Alternative titles; symbols
HGNC Approved Gene Symbol: FLCN
SNOMEDCT: 1263460007, 328561000119107; ICD10CM: J93.11; ICD9CM: 512.81;
Cytogenetic location: 17p11.2 Genomic coordinates (GRCh38) : 17:17,212,212-17,237,330 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p11.2 | Birt-Hogg-Dube syndrome | 135150 | Autosomal dominant | 3 |
| Colorectal cancer, somatic | 114500 | 3 | ||
| Pneumothorax, primary spontaneous | 173600 | Autosomal dominant | 3 | |
| Renal carcinoma, chromophobe, somatic | 144700 | 3 |
By positional cloning in a 700-kb critical region for Birt-Hogg-Dube syndrome (BHD1; 135150) on chromosome 17p11.2, Nickerson et al. (2002) identified a novel gene encoding a deduced 579-amino acid protein designated folliculin. The protein contains a conserved SLS potential phosphorylation site, a glutamic acid-rich coiled-coil domain, an N-glycosylation site, and 3 myristoylation sites. High sequence conservation was found between human folliculin and homologs in mice, Drosophila, and C. elegans. Northern blot analysis detected expression of a 3.8-kb transcript in most normal adult tissues, including skin, lung, and kidney, and in fetal lung, kidney, liver, and brain tissue.
The FLCN gene contains 14 exons (Nickerson et al., 2002).
By positional cloning, Nickerson et al. (2002) identified the FLCN gene on chromosome 17p11.2.
Using coimmunoprecipitation of FNIP1 (610594) and FLCN expressed in HEK293 cells and in vitro binding assays, Baba et al. (2006) showed that the C terminus of FLCN and amino acids 300 to 1166 of FNIP1 were required for optimal FLCN-FNIP1 binding. FLCN and FNIP1 colocalized to the cytoplasm in a reticular pattern. FNIP1 was phosphorylated by AMPK (see 602739), and its phosphorylation was inhibited in a dose-dependent manner by an AMPK inhibitor, resulting in reduced FNIP1 expression. FLCN phosphorylation was diminished by rapamycin and amino acid starvation and facilitated by FNIP1 overexpression, suggesting that FLCN phosphorylation may be regulated by mTOR (601231) and AMPK signaling. Baba et al. (2006) concluded that FLCN and FNIP1 may be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways.
Using small interfering RNAs with several human cell lines, Hartman et al. (2009) found that downregulation of TSC2 (191092) enhanced phosphorylation of ribosomal protein S6 (RPS6; 180460), whereas downregulation of BHD reduced phosphorylation of RPS6, suggesting that TSC2 and BHD down- and upregulate activity of the TORC1 complex (see 601231), respectively.
Hudon et al. (2010) confirmed the tumor suppressor activity of FLCN by nude mouse xenograft assays of 2 human renal cell carcinoma (RCC) lines with either diminished or reexpressed FLCN. Loss of FLCN expression led to context-dependent effects on RPS6. The authors observed diminished and increased activation of Rps6 resulting from diminished and increased expression levels of FLCN in human RCC cells when grown subcutaneously as solid tumors. In mouse Flcn +/- kidney sections, Rps6 was elevated in multilocular and large cysts from polycystic kidneys but was absent in small single cysts and very low in surrounding normal tissue. Hudon et al. (2010) concluded that FLCN is a general tumor suppressor in the kidney, and that loss of FLCN expression results in improperly elevated or diminished activation of RPS6, depending on cellular context.
By immunoprecipitation analysis of transfected HEK293 cells, followed by protein pull-down assays, Xia et al. (2016) showed that FLCN interacted directly with TDP43 (TARDBP; 605078). Overexpression of FLCN led to localization of TDP43 in cytoplasm, where it colocalized with markers of lysosomes, autophagosomes, and the ubiquitin-proteasome system. Under arsenite stress, TDP43 colocalized with stress granules. In contrast, RNA interference-mediated depletion of FLCN in arsenite-treated cells caused dissociation of TDP43 from stress granules and nuclear accumulation of TDP43. Xia et al. (2016) concluded that FLCN is critical for TDP43 translocation from nucleus to cytoplasm, which is required for stress granule assembly.
Benhammou et al. (2011) identified heterozygosity for deletion rearrangements in the FLCN gene in 9 patients from 6 families with BHD1. The mutations were identified by a combination of real-time qPCR, multiplex ligation-dependent probe amplification assay (MLPA), array-based genomic hybridization, and Sanger sequencing. Patient 1 (family A) had a deletion involving exons 2-5, patients 2 and 3 (family B) had a mutation involving exons 7-14, and patients 4-9 from 4 families (families C-F) had mutations involving exon 1. A luciferase reporter assay testing the shared region among patients 4-9 demonstrated decreased activity compared to wildtype FLCN. The deletions in FLCN in families A, C, and E were flanked by Alu repeats, which Benhammou et al. (2011) hypothesized explained the deletion mechanism. Clinical features in this patient cohort were similar to those in patients with point mutations in the FLCN gene.
Birt-Hogg-Dube Syndrome 1
Birt-Hogg-Dube syndrome (BHD1; 135150) is a rare inherited genodermatosis characterized by hair follicle hamartomas, kidney tumors, and spontaneous pneumothorax. In 9 BHD1 families and an additional 53 probands from small BHD1 families, Nickerson et al. (2002) identified insertion or deletion mutations within a hypermutable C8 tract in exon 11 of the BHD gene in 27 (44%) of 62 patients. Eighteen had a 1-bp duplication (1285dupC; 607273.0001), and 9 had a 1-bp deletion (1285delC; 607273.0002) in the C8 tract. A slippage-mediated mechanism during DNA replication was thought to be responsible for these frameshift mutations leading to protein truncation. Nickerson et al. (2002) also identified an insertion-deletion mutation (607273.0003), a 28-bp duplication (607273.0004), and a tyr463-to-ter (Y463X; 607273.0005) mutation.
The studies of Khoo et al. (2002) further confirmed that the poly(C) tract in exon 11 of the BHD gene is a mutation hotspot.
Shin et al. (2003) screened the poly(C)8 tract of the BHD gene and identified mutations in 5 (16%) of 32 microsatellite instability (MSI) sporadic colorectal carcinomas and in 1 (7.7%) of 13 MSI colorectal carcinoma cell lines. They were unable, however, to find any frameshift mutation in 80 microsatellite stable (MSS) sporadic carcinomas or 9 MSS colorectal carcinoma cell lines. In addition, they identified 2 heterozygous missense mutations in different cell lines with MSI. Shin et al. (2003) found that the 16% frequency of mutations in the BHD gene was the same as that in the IGF2R gene (147280) and this was less than that of the TGFBR2 (190182), MSH3 (600887), BAX (600040), and MSH6 (600678) genes. All tumors with the BHD gene mutation harbored concurrent mutations of the poly(C)8 tract of the MSH6 gene, but the frameshift mutations of the BHD and IGF2R genes were mutually exclusive. These findings strongly suggested that the BHD gene is associated with colon cancer and that putative MSI target genes are involved in the development of MSI colorectal carcinomas.
Khoo et al. (2002) reported a high incidence of colorectal polyps and carcinomas in patients with confirmed BHD germline mutations, indicating that the BHD gene may be involved in colorectal tumorigenesis. Kahnoski et al. (2003) evaluated the role of the BHD gene in 47 unselected colorectal tumors (10 polyps and 37 carcinomas) by screening all coding exons of the BHD gene for mutations and analyzing 46 of the tumors for loss of heterozygosity (LOH) in the chromosome region surrounding the BHD locus. Alterations in BHD promoter methylation profiles were determined in 23 cases of matched normal/carcinoma tissues. They reported the detection of 2 novel somatic missense mutations of the BHD gene and LOH in 81% of primary sporadic colorectal tumors with no change in promoter methylation profile. All mutations were detected in microsatellite stable (MSS) tumors.
Schmidt et al. (2005) performed direct sequencing of the BHD gene in 30 families with BHD and reported that combined with their previous data (Nickerson et al., 2002), they had identified germline BHD mutations in 51 (84%) of 61 families with BHD; 27 (53%) of the mutations involved either a cytosine insertion or deletion in the mononucleotide tract of 8 cytosines in exon 11 (607273.0001 and 607273.0002, respectively), which appears to represent a mutation hotspot. Schmidt et al. (2005) noted that most reported mutations were predicted to terminate folliculin prematurely and to result in loss of function and suggested that BHD may act as a tumor suppressor gene.
In affected individuals from 51 (88%) of 58 families with BHD, Toro et al. (2008) identified 23 different mutations in the FLCN gene, including 13 novel mutations (see, e.g., 607273.0014). The 1285insC and 1285delC mutations were most common, occurring in 14 and 5 families, respectively. All mutations except 1 were predicted to result in a truncated protein. There were no apparent genotype/phenotype correlations.
Nahorski et al. (2010) did not find any germline mutations in the FLCN gene among 50 patients with familial nonsyndromic colorectal cancer. In the same study involving 51 families with BHD, the authors found that those with the 1285dupC mutation (607273.0001) had a higher risk of colorectal neoplasia compared to those with the 610delGCinsTA mutation (607273.0016) (p = 0.016). Furthermore, somatic frameshift mutations in the exon 11 C(8) mononucleotide tract of FLCN were detected in 7 (23%) of 30 sporadic colorectal cancers with microsatellite instability, and the frequency of these somatic mutations was more common in tumors that also showed loss of MLH1 (120436) or MSH2 (609309) protein expression. The findings suggested that FLCN inactivation may contribute to colorectal tumorigenesis.
In 2 sibs (patients 10 and 11, family G) with BHD, Benhammou et al. (2011) identified a duplication involving exons 10-11 in the FLCN gene (607273.0018).
Primary Spontaneous Pneumothorax
Primary spontaneous pneumothorax (PSP; 173600), a condition in which air enters the pleural space and causes secondary lung collapse, is most often a sporadic trait but also occurs in families. In almost all patients it is associated with emphysema-like changes (bullae) in the lungs. By a genomewide scan in a large Finnish family with a dominantly inherited tendency to PSP, Painter et al. (2005) mapped the PSP locus to chromosome 17p11 where the FLCN gene maps. Screening of the FLCN gene revealed a 4-bp deletion in the first coding exon, which created a frameshift and protein truncation (607273.0009). All carriers of the deletion had bullous lung lesions. Unlike previously identified mutations in the FLCN gene, the exon 4 deletion seemed to be associated only with PSP, which showed 100% penetrance. The results suggested that changes in FLCN may have an important role in the development of PSP and, more importantly, of emphysema. Because of the strong association between primary spontaneous pneumothorax and the Birt-Hogg-Dube syndrome, Painter et al. (2005) suggested that patients with familial PSP should be investigated for increased risk of renal cancer.
In 5 of 8 unrelated Japanese patients with multiple lung cysts and spontaneous pneumothorax, but without skin or renal lesions, Gunji et al. (2007) identified mutations in the BHD gene (see, e.g., 607273.0001; 607273.0010; 607273.0011). All 5 patients had a family history of the disorder. Gunji et al. (2007) suggested that isolated pulmonary cysts and pneumothorax may be a milder form of the BHD syndrome and that patients should be monitored for renal or skin lesions.
In 10 of 102 Chinese probands with spontaneous pneumothorax, Ren et al. (2008) identified 4 different mutations in the FLCN gene (see, e.g., 607273.0001; 607272.0012-607272.0013). Although only 5 of the probands reported a family history of the disorder, genetic analysis showed that 8 of the probands had family members with either pneumothorax or pulmonary cysts as determined by imaging studies. Two mutation carriers from 2 different families did not have pulmonary cysts. The findings indicated reduced penetrance of both the pneumothorax phenotype and the cyst phenotype.
Kunogi et al. (2010) identified 15 different heterozygous germline FLCN mutations, including 2 large genomic deletions (see, e.g., 607273.0017), in 25 (69.4%) of the 36 Japanese patients with multiple lung cysts of undetermined cause, all but 1 of whom had suffered at least 1 pneumothorax. Only 6 of the mutation-positive patients had skin lesions, and 2 others had renal tumors. Kunogi et al. (2010) noted that mutations were most frequently identified in the 3-prime end of the FLCN gene, and that these Japanese patients with FLCN mutation had a very low incidence of skin and renal involvement.
Somatic Mutations
Kahnoski et al. (2003) reported the detection of 2 novel somatic missense mutations in the BHD gene (607273.0007 and 607273.0008) and LOH in 81% of primary sporadic colorectal tumors with no change in promoter methylation profile. The mutations were detected in microsatellite stable (MSS) tumors.
Nahorski et al. (2010) detected somatic frameshift mutations in the exon 11 C(8) mononucleotide tract of FLCN in 7 (23%) of 30 sporadic colorectal cancers with microsatellite instability, and the frequency of these somatic mutations was more common in tumors that also showed loss of MLH1 (120436) or MSH2 (609309) protein expression. The findings suggested that FLCN inactivation may contribute to colorectal tumorigenesis.
Nickerson et al. (2002) pointed to mapping studies suggesting that germline mutations in dog and rat BHD homologs lead to inherited renal cancer.
Hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis (RCND) is a naturally occurring canine kidney cancer syndrome that was originally described in German shepherd dogs. Lingaas et al. (2003) narrowed the RCND interval to a small region on canine chromosome 5 that overlapped the human BHD gene. The authors described a his255-to-arg mutation in exon 7 of the canine Bhd gene that segregated with the disease phenotype.
Okimoto et al. (2004) studied a model of renal carcinoma found in a colony of Sprague-Dawley rats in Japan. This hereditary renal carcinoma model was designated the 'Nihon' rat. In heterozygotes, renal carcinomas developed from early preneoplastic lesions, seen as early as 3 weeks of age, into adenomas by 8 weeks of age with complete penetrance of this renal carcinoma gene by the age of 6 months. The renal carcinomas that developed in heterozygotes were predominantly of the clear cell type, as is the case in the Eker rat, which likewise carries a single gene mutation, in the TSC2 gene (191092), as the cause of renal carcinoma. The Nihon mutation is tightly linked to genes located on the distal part of rat chromosome 10 close to the TSC2 gene (Hino et al., 2001). In the Nihon rat, Okimoto et al. (2004) identified a germline mutation in the BHD gene caused by insertion of a single nucleotide, resulting in a frameshift with a stop codon 26 amino acids downstream. They found that the homozygous mutant condition was lethal at an early stage of fetal life in the rat. They detected loss of heterozygosity (LOH) at the BHD locus in 10 of 11 primary renal carcinomas and found a nonsense point mutation in 1 LOH-negative case, fitting the Knudson 2-hit model. Okimoto et al. (2004) concluded that the Nihon rat provides insights into a tumor suppressor gene that is related to renal carcinogenesis and an animal model of human BHD syndrome. In the rat, the TSC2 gene on chromosome 10 is separated from the BHD gene by the IL3 gene (147740). In the human, the TSC2 gene is located on 16p13.3 and the BHD gene on 17p11.2. Demonstration of a germline mutation in the BHD gene in the Nihon rat indicates that there is no homology of synteny in this case.
Hartman et al. (2009) found that targeted deletion of Bhd in mice was embryonic lethal. Bhd +/- mice had no obvious physical or behavioral abnormalities, but they developed renal cysts and solid tumors made up of oncocyte-like cells. These cysts and tumors were visible microscopically between 3 and 6 months of age, and they increased in size and severity with age. Between 9 and 17 months of age, Bhd +/- mice also showed various hyperproliferative diseases of lung, skin, heart, liver, and spleen. Renal cyst formation in Bhd +/- mice was enhanced by exposure to the mitogen N-ethyl-N-nitrosourea. The oncocytic cells lining renal cysts were uniformly negative for phosphorylated Rps6, while adjacent normal tubules were moderately positive.
Hasumi et al. (2009) reported that heterozygous loss of Bhd in mice caused kidney tumor development with activation of Torc1 (CRTC1; 607536) and Torc2 (CRTC2; 608972). Human BHD kidney tumors showed similar activation of TORC1 and TORC2.
Hudon et al. (2010) generated a mouse model of Birt-Hogg-Dube syndrome. Flcn -/- mice died before embryonic day 8.5, whereas heterozygous mice manifested early preneoplastic kidney lesions, devoid of Flcn expression, that progressed toward malignancy, including cytopapillary adenomas.
Gosis et al. (2022) showed that mice with a liver-specific knockout of Flcn were partially protected against nonalcoholic fatty liver disease (NAFLD) when fed a diet high in trans fat, fructose, and cholesterol. The loss of Flcn in the liver prevented the mice from developing nonalcoholic steatohepatitis (NASH) and reversed disease when it had developed. The mechanism of action was proposed to be that, when FLCN is absent, mTORC1 (601231), which normally phosphorylates TFE3 (314310), is selectively inhibited. The unphosphorylated TFE3 then activates lipid catabolism and suppresses genes necessary for lipogenesis.
Based on the numbering system used by Wei et al. (2009), the 1733dupC mutation has been renumbered as 1285dupC. Nickerson et al. (2002) found that 27 (44%) of 62 cases of Birt-Hogg-Dube syndrome (BHD1; 135150) were due to a duplication (1285dupC) or a deletion (1285delC; 607273.0002) of 1 cytosine in a hypermutable C8 tract in exon 11 of the FLCN gene. In 18 (29%) of 62 unrelated BHD patients, they found the 1285dupC mutation, also known as the C9 mutation, resulted in a frameshift and protein truncation. In 9 (15%) of 62 BHD patients, they found the 1285delC mutation, also known as the C7 mutation.
Khoo et al. (2002) found the 1285insC and 1285delC mutations in exon 11 of the FLCN gene in 3 of 4 families with BHD1 as well as in 2 of 4 sporadic cases.
Gunji et al. (2007) identified the 1285insC mutation in a Japanese patient with isolated pulmonary cysts and primary spontaneous pneumothorax (173600), but no renal or skin manifestations of the BHD syndrome. She had her first pneumothorax at age 16 years and had a cousin with spontaneous pneumothorax.
Ren et al. (2008) identified the 1285insC mutation in affected members of a Chinese family with primary spontaneous pneumothorax and pulmonary cysts.
Nahorski et al. (2010), who referred to this mutation as 1285dupC based on numbering of +1 at the A of the initiation codon, found this mutation in 37 individuals from 9 families with BHD syndrome. Five individuals developed a colorectal neoplasm, including 3 with a malignant colorectal neoplasm, suggesting a genotype/phenotype correlation.
Based on the numbering system used by Wei et al. (2009), the 1733delC mutation has been renumbered as 1285delC. See 607273.0001 and Nickerson et al. (2002). The 1285delC mutation, which occurs in exon 11 of the FLCN gene, produces a frameshift and protein truncation.
Based on the numbering system used by Wei et al. (2009), the 1087delAGinsC mutation has been renumbered as 632delAGinsC. In affected members of a family with Birt-Hogg-Dube syndrome (BHD1; 135150), Nickerson et al. (2002) found an insertion-deletion mutation in exon 7 of the FLCN gene, resulting in a frameshift with protein truncation.
Based on the numbering system used by Wei et al. (2009), the 1378_1405dup mutation has been renumbered as 923_950dup. In a family with Birt-Hogg-Dube syndrome (BHD1; 135150), Nickerson et al. (2002) found that affected members had a 28-bp duplication in exon 9 of the FLCN gene. The mutation produced a frameshift and protein truncation.
Nickerson et al. (2002) found that affected members of a family with Birt-Hogg-Dube syndrome (BHD1; 135150) had a tyr463-to-ter (Y463X) mutation resulting from a C-to-G transversion at nucleotide 1844 in exon 12. Based on the numbering system used by Wei et al. (2009), this mutation has been renumbered as 1389C-G.
Based on the numbering system used by Wei et al. (2009), this mutation has been renumbered as 1284delTCinsA. In a chromophobe renal carcinoma occurring in a patient with Birt-Hogg-Dube syndrome (BHD; 135150), Khoo et al. (2002) identified a novel somatic mutation, 1732delTCinsA. This demonstrated that the Knudson second hit in some BHD-related tumors is a somatic mutation rather than loss of heterozygosity. The pedigree indicated affected members in 3 successive generations and by inference in a fourth earlier generation. The germline mutation occurred in the poly(C) tract in exon 11 of the FLCN gene.
In a colorectal carcinoma (114500), Kahnoski et al. (2003) identified a somatic ser79-to-trp (S79W) missense mutation.
In a colorectal carcinoma (114500), Kahnoski et al. (2003) identified a somatic ala445-to-thr (A445T) missense mutation.
In affected members of a Finnish family with primary spontaneous pneumothorax (173600) inherited in an autosomal dominant pattern, Painter et al. (2005) identified a 4-bp deletion in exon 4 (the first coding exon) of the FLCN gene (733delTCGG, or 690delTCGG), causing a frameshift and a stop codon 50 amino acids downstream. All family members with bullous lung lesions were heterozygous for the mutation with the exception of 1 male who had experienced one PSP episode; the authors considered PSP in this individual to be sporadic. Based on the numbering system used by Wei et al. (2009), this mutation has been renumbered as 235delTCGG.
In affected members of a Japanese family with pulmonary cysts and primary spontaneous pneumothorax (173600), Gunji et al. (2007) identified a heterozygous 4-bp deletion (1988delGATG) in exon 13 of the FLCN gene, resulting in a frameshift and premature protein termination. Based on the numbering system used by Wei et al. (2009), this mutation has been renumbered as 1533delGATG.
In a Japanese woman with pulmonary cysts and spontaneous pneumothorax (173600), Gunji et al. (2007) identified a heterozygous 1-bp deletion (857DELC) in exon 6 of the FLCN gene, resulting in a frameshift and premature protein termination. She had her first pneumothorax at age 25 years. Her brother and father were affected; her father also had a history of renal cancer. Based on the numbering system used by Wei et al. (2009), this mutation has been renumbered as 404delC.
Based on the numbering system used by Wei et al. (2009), this mutation has been renumbered as 469delTTC. In affected members of 4 unrelated Chinese families with spontaneous pneumothorax and/or pulmonary cysts (173600), Ren et al. (2008) identified a 3-bp in-frame deletion (924delTTC) in exon 6 of the FLCN gene, resulting in loss of the phe157 residue. One of the families had 6 mutation carriers. Two patients from different families were unaffected. Haplotype analysis excluded a common ancestry.
Based on the numbering system used by Wei et al. (2009), this mutation has been renumbered as 1156_1175del. In affected members of 4 unrelated Chinese families with spontaneous pneumothorax and/or pulmonary cysts (173600), Ren et al. (2008) identified a 20-bp deletion at nucleotide 1611 in exon 10 of the FLCN gene, resulting a frameshift and premature termination. Haplotype analysis excluded a common ancestry.
In affected individuals from 4 unrelated families with Birt-Hogg-Dube syndrome (BHD1; 135150), Toro et al. (2008) identified a heterozygous A-to-G transition in intron 4 of the FLCN gene, predicted to result in premature protein termination. Based on the numbering system used by Wei et al. (2009), this mutation has been renumbered as 250-2A-G.
In 18 members of a large Dutch family with Birt-Hogg-Dube syndrome (BHD1; 135150), Kluijt et al. (2009) identified a heterozygous complex mutation in the FLCN gene consisting of an 11-bp deletion in intron 11 (c.1756-7del11), resulting in the deletion of the splice acceptor site of exon 12, and a 1-bp deletion/2-bp insertion in exon 12 (c.1778delCinsGA). Two family members developed early-onset renal cancer at age 27 and 32 years, respectively. Based on the numbering system used by Wei et al. (2009), these mutations have been renumbered as c.1301-2del11 and c.1323delCinsGA, respectively.
In 32 individuals from 6 families with Birt-Hogg-Dube syndrome (BHD1; 135150), Nahorski et al. (2010) identified a heterozygous 2-bp deletion and 2-bp insertion (610delGCinsTA) in exon 6 of the FLCN gene. None of the patients with this mutation developed a colorectal polyp or colorectal cancer. The authors noted that the mutation had been previously designated 1065_1066delGCinsTA.
In a Japanese patient with multiple lung cysts and recurrent pneumothorax (173600), Kunogi et al. (2010) identified a large heterozygous deletion encompassing exons 9 to 14 of the FLCN gene using quantitative PCR and confirmed by Southern blot analysis. The patient had 7 pneumothorax episodes but no skin lesions or renal disease.
In 2 patients from a family (family G) with Birt-Hogg-Dube syndrome (BHD1; 135150), Benhammou et al. (2011) identified heterozygosity for a 1,342-bp duplication (c.1063-154_1300+410dup) in exons 10-11 of the FLCN gene, resulting in a frameshift and premature termination (Glu434GlyfsTer35). The mutation was identified by a combination of real-time qPCR, multiplex ligation-dependent probe amplification assay (MLPA), and Sanger sequencing.
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