

160

140

120

100

Sweat Cl-

(μg/g)

1,400

3,000

(%)

120

1,200

(2,531) 100

1,000

800

400

200

Male

Female

Height SD score

2.0

1.0

0.0

-1.0

-2.0

-3.0

-4.0

-5.0

-6.0

1.0

0.0

-1.0

-2.0

-3.0

-4.0

-5.0

Male

(g/dL)

5.5

Female

(mg/dL)

240

220

200

180

160

140

120

100

Albumin

5.0

4.5

4.0

3.5

3.0

2.5

Male

B (mmol/L)

160

140

120

100

Female

(μg/g)

3,000

1,400

Sweat Cl-

Male

Female

Male

Female

Fecal pancreatic

elastase

(2,531)

1,200

Female

%FEV1

(%ile)

100

Fecal pancreatic

elastase

(2,531)

%FEV1

100

BMI %ile

Japanese European

-Japanese -European

(%ile)

100

200

400

dele16-17a-17b

600

dele16-17a-17b

(%)

120

BMI %ile

800

Male

1,000

Japanese European

-Japanese -European

Hemoglobin

(%)

120

dele16-17a-17b

(μg/g)

3,000

1,400

Female

200

Sweat Cl-

Male

400

C (mmol/L)

Total cholesterol (g/dL)

600

dele16-17a-17b

Female

BMI %ile

100

800

Male

Weight SD score (%ile)

1,000

Female

1,200

Figure 1

%FEV1

600

2.0

160

140

120

100

Fecal pancreatic

elastase

Japanese European

-Japanese -European

Japanese European

-Japanese -European

D (mmol/L)

160

140

120

100

(%ile)

100

Sweat Cl-

%FEV1

2.0

100

1.0

0.0

-2.0

-3.0

BMI %ile

(g/dL)

5.5

-4.0

Albumin

5.0

4.5

4.0

3.5

3.0

2.5

Height SD score

-1.0

(%)

120

-5.0

(mg/dL)

240

220

200

180

160

140

120

100

Total cholesterol

2.0

1.0

0.0

-1.0

-2.0

-3.0

-4.0

-5.0

-6.0

(g/dL)

Weight SD score

Hemoglobin

Figure 1

Table 1. Summary of CF patients in Japan since 1994

All patients

Male

Female

Diagnosis

Definite

Probable

132

116

Sweat [Cl-]

Positive

Borderline

Negative

Not examined

103

(78.0)

(4.5)

(3.0)

(14.4)

Pancreatic

exocrine

function

Not examined

(66.7)

(29.5)

(3.8)

Chronic sinopulmonary disease

113

(85.6)

112

(39.4)

(84.8)

Meconium ileus

(35.6)

Family history

(22.0)

Electrolyte imbalance

(21.2)

CF-associated liver disease (CFLD)

(14.4)

CF-related diabetes

(6.1)

CF-causing

CFTR variants 0

Not examined/unknown

(34.8)

(10.6)

(18.9)

(35.6)

Sinusitis

Pulmonary disase

(%)

(87.9)

(12.1)

Data are presented as numbers of patients (with percentage in parentheses).

Table 2. Genetic and clinical features of definite CF patients since 2007

Age at

onset

Age at

diagnosis

Male

Female

10.3

0.0

0.5

0.0

32.5

0.4

0.0

15.8

6.5

0.3

1.5

1.0

Male

0.0

Female

Male

Female

Male

Female

Male

Female

Male

Female

Male

Female

Male

Female

Male

Female

Male

Female

Male

Female

Male

1.0

4.6

0.0

0.4

3.0

10.0

0.4

0.1

1.8

6.6

0.5

10.0

0.1

0.8

0.4

0.9

0.0

4.3

0.1

9.8

0.0

0.4

1.0

0.0

15.1

0.0

10.4

3.4

0.0

0.4

4.5

0.0

15.0

19.7

Patient Gender

Allele-1

Allele-2

Ethnicity/

Country of origin

Japanese

Peruvian

Japanese

Ethnicity/

Country of origin

Japanese

Peruvian

Japanese

CFTR variant

(TG)mTn

CFTR-dele 16-17a-17b

R75X

L441P

G85R

G542X

CFTR-dele 16-17a-17b

TG12T7

TG11T7

TG12T7

TG11T7

TG12T7

TG10T9

TG12T7

0.9

Japanese

CFTR-dele 16-17a-17b

TG12T7

Japanese

3.3

4.8

0.8

10.7

3.9

28.6

0.6

0.4

3.4

6.6

0.9

16.0

1.0

0.9

0.4

5.4

10.3

0.1

4.3

5.0

10.5

0.7

11.4

2.5

0.2

15.2

0.2

18.5

13.7

0.5

0.4

5.0

5.8

0.2

31.0

20.0

Azerbaijani

Canadian

Filipino

Japanese

Pakistani

Japanese

Sri Lankan

Japanese

Pakistani

Japanese

Egyptian

Japanese

Pakistani

Japanese

Paraguayan

Japanese

European

Japanese

F508del

R1066C

Y517H

CFTR-dele 16-17a-17b

R347H

H1085R

Q1042fsX

H1085R

3499+56T>C

CFTR-dele 16-17a-17b

R75X

F508del

CFTR-dele 16-17a-17b

E474X

CFTR-dele 16-17a-17b

E585X

F508del

CFTR-dele 16-17a-17b

N1303K

CFTR-dele 16-17a-17b

G934S

3121-2A->G

F508del

L1156F

H1085R

CFTR-dele 16-17a-17b

405+1G->A

L812fsX

F508del

CFTR-dele 16-17a-17b

3121-2A->G

F508del

I148F

TG10T9

TG11T7

TG12T7

TG11T7

TG12T7

TG11T7

TG12T7

TG10T9

TG12T7

TG11T9

TG12T7

TG11T7

TG10T9

TG12T7

TG11T7

TG12T7

TG10T9

TG11T7

TG12T7

Azerbaijani

Japanese

Filipino

Japanese

European

Japanese

Pakistani

Japanese

Sri Lankan

Japanese

Pakistani

Japanese

Moroccan

Japanese

Pakistani

Japanese

Filipino

Japanese

Turk

Japanese

ND: not detected

Patient No. 45 had congenital bilateral absence of the vas deferens.

TG10T9

TG12T7

TG10T9

TG11T7

Pseudomonas

Chronic

Sweat

PS/PI

Meconium Electrolyte

CFLD Transplant

aeruginosa

sinopulmonary %FEV1

(Fecal elastase)

ileus

imbalance

infection

disease

CFTR variant

(TG)mTn

T1086I

CFTR-dele 16-17a-17b

L441P

E217G

L441P

CFTR-dele 16-17a-17b

1609delCA

CFTR-dele 16-17a-17b

Deletion of exon1 in

CFTR transcript

182delT

CFTR-dele 16-17a-17b

R1066C

1540del10

CFTR-dele 16-17a-17b

Y563H

F508del

L441P

CFTRdele 2-3

R347H

F508del

CFTR-dele 16-17a-17b

I1315fsX

876-3C>G

CFTR-dele 16-17a-17b

F508del

CFTR-dele 16-17a-17b

H1085R

CFTRdele promoter

Q1352X

CFTRdele promoter

3121-2A->G

F508del

R352W

CFTR-dele 16-17a-17b

L1156F

R347H

CFTRdele 20

CFTR-dele 16-17a-17b

1949del84

3272-3C>G

3121-2A->G

CFTR-dele 16-17a-17b

TG12T7

TG11T7

TG12T7

TG11T7

TG12T7

TG11T7

TG12T7

114

108

150

PI (19)

PS (600)

PS (2,531)

PI (0)

PI (1)

91.2

22.8

20.5

104.4

72.5

74.9

Lung

Liver

Lung

TG12T7

127

PI (0)

85.9

TG10T7

TG12T7

TG11T7

150

117

150

110

150

110

PI (0)

PI (4)

PI (16)

PS (910)

PI (2)

PI (70)

PS (852)

PS (493)

PI (1)

PI (0)

90.8

32.5

PI (5)

PI (2)

PI (5)

PI (3)

PI (1)

PI (3)

PS (204)

PS (1,100)

PI (75)

PS (622)

PS (926)

PI (0)

122

139

Lung

TG12T7

TG10T9

TG11T7

TG12T7

TG11T7

TG10T9

TG11T7

TG12T7

TG10T9

TG11T7

TG12T7

TG11T7

TG12T7

TG10T9

TG11T7

TG12T7

TG11T7

TG12T7

TG11T7

TG12T7

TG12T5

TG12T7

119

120

126

106

113

105

150

89.0

38.5

79.3

22.3

84.3

28.0

88.0

96.6

80.3

48.0

86.5

63.6

99.2

Table 3. Pathogenic CFTR variants in definite CF patients since 2007

Variant cDNA name

(gDNA name)

c.2908+1085_3367+260del

c.1521_1523delCTT

c.1322T>C

c.2989-2A>G

c.3254A>G

c.1040G>A

(g.117,361,112_117,498,678del)

c.223C>T

c.3196C>T

c.3468G>T

c.50delT

c.54-1760_274-10222del

rs ID

(Variation ID)

(690360)

rs113993960

rs397508188

rs193922515

rs79635528

rs77932196

rs121908749

rs78194216

rs139729994

rs397508714

Number of

alleles

Ethnicity

Variant protein name

Variant legacy name

Location

East Asian/Japanese

European

East Asian/Japanese

East Asian/Japanese?

East Asian/Japanese

East Asian/Japanese?

European

East Asian/Japanese

European

East Asian/Japanese

p.Gly970_Thr1122del

p.Phe508del

p.Leu441Pro

p.His1085Arg

p.Arg347His

p.Arg75Ter

p.Arg1066Cys

p.Leu1156Phe

p.Phe17SerfsTer8

East Asian/Japanese

c.253G>A

c.273+1G>A

c.442A>T

c.650A>G

c.744-3C>G

c.1054C>T

c.1210-12T[5]

c.1408_1417delATGATTATGG

c.1420G>T

c.1477_1478delCA

c.1549T>C

c.1624G>T

c.1687T>C

c.1753G>T

c.1820_1903del

c.2433_2437delinsATA

c.2800G>A

c.3123_3124insA

c.3140-3C>G

rs121908791

rs121909046

rs193922497

rs1805177

rs397508204

rs756206533

rs121908775

rs113993959

rs121909006

rs397508296

rs121908777

rs750655055

East Asian/Japanese

European

East Asian/Japanese

European

East Asian/Japanese

European

East Asian/Japanese

European

East Asian/Japanese

p.Gly85Arg

p.Ile148Phe

p.Glu217Gly

p.Arg352Trp

p.Met470GlufsTer54

p.Glu474Ter

p.Gln493ValfsTer10

p.Tyr517His

p.Gly542Ter

p.Tyr563His

p.Glu585Ter

p.Met607_Gln634del

p.Leu812TyrfsTer10

p.Gly934Ser

p.Gln1042fsTer

CFTR-dele 16-17a-17b

F508del

L441P

3121-2A->G

H1085R

R347H

CFTRdele promoter

R75X

R1066C

L1156F

182delT

CFTRdele 2-3

Deletion of exon 1 in

CFTR transcript

G85R

405+1G->A

I148F

E217G

876-3C>G

R352W

1540del10

E474X

1609delCA

Y517H

G542X

Y563H

E585X

1949del84

L812fsX

G934S

Q1042fsX

3272-3C>G

c.3257C>T

rs77958296

East Asian/Japanese

p.Thr1086Ile

T1086I

Exon 20

c.3367+56T>C

c.3717+3170_3874-4971del

c.3909C>G

c.3944_3951delTATGGAAA

c.4054C>T

rs80034486

rs754392413

rs751098333

East Asian/Japanese

European

p.Val1240_Gln1291del

p.Asn1303Lys

p.Ile1315fsTer

p.Gln1352Ter

3499+56T>C

CFTRdele 20

N1303K

I1315fsX

Q1352X

Intron 20

Intron 22~Intron 23

Exon 24

Exon 25

Reference transcript number: NM_00492.4

Human genome reference sequence: GRCh38/hg38

Intron 17~Intron 20

Exon 11

Exon 10

Intron 18

Exon 20

Exon 8

ASZ1 Exon 13~CFTR Intron 1

Exon 3

Exon 20

Exon 21

Exon 1

Intron 1~Intron 3

Pathological significance

(mutation class)

CF-causing (II)

CF-causing (V)

CF-causing (II)

CF-causing (III)

CF-causing (I)

CF-causing (II)

Pathogenic

CF-causing (I)

CFMD, CFTR2, ref. 17, ref. 24

CFMD, CFTR2

CFMD, ref. 25

CFMD, CFTR2

CFMD, ref. 26

CFMD, CFTR2, ref. 27

ref. 28

CFMD, CFTR2

CFMD, CFTR2, ref. 29

CFMD, ref. 8

CFMD, CFTR2

CF-causing (V)

ref. 17

Exon 3

Intron 3

Exon 4

Exon 6

Intron 6

Exon 8

Intron 9

Exon 11

Exon 13

Exon 14

Exon 17

Exon 19

Intron19

Pathogenic

CF-causing (I)

Likely pathogenic

Pathogenic

CF-causing (V)

Pathogenic

CF-causing (V)

CF-causing (I)

Likely pathogenic

CF-causing (I)

Pathogenic

CF-causing (I)

CF-causing

CF-causing (I)

Uncertain significance

CF-causing (I)

CF-causing (V)

Likely pathogenic/

Uncertain significance

Likely benign

CF-causing

CF-causing (II)

CF-causing (I)

VarSome

CFMD, CFTR2

VarSome

CFMD, ref. 10

CFMD, CFTR2

CFMD

ClinVar

CFMD, CFTR2

VarSome

CFMD, CFTR2

ClinVar

CFMD, CFTR2

CFMD

ClinVar

Reference

CFMD, ClinVar, Varsome

VarSome

CFMD, CFTR2, ref. 30

ClinVar

Table 4. Genotype-phenotype relationship and impact of ethnicity

CFTR-dele 16-17a-17b

Meconium ileus

CF-associated

liver disease

Pancreatic exocrine

function

Electrolyte imbalance

Meconium ileus

CF-associated

liver disease

Pancreatic exocrine

function

Electrolyte imbalance

Japanese-Japanese

European-European

Data are presented as numbers of patients. NS: not significant

...

参考文献をもっと見る

分野

大学

学位論文種類・取得年

言語

Clinical and genetic features of cystic fibrosis in Japan

概要

関連論文

Genomic analysis for the prediction of prognosis in small-bowel cancer

Genomic analysis for the prediction of prognosis in small-bowel cancer

Case report: Late middle-aged features of FAM111A variant, Kenny–Caffey syndrome type 2-suggestive symptoms during a long follow-up

Clinical and genetic investigation of 136 Japanese patients with congenital hypothyroidism<Abstract of dissertation>

Genome-wide association study of IgA nephropathy using 23 465 microsatellite markers in a Japanese population

参考文献

分野

大学

学位論文種類・取得年

言語

コピーが完了しました

URLをコピーしました

Clinical and genetic features of cystic fibrosis in Japan

概要

関連論文

Genomic analysis for the prediction of prognosis in small-bowel cancer

Genomic analysis for the prediction of prognosis in small-bowel cancer

Case report: Late middle-aged features of FAM111A variant, Kenny–Caffey syndrome type 2-suggestive symptoms during a long follow-up

Clinical and genetic investigation of 136 Japanese patients with congenital hypothyroidism<Abstract of dissertation>

Genome-wide association study of IgA nephropathy using 23 465 microsatellite markers in a Japanese population

参考文献