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  • Research article
  • Open Access
  • Open Peer Review

Birt-Hogg-Dubé syndrome in two Chinese families with mutations in the FLCN gene

Contributed equally
BMC Medical GeneticsBMC series – open, inclusive and trusted201819:14

https://doi.org/10.1186/s12881-017-0519-z

  • Received: 3 October 2017
  • Accepted: 22 December 2017
  • Published:
Open Peer Review reports

Abstract

Background

Birt-Hogg-Dubé syndrome is an autosomal dominant hereditary condition caused by mutations in the folliculin-encoding gene FLCN (NM_144997). It is associated with skin lesions such as fibrofolliculoma, acrochordon and trichodiscoma; pulmonary lesions including spontaneous pneumothorax and pulmonary cysts and renal cancer.

Methods

Genomic DNA was extracted from peripheral venous blood samples of the propositi and their family members. Genetic analysis was performed by whole exome sequencing and Sanger sequencing aiming at corresponding exons in FLCN gene to explore the genetic mutations of these two families.

Results

In this study, we performed genetic analysis by whole exome sequencing and Sanger sequencing aiming at corresponding exons in FLCN gene to explore the genetic mutations in two Chinese families. Patients from family 1 mostly suffered from pneumothorax and pulmonary cysts, several of whom also mentioned skin lesions or kidney lesions. While in family 2, only thoracic lesions were found in the patients, without any other clinical manifestations. Two FLCN mutations have been identified: One is an insertion mutation (c.1579_1580insA/p.R527Xfs on exon 14) previously reported in three Asian families (one mainland family and two Taiwanese families); while the other is a firstly reviewed mutation in Asian population (c.649C > T / p.Gln217X on exon 7) that ever been detected in a French family.

Conclusions

Overall, The detection of these two mutations expands the spectrum of FLCN mutations and will provide insight into genetic diagnosis and counseling of Birt-Hogg-Dubé syndrome.

Keywords

  • Birt-Hogg-Dubé syndrome
  • FLCN
  • Pneumothorax

Background

Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant hereditary condition associated with skin lesions such as fibrofolliculoma, acrochordon and trichodiscoma, pulmonary lesions including spontaneous pneumothorax and pulmonary cysts and renal cancer. In 1925, Burnier and Rejsek reported an elderly female with multiple small skincolored papules on the head and neck, which was probably the first case of BHD [1]. In 1960, Zackheim and Pinkus described five more cases with similar clinical manifestations and histopathologic features [2]. In 1977, Birt, Hogg, and Dubé found that a few members of a thyroid cancer family had fibrofolliculoma that occurred in an autosomal dominant hereditary pattern [3]. In 2001, the susceptible locus was localised to chromosome 17p11.2 [4, 5]. Subsequently, protein-truncating mutations were identified in the FLCN (BHD) gene comprising 14 exons and encoding a protein called folliculin with unknown function [6]. Folliculin is expressed in most tissues including the skin and its appendages, the lungs (type 1 pneumocytes) and the kidney (distal nephron). Although the accurate function of this protein has not yet been clarified, it seems to be involved in the adenosine-monophosphate-activated protein kinase and mTOR pathways [7, 8]. Some studies have proved that downstream molecules of insufficient FLCN such as S6 kinase and hypoxia-inducible factor 1-alpha (HIF-1a) increases in renal tumors derived from BHDS patients. In the lung, cyst-lining cells were suggested to be activated due to their immunostaining positivity for phospho-mTOR and phospho-S6 ribosomal protein [912]. As neoplastic hyperplasia hardly occurs in cyst-lining cells, the mTOR pathway may be less distinctively detected in pulmonary cysts [11].

More than 200 mutations in the FLCN gene have been identifed, most of which are frameshift, nonsense, missense, or splice site mutations. The most common mutation in patients with Birt-Hogg-Dubé syndrome is c.1285dupC located in exon 11 [1322], followed by c.1533_1536delGATG [12, 15, 2325] and c.1278dupC [2629] depending on literatures listed worldwide up to date. Table 1 presents the mutations described in the FLCN gene up to now according to literatures summarized by searching “Birt-Hogg-Dubé syndrome” and “FLCN” on pubmed and Embase line.
Table 1

Germline mutations in Birt-Hogg-Dubé syndrome

Exon/Intron

Nucleotide changes

Amino acid changes

Exon 1

Exon1 deletion

Splice mutation

Exon 1

c.-487G > C

Splice mutation

Exon 1

c.-302G > A

Splice mutation

Exon 1

c.-299C > T

Splice mutation

Exon 1

chr17:17080497_17087267del; 17084378_17084502invins

Splice mutation

Exon 1

chr17:17078506_17084897del

Splice mutation

Exon 1

chr17:17080610_17086298del; insCCATGGGGG

Splice mutation

Exon 2–5

c.-227-853_c.397-295del

Splice mutation

Exon 3

c.-90A > G

Splice mutation

Exon 3

c. − 84G > A

Splice mutation

Exon 4

c.1A > G

p.Met1Val

Exon 4

c.3delG

p.Met1Xfs

Exon 4

c.3G > A

p.Met1?

Exon 4

c.50G > C

p.Arg17Pro

Exon 4

c.57_58delCT

p.Phe20Xfs

Exon 4

c.59delT

p.Phe20Xfs

Exon 4

c.119delG

p.Gly40Xfs

Exon 4

c.145G > T

p.Glu49a

Exon 4

c.147delA

p.Glu49Xfs

Exon 4

c.157C > T

p.Gln53a

Exon 4

c.158delA

p.Gln53Xfs

Exon 4

c.214delA

p.Ser72Xfs

Exon 4

c.235_238delTCGG

p.Ser79Xfs

Exon 4

c.240delC

p.Asp80Xfs

Exon 4

c.241delA

p.Met81Xfs

Exon 5

Deletion of Exon 5

Protein truncation

Exon 5

c.252delC

p.Gly84Xfs

Exon 5

c.296delA

p.Asp99Xfs

Exon 5

c.319_320delGTinsCAG

p.Val107 deletion/ insertion

Exon 5

c.319_320delGTinsCAC

p.Val107 deletion/ insertion

Exon 5

c.323G > T (778G > T)

p.Ser108Ile

Exon 5

c.328C > T

p.Gln110a

Exon 5

c.332_349del(18nucleotides)

p.His111_Gln116delXfs

Exon 5

c.340dupC

p.His114Xfs

Exon 5

c.347dupA

p.Leu117Xfs

Exon 5

c.376delG

p.Val126Xfs

Exon 5

c.394G > A

p.Glu132Lys

Exon 6

c.402delC

p.Pro135Xfs

Exon 6

c.404delC

p.Pro135Xfs

Exon 6

c.420delC

p.Ile141fs

Exon 6

c.427_429delTTC

p.Phe143del

Exon 6

c.443_459delACGGCTTTGTGTTCAGC

p.His148_153SerdelXfs

Exon 6

c.469_471delTTC

p.Phe157Xfs

Exon 6

c.499C > T

p.Gln167a

Exon 6

c.510C > G

p.Tyr170a

Exon 6

c.510C > A

p.Tyr170a

Exon 6

c.553 T > C

p.Ser185Pro

Exon 6

c.563delT

p.Phe188Xfs

Exon 6

c.[564_565dupCC;566_577delTGCTGGGGAAGG]

p.Leu189Xfs

Exon 6

c.573_574delinsT

p.Lys192Xfs

Exon 6

c.581delG

p.Gly195Xfs

Exon 6

c.583G > T

p.Gly195a

Exon 6

c.584delG

p.Gly195Xfs

Exon 6

c.601C > T

p.Gln201a

Exon 6

c.610_611delinsTA

p.Ala204a

Exon 7

c.632 633delAGinsC

p.Glu211Xfs

Exon 7

c.637delT

p.Phe213Xfs

Exon 7

c.649C > T

p.Gln217a

Exon 7

c.655dupG

p.Ala219Xfs

Exon 7

c.658C > T

p.Gln220a

Exon 7

c.668delA

p.Asn223Xfs

Exon 7

c.689dupT

p.Leu230Xfs

Exon 7

c.671_672delCA

p.Thr224Xfs

Exon 7

c.715C > T

p.Arg239Cys

Exon 7

c.726A > T

NS

Exon 7

c.769_771delTCC

p.Ser257Xfs

Exon 7

c.770_772delCCT

p.Ser257Xfs

Exon 7

c.747_756insGTGATGACAA

p.Asn249Xfs

Exon 7

c.779G > A

p.Trp260a

Exons 7–14

c.675-?_c.a +?del

 

Exon 8

∆E8

p.Trp260Xfs

Exon 8

c.836_839delCCGA

p.Thr279Xfs

Exon 8

c.853C > T

p.Gln285a

Exon 9

c.887C > A

p.Ser296a

Exon 9

c.889_890delGA

p.Glu297Xfs

Exon 9

c.890_893del

p.Glu297Xfs

Exon 9

c.923_950dup

Frameshift

Exon 9

c.932_933delCT

p.Pro311Xfs

Exon 9

c.933delT

p.Val312Xfs

Exon 9

c.943 G > T

p.Glu315a

Exon 9

c.946_947delAG

p.Ser316Xfs

Exon 9

c.991_992dupTC

p.Leu332Xfs

Exon 9

c.997_998delTC

p.Ser333Xfs

Exon 9

c.997_998dupTC

p.Gly334Xfs

Exon 9

c.1013delG

p.Trp338Xfs

Exon 9

c.1015C > T

p.Gln339a

Exon 9

c.1018delC

p.Arg341Xfs

Exon 9

c.1021delC

p.Arg341Xfs

Exons 9–14

c.872-?_c.1740 +? del

Protein truncation

Exon 10

c.1063 1065delGTC

p.Val355Xfs

Exon 10

c.1067 T > C

p.Leu356Pro

Exon 10

c.1076delC

p.Pro359Xfs

Exon 10

c.1095C > G

NS

Exon 10

c.1117C > T

p.Gln373a

Exon 10

c.1127G > A

p.Trp376a

Exon 10

c.1153 C > T

p.Gln385a

Exon 10

c.1156_1175del

Frameshift

Exon 10

c.1156_1176del

Frameshift

Exon 10

c.1165G > T

p.Glu389a

Exon 10–11

c.1063-154_1300 + 410dup

Exon 10 deletion

Exon 11

c.1183_1198del

Frameshift

Exon 11

c.1198G > A

p.Val400Ile

Exon 11

c.1215C > G

p.Tyr405a

Exon 11

c.1219delA

p.Ser407Xfs

Exon 11

c.1228G > T

p.Glu410a

Exon 11

c.1252delC

p.Leu418Xfs

Exon 11

c.1269C > T

NS

Exon 11

c.1278dupC

p.His429Xfs

Exon 11

c.1278delC

p.His429Xfs

Exon 11

c.1285dupC

p.His429Xfs

Exon 11

c.1285delC

p.His429Xfs

Exon 11

c.1285C > T

p.His429Tyr

Exon 11

c.1286dupA

p.His429Xfs

Exon 11

c.1294_1298delTCCTC

p.Ser432Xfs

Exon 11

c.1300G > A

Splice mutation

Exon 11

c.1300G > C

Splice mutation

Exon 12

c.1301-7_1304del;1323delCinsGA

Frameshift

Exon 12

c.1303delT

p.Phe435Xfs

Exon 12

c.1305delT

p.Phe435Xfs

Exon 12

c.1318 1334dup

Frameshift

Exon 12

c.1323delCinsGA

p.His442Xfs

Exon 12

c.1333G > A

p.Ala445Thr

Exon 12

c.1335_1351dup

Frameshift

Exon 12

c.1337 1343dup

Frameshift

Exon 12

c.1340 1346dup

Frameshift

Exon 12

c.1347_1353dupCCACCCT

Frameshift

Exon 12

c.1372dup (1827insC)

p.Gln458Xfs

Exon 12

c.1379_1380delTC

p.Leu460Xfs

Exon 12

c.1389C > G

p.Tyr463a

Exon 12

c.1408_1418 insGGGAGCCCTGT

Frameshift

Exon 12

c.1426dupG

Frameshift

Exon 12

c.1429C > T

p.Arg477a

Exon 12

CCACCCT insertion

 

Exon 13

c.1487_1490dup

Frameshift

Exon 13

c.1481A > G

p.Asn494Ser

Exon 13

c.1489_1490delGT

p.Val497Xfs

Exon 13

c.1490insCTGT

Frameshift

Exon 13

c.1522_1524del AAG

p.Lys508Xfs

Exon 13

c.1523A > G

p.Lys508Arg

Exon 13

c.1528_1530delGAG

p.Glu510Xfs

Exon 13

c.1533G > A

p.Trp511a

Exon 13

c.1533_1536delGATG

p.Trp511aXfs

Exon 14

c.1539-?_c.1740 +? del

Exon14 deletion

Exon 14

c.1552delC

p.Leu518Xfs

Exon 14

c.1557delT

p.Phe519Xfs

Exon 14

c.1579_1580insA

p.Arg527Xfs

Exon 14

c.1579C > T

p.Arg527a

Exon 14

c.1597_1598delCA

p.Gln533Xfs

Exon 14

c.1645C > G

p.Leu549Val

Exon 14

c.1658G > A

p.Trp553a

Exon 14

c.1677G > A

NS

Exon 14

c.1715 + 16insC(14–22)

Splice mutation

Exon 14

c.1715 + 582 T > C

Splice mutation

Intron1

c.-228 + 1368G > T

Splice mutation

Intron1

c.-229 + 994A > G

Splice mutation

Intron3

c.-25 + 100C > G

Splice mutation

Intron3

c.1-64A > G

Splice mutation

Intron 4

c.249 + 1G > T

Splice mutation

Intron 4

c.250-2A > G

Splice mutation

Intron 4

c.250-1G > A

Splice mutation

Intron 5

c.396 + 1G > A

Splice mutation

Intron 5

c.396 + 59 T > C

Splice mutation

Intron 5

c.397-14C > T

Splice mutation

Intron 5

c.397-13G > A

Splice mutation

Intron 5

c.397-13_397-4delGGCCCTCCAG

Splice mutation

Intron 5

c.397-10_397-2delGTCCCTCCA

Splice mutation

Intron 5

c.397-7_399delcctccagGTC

Splice mutation

Intron 5

c.397-2A > C

Splice mutation

Intron 5

c.397-1G > C

Splice mutation

Intron 5

c.397-7_399del

Splice mutation

Intron5-Exon6

cctccagGTCdeletion

Splice mutation

Intron6

c.618 + 2 T > A

Splice mutation

Intron6

c.619-66C > T

Splice mutation

Intron6

c.619-1G > A

Splice mutation

Intron 7

c.779 + 1G > T

Splice mutation

Intron 7

c.779 + 113C > T

Splice mutation

Intron 7

c.780-1G > T

Splice mutation

Intron8

c.871 + 3_871 + 4delGAinsTCCAGAT

Splice mutation

Intron8

c.871 + 13 T > C

Splice mutation

Intron8

c.871 + 16 T > A

Splice mutation

Intron8

c.871 + 36G > A

Splice mutation

Intron8

c.871 + 204A > G

Splice mutation

Intron8

c.871 + 226G > A

Splice mutation

Intron8

c.871 + 684G > A

Splice mutation

Intron 9

c.1062 + 1G > A

Splice mutation

Intron 9

c.1062 + 2 T > G

Splice mutation

Intron 9

c.1062 + 5G > A

Splice mutation

Intron 9

c.1062 + 6C > T

Splice mutation

Intron 9

c.1062 + 47G > A

Splice mutation

Intron 9

c.1063-172C > G

Splice mutation

Intron 9

c.1063-117C > T

Splice mutation

Intron9

c.1063-10_1065delTCTTGTTTAGGTC

Exon 10 skip

Intron 9

c.1063-2A > G

Splice mutation

Intron 10

c.1176 + 31G > A

Splice mutation

Intron 10

c.1176 + 39G > A

Splice mutation

Intron 10

c.1176 + 68G > C

Splice mutation

Intron 10

c.1176 + 134G > C

Splice mutation

Intron 10

c.1176 + 179A > G

Splice mutation

Intron 10

c.1177-165C > T

Splice mutation

Intron 10

c.1177-8_1177-6delTCC

Splice mutation

Intron 10

c.1177-5_1177-3delCTC

Splice mutation

Intron10

c.1177-2A > G

Splice mutation

Intron 11

c.1300 + 2 T > C

Splice mutation

Intron 11

c.1301-59C > T

Splice mutation

Intron 11

c.1301-7del11; 1323delCinsGA

Splice mutation

Intron 12

c.1432 + 1G > A

Splice mutation

Intron 12

c.1432 + 4 C > T

Splice mutation

Intron 12

c.1433-38A > G

Splice mutation

Intron 12

c.1433-1G > T

Splice mutation

Intron 13

c.1538 + 121C > T

Splice mutation

NS represented that the mutation was synonymous and the amino acid was not changed

fs represented frameshift

adesignates a stop codon

Objectives

The aim of this study is to explore the genetic mutations of two suspected BHDS families, and to see if they could expand the spectrum of FLCN mutations.

Methods

The two BHDS families were recruited from Peking Union Medical College Hospital and Xiangya Hospital Central South University. Detailed physical examination and other relevant examination of the participants were carried out. Peripheral venous blood samples of the participants were collected with anticoagulant tubes, storage and transportation of which were under the condition of 4 °C, then genomic DNA was extracted from blood samples within 6 h for further gene analysis: The whole blood and erythrocyte lysate were mixed thoroughly, kept still on ice for about 30 min until clear and then centrifuged at 3000 rpm for 10 min (4 °C); abandoned the supernatant, and mixed the remnant with nuclear lysate. Then added proteinase K into the mixture and mixed them thoroughly until there was no cell precipitate. Added SDS and shook at 37°Cfor 6 h or overnight. Added saturated phenol, mixed well up and down and centrifuged at 3000 rpm for 10 min (4 °C). Then put the supernatant into the mixture of saturated phenol and chloroform (1: 1), mixed well up and down and centrifuged at 3000 rpm for 10 min (4 °C); after that, put the supernatant into chloroform, mixed thoroughly up and down and centrifuged at 3000 rpm for 10 min (4 °C). The supernatant was added to a centrifuge tube previously charged with ethanol, gently inverted it to precipitate the DNA. The DNA and a small amount of ethanol was transferred to an eppendorf tube finally and stored at −20 °C in reserve.

With clinical manifestations and family history of pneumothorax, the patients and some of their relatives were diagnosed with suspected BHDS, at the meantime, unaffected relatives were invited to participate as controls. Members II10, III8, III10, III11, III12, III13, III14, IV1, IV2, IV3, IV4 in family 1 and II1, III2 in family 2 were sequenced. Publication of all the medical data has obtained consent of the participants, and the propositi consented on behalf of the deceased patients to both participate and to have their data published.

We selected one patient from each family respectively (IV3 in family 1 and III2 in family 2), carrying out whole exome sequencing for mutation detection: The 300 ng genomic DNA concentrations were sheared with Covaris LE220 Sonicator (Covaris) to target of 150-200 bp average size. DNA libraries were prepared using SureselectXT reagent kit (Agilent). The fragments were repaired the 3′ and 5′ overhangs using End repair mix (component of SureselectXT) and purified using Agencourt AMPure XP Beads (Beckman). The purified fragments were added with’A’ tail using A tailing Mix (component of SureSelectXT) and then ligated with adapter using the DNA ligase (component of SureselectXT). The adapter-ligated DNA fragments were amplified with Herculase II Fusion DNA Polymerase (Agilent). Finally, the pre-capture libraries containing exome sequences were captured using SureSelect capture library kit (Agilent). DNA concentration of the enriched sequencing libraries was measured with the Qubit 2.0 fluorometer dsDNA HS Assay (Thermo Fisher Scientific). Size distribution of the resulting sequencing libraries was analyzed using Agilent BioAnalyzer 2100 (Agilent). The libraries were used in cluster formation on an Illumina cBOT cluster generation system with HiSeq PE Cluster Kits (illumina). Paired-end sequencing is performed using an Illumina HiSeq system following Illumina-provided protocols for 2 × 150 paired-end sequencing. Then we applied Sanger sequencing aiming at corresponding exons in FLCN gene for subsequent validation of other family members roughly as follows: PCR amplification with appropriate primers on PCR amplifier - PCR cleanup in magnetic bead purification system - cycle sequencing on PCR amplifier - sequencing cleanup on magnetic bead purification platform - capillary electrophoresis on ABI3730. Interpretation of Sanger sequencing results was performed using SnapGene Software.

Results

Family 1 (F1)

The proband, a 47-year-old woman with a 25-year history of left-lung-pneumothorax, has had her left lung partially resected. Moreover, she was diagnosed with cerebral infarction 3 years ago on account of right limb numbness and visual defect in the lower half of the right eye. In addition, two of her sisters and their sons (Fig. 1: III8, III12, IV1, IV3) also had spontaneous pneumothorax history at the age of 39, 48, 21 and 21 respectively, a maximum frequency of which was six times. Diffuse lesions of the thyroid gland, superficial lymph node enlargement of the neck and extremities and subcutaneous nodules of the head, neck and hands were also revealed in one of her sister (III8) after pulmonary bubble resection; computed tomography (CT) scans of the other sister (III12) who had a history of hysteromyoma excision ever showed double renal cysts, which disappeared 2 years later in the renal ultrasonic examination results. While one nephew (IV1) of the proband had fat granules on his face and neck, who once underwent right branchial cystectomy; the other nephew (IV3) was diagnosed with chronic pancreatitis at 11 years old. A few of her other family members (Fig. 1:II1, II4, II7, II9, II11; II9: cerebral hemorrhage, others: cerebral infarction) also suffered from stroke, all of whom have passed away. One died of thrombocythemia (Fig. 1:III1). (Fig. 2).
Fig. 1
Fig. 1

Pedigre of family 1. proband. Cases with stroke. Thrombocythemia Case

Fig. 2
Fig. 2

Examination results and Sequence diagram of family 1. a, b, c Computed tomography scans showing multiple cystic lesions in the lungs of patients (III8、III12、III14). b, e Computed tomography scan and X-ray examination results showing pneumothorax (III8、IV3). d Fat granules on the skin (IV1). f Direct sequencing of exon 14 of FLCN revealed the frameshift mutation: c.1579_1580insA on exon 14

Family 2 (F2)

A 26-year-old man with after-exercise pectoralgia was diagnosed pneumothorax with CT scans, and before that, he once had a pneumothorax attack. In his family members, his father and grandfather also had pneumothorax history, for which his father had a thoracoscopic surgery. Besides, his grandfather passed away because of nephropathy without concrete information (Figs. 3 and 4). The clinical information of the two families are listed in Table 2.
Fig. 3
Fig. 3

Pedigre of family 2. proband

Fig. 4
Fig. 4

Examination results and Sequence diagram of family 2. a Computed tomography scans showing pulmonary cyst and pneumothorax (III2). b, c Multiple pulmonary cysts and pneumothorax in the lung of the proband’s father (II1). d, e Direct sequencing of exon7 of FLCN revealed the nonsense mutation: c.649C > T on exon 7

Table 2

Summary of clinical information of the two families

Number

Family

Sex

Age

Pneumothorax

Pulmonary Cysts

Skin lesion

Kidney lesion

Mutation Region

III8

F1

Female

53

Yes

Yes

Subcutaneous nodule

No

Exon 14

III12

F1

Female

48

Yes

Yes

No

Renal cysts

Exon 14

III14

F1

Female

47

Yes

Yes

No

No

Exon 14

IV1

F1

Male

28

Yes

No

Fat granules

No

Exon 14

IV3

F1

Male

21

Yes

Yes

No

No

Exon 14

IV4

F1

Female

18

No

No

No

No

Exon 14

II1

F2

Male

52

Yes

Yes

No

No

Exon 7

III2

F2

Male

26

Yes

Yes

No

No

Exon 7

Mutation examinations revealed that the proband, her two sisters, two nephews (III8, III12, IV1, IV3) and her son (IV4) in F1 all carried a one-base (A) -insertion between nucleotides c.1579_1580 on exon 14 (c.1579_1580insA) (Fig. 2f), resulting in a frameshift mutation (p.Arg527Xfs), which has ever been reported in three Asian families [3032]; while the proband and his father in F2 carried a one-base-substitution of C by T at nucleotide c.649 on exon 7 (c.649C > T) (Fig. 4d, e), resulting in a nonsense mutation (p.Gln217X), which was once recovered in a French family [22]. In addition, there are no mutations detected in the control subjects (II10, III10, III11, III13, IV2).

Discussion

Studies of patients with Birt-Hogg-Dubé syndrome are very rare especially in Asian countries.

In this study, we described two BHDS families and applied whole exome sequencing and Sanger sequencing to explore the genetic mutations. Patients from family 1 mostly suffered from pneumothorax and pulmonary cysts, several of whom also mentioned skin lesions or kidney lesions. While in family 2, only thoracic lesions were found in the patients, without any other clinical manifestations. Two FLCN mutations have been identified: One is an insertion mutation (c.1579_1580insA/p.R527Xfs) previously reported in three Asian families (one mainland family and two Taiwanese families); while the other is a firstly reviewed mutation in Asian population (c.649C > T/p.Gln217X) that ever been detected in a french family.

As we have reported above, patients from these two families were mostly characterized by pneumothorax, and even without any other clinical manifestations, which may remind us of BHDS and carrying out genetic tests for patients with familial pneumothorax history. However, the exact mechanism of this syndrome is still unclear till now. Our study could only expand the spectrum of FLCN mutations ethnically, there are still many aspects of BHDS to be explored.

Conclusions

Our detection of these two mutations expands the spectrum of FLCN mutations and will provide insight into genetic diagnosis and counseling of Birt-Hogg-Dubé syndrome.

Abbreviation

BHDS: 

Birt-Hogg-Dubé syndrome

Declarations

Funding

This study was supported by the National Key Research and Development Program of China (Nos. 2016YFC0901504, 2016YFC0905100, to Hong Jiang), the National Natural Science Foundation of China (Nos. 81471156, 81771231, to Hong Jiang), the National Natural Science Foundation of China (No.31401135, to Rong Qiu), High-level medical personnel of Hunan province “225” Project and Clinical Research Funds of Xiangya Hospital (No. 2014 L03, to Hong Jiang), the Natural Science Foundation of Hunan Province, China (No. 2017JJ2345, to Wei Zhuang). We are grateful for the assistance from Wuxi AppTec and TsingKe Biological Technology service.

Availability of data and materials

The data and materials generated during the study are available from the corresponding author on reasonable request. The datasets generated during the current study are available at the Sequence Read Archive (SRA) repository under accession code SRP127011. Confidential patient data has not been shared.

Authors’ contributions

Guarantor of integrity of entire study: WZ, HJ, KX, BS T; Study design: WZ and HJ; Literature research: XC H; Clinical studies: YZ; Experimental studies: XC H and YP; Data acquisition: YZ and YP; Data analysis/interpretation: XC H; Statistical analysis: XC H and YZ; Manuscript preparation: XC H and HJ; Manuscript defnition of intellectual content: WZ and YZ; Manuscript editing: XC H; Manuscript revision/review: RQ, KX; BS T; Experimental condition and facilities provision: KX; BS T; Final approval of the version to be published: all authors.

Ethics approval and consent to participate

This research has been approved by Medical Ethics Committee of Xiangya Hospital Central South University, China with the reference number of 201709983 (IRB(s) No.). Informed consent of all participants has been obtained, and the propositi consented on behalf of the deceased patients to both participate and to have their data published.

Consent for publication

Publication of all the medical data included in this article has obtained consent of the participants, and the propositi consented on behalf of the deceased patients to both participate and to have their data published.

Competing interests

The authors declare that they have no competing interests.

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Authors’ Affiliations

(1)
Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
(2)
School of Information Science and Engineering, Central South University, Changsha, Hunan, People’s Republic of China
(3)
Laboratory of Medical Genetics, Central South University, Changsha, Hunan, People’s Republic of China
(4)
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, People’s Republic of China
(5)
Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
(6)
Xiangya Hospital, Central South University, 87 Xiangya, Kaifu, Changsha, Hunan province, 410008, China
(7)
National Institute of Geriatrics Clinical Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China

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