BMPR2 Database

Results in a novel start codon and the mutation segregated with the disease, not found in 400 ethnically matched controls.

Age at diagnosis 36, this mutation abolished a potential specificity protein 3 transcription factor-binding site and a dual luciferase assay showed that the promoter carrying this variant allele had significantly decreased transcriptional activity compared with the -669G allele. Similar findings by (Li 2009). rs115604088: minor allele frequency 0.008 (1000 Genomes) and 0.017 (CEU).

ID: 21646, complete null, confirmed de novo, deletion extended into the 5' region (Aldred 2006). Patient 68 in (Sztrymf 2008). Also reported in (Girerd 2010).

Reported once.

Family UKSp15: 31 years old at disease onset, Exon 01 and 12 analyzed for dosage; Family: UK01: eight affected individuals in the same family, age at disease onset for this family ranged from 1-42, Exon 01 and 12 analyzed for dosage (Machado 2001). ID: 3577 & ID:20801: predicted consequence: Altered translation start site or promoter deletion/complete null (Aldred 2006). Family 30 & 110: MLPA analysis showed a deletion of Exon 01; transcript was subject to nonsense mediated decay (Cogan 2006).

Patient 64 in (Sztrymf 2008). Also reported in (Girerd 2010).

Found in a patient with no family history of PAH, internal case.

Case 1: patient was 31 years old at time of study.

Age of onset: 72 years, published protein change was p.T10W; no family history of PAH.

Transcript escaped nonsense mediated decay, cultured lymphocytes contained detectable levels of the mutant transcript by translational re-initiation at a downstream Kozak sequence resulting in the omission of 173 amino acids; disease presentation at age 56 with family history; sequence published TGCCCTGG/ACTACCAT.

Family US70: two affected individuals in this family, age of disease onset ranged from 36-38 (Machado 2001). Reported in patient with pulmonary veno-occlusive disease, 36 years old at diagnosis, the truncated protein is predicted to contain only a segment of the extracellular domain and is therefore unlikely to be expressed on the cell surface, also found in an unaffected sibling (Runo 2003). Patient had pulmonary veno-occlusive disease (Machado 2006).

Patient 21140: diagnosis of PAH at 6 year of age, the mutant transcript was expected to be subject to nonsense mediated decay, mutation was de novo.

Patients 1 and 2 in (Sztrymf 2008). Also reported twice in (Girerd 2010).

Family UKsp14: 26 years old at age of onset; RT-PCR using mRNA isolated from whole-lung tissue yielded a PCR product deleted for nucleotides 51-814 encompassing the last 26 nucleotides of Exon 01, all of exons 2-5, and two-thirds of Exon 06.

Found in a patient with a family history of PAH, internal case.

rs34040645

ID: 21016; functional null; confirmed in affected sibling, Exon 01 encodes a 25 amino acid leader sequence and deletion results in a complete null (Aldred 2006). Family 57: MLPA analysis showed deletions of Exon 02-13, transcript was subject to nonsense mediate decay (Cogan 2006).

Family 12 and 108: MLPA analysis showed a deletion of Exon 02, predicted to result in an in-frame loss of amino acids 26-82, transcript was subject to nonsense mediated decay (Cogan 2006). Predicted consequence: In-frame deletion of 57 amino acids, extracellular ligand binding domain. ID: 5196. ID: 6224: peripheral occlusive vascular disease, RNA from lung tissue: exons 1 and 4 were amplified and sequenced, confirming deletion of Exon 02. Also reported in (Girerd 2010).

Patient 21: age 2, no family history of PAH (Rosenzweig 2008). Found in a patient with no family history of PAH, internal case (Smith unpublished).

Family 65: MLPA analysis showed a duplication of Exon 02, predicted to result in an in-frame duplication of amino acids 26-82, transcript was subject to nonsense mediated decay.

Classified as a polymorphism with a frequency 1/76 in a Chinese cohort.

rs112862820. Average heterozygosity: 0.005, chromosome count: 4532.

Patient ID K4518A: also found in unaffected parent.

Found in a patient with a family history of PAH.

Patient 21: age 30, no family history of PAH.

Patient also has pulmonary veno-occlusive disease.

Proband 17: symptom onset at age 14.

Adult 1: patient's age was 19 at initial catheterization, PAH diagnosis at age 1, patient also had down syndrome, and a congenital heart defect: complete atrial ventricular canal defect type C; this variant was not found in 196 healthy controls or 1,000 other PAH cases.

Child 6: PAH diagnosis at 19 months and was reported to have congenital hearth defect: aortopulmonary window and ventricular septal defect; this variant was not found in 196 healthy controls or 1,000 other PAH cases.

Family US42: Three affected family members; age of disease onset ranged from 32-39.

Polymorphism found in the general population with an allele frequency of 1.1% (Morisaki 2004). Classified as a polymorphism with a frequency of 1/76 in a Chinese cohort (Wang 2010). Polymorphism with a frequency of 1.1% (Machado 2006).

Patient 1: paternal inheritance, not found in 150 normal control chromosomes.

Pt 91: age 19 in (Elliott 2006). Also reported in (Machado 2006)

Diagnosis at 26 years of age, the variant was also found in two unaffected family members (father and sister), family history of PAH, nucleotide position was found using the published sequence because the nucleotide position was reported as 604 (Cahn 2004). Also reported in (Wang 2009) and (Wang 2010).

Patient 3 in (Sztrymf 2008). Reported twice in (Girerd 2010). Also reported in (Machado 2006).

Case 2: patient was 33 years old at time of study (Morisaki 2004). Reported twice in (Machado 2006). Patient 4 in (Sztrymf 2008). Patient 1: age 33 in (Wang 2010). Reported twice in (Girerd 2010).

Patient 9: age 41, family history of PAH.

Reported twice in (Machado 2006). Pt 60: age 46 in (Elliott 2006).

Family US35: not found in 214 chromosomes from healthy controls, this variant truncates the protein before the transmembrane domain and if translated may fail to reach the cell surface (Lane 2000). Pt 159: age 33 in (Elliott 2006).

Patient age at disease presentation was 83 with a family history of PAH, A low level of aberrant mRNA was detected in the lymphocytes from this patient.

Family 4452 in (Rindermann 2003). Reported once in (Machado 2006).

Patient had taken dexfenfluramine for 5 months, affected amino acid is in the extra cellular domain that is responsible for ligand binding and dimerization, not found in 130 healthy controls.

Patient 5 in (Sztrymf 2008). Also reported in (Girerd 2010).

Patient 1: age 12, family history of PAH.

Family 76: splice-site mutation led to the loss of amino acids 63-82 and less commonly the loss of amino acids 47-82 from the use of an Exon 02 cryptic splice-site 108bp upstream, transcript was subject to nonsense mediated decay.

Family 68: this alteration resulted in alternative use of two upstream GT cryptic donor sites located within Exon 02. One mutant species resulted from us on an Exon 02 cryptic splice site 108bp upstream resulting in loss of amino acids 63-82 and the other mutant species resulted from use of a second Exon 02 cryptic splice site 108 bp upstream resulting in loss of amino acids 47-82, transcript was subject to nonsense mediated decay.

Patient 3: age 5, family history of PAH.

Family 92 and 95: MLPA analysis showed a deletion of Exon 03, predicted to result in an in-frame loss of amino acids 83-139, transcript was subject to nonsense mediated decay (Cogan 2006). Found in a patient with no family history of PAH, internal case (Smith unpublished).

Splice defect, this substitution is located in the acceptor splice site of intron 2 (Machado 2006). Also reported in (Sztrymf 2008) and (Girerd 2010).

Patient 6 in (Sztrymf 2008). Also reported in (Girerd 2010) and (Machado 2006).

Patient 7 in (Sztrymf 2008). Also reported in (Girerd 2010) and (Machado 2006).

Polymorphism with a frequency of 1.1%.

Pt 303: transcript was subject to nonsense mediated decay.

Patient 8 in (Sztrymf 2008). Also reported in (Girerd 2010) and (Machado 2006).

Reported once, age: 34, no family history of PAH (Wang 2009 and 2010).

Patient 2: age 34; no family history of PAH.

Pt 113: age 38 in (Elliott 2006). Patient 4: age 14, family history of PAH in (Rosenzweig 2008). Also reported twice in (Machado 2006).

Adult 2: PAH diagnosis at 16 years and was reported to have congenital heart defect: complete atrial ventricular canal defect type C; this variant was not found in 196 healthy controls or 1,000 other PAH cases.

Adult 3: PAH diagnosis at 5 years, congenital heart defect: complete atrial ventricular canal defect type C; this variant was not found in 196 healthy controls or 1,000 other PAH cases.

Patient 9 in (Sztrymf 2008). Also reported in (Girerd 2010).

Proband 10: symptoms started at age 9, de novo mutation.

Patient 10 in (Sztrymf 2008). Also reported in (Girerd 2010).

Patient 11 in (Sztrymf 2008). Also reported in (Girerd 2010) and (Machado 2006).

Patient 2: paternal inheritance, not found in 150 normal control chromosomes (Thomson 2000). Pt 7: age 32 in (Elliott 2006). Found in a patient with a family history of PAH, internal case (Smith, unpublished).

No family history of PAH.

Family US14: not found in 214 chromosomes from healthy controls, extracellular domain affected, predicted to perturb ligand binding (Lane 2000). Family study of affected and unaffected carriers showed altered protein expression between the two groups; differences highlight proteins that may be involved in the mechanism(s) that differentiates those individuals with a mutation that developed disease (Meyrick 2008).

Family UK13: not found in 214 chromosomes from healthy controls, this variant truncates the protein before the transmembrane domain and if translated may fail to reach the cell surface (Lane 2000). Diagnosis at 6 years old (Atkinson 2002).

Family NOR01: five affected family members.

Family UK09: two affected family members, age at disease onset ranged from 9-26 (Machado 2001). Proband 7: onset of symptoms at age 9, ligand binding domain (Fujiwara 2008). Also reported in (Girerd 2010).

Patient 12 in (Sztrymf 2008). Also reported in (Girerd 2010).

Predicted to escape nonsense mediated decay.

Reported twice.

Case 3: patient was 19 years old at time of study, inactivates splice donor site, absent in both parents.

Splice defect detected in Patient 58, 59, and 60 (Sztrymf 2008). Reported 3 times in (Girerd 2010). Also reported in (Machado 2006).

Patient 10: age 46; splice defect, family history of PAH.

Polymorphism with a frequency of 13.8% (Machado 2006). Found with c.529+64C>T; frequency in PAH 15%; 20% frequency in chronic thromboembolic pulmonary hypertension and in 17% of controls (Ulrich 2009). rs34006388.

Pt 20: RT-PCR studies showed a deletion of Exon 04 and 5, this causes a frameshift that leads to a premature stop codon in Exon 06 nucleotides 33-35 (Cogan 2005). MLPA analysis (family 20) showed a deletion of Exon 04 and 5, out-of-frame deletion beginning at codon 140 with a PTC at codon 151, mutant transcripts were not detected in RNA and were subject to nonsense mediated decay (Cogan 2006). Patient 13: age 60, family history of PAH (Rosenzweig 2008).

Found in a patient with a family history of PAH, internal case.

Found in a patient with a family history of PAH, internal case.

Family US37: three affected family members, age at disease onset ranged from 10-39 (Machado 2001). Case 4: patient was 32 years old at time of study (Morisaki 2004). Reported 3 times in (Machado 2006). Patient 11: age 30, family history of PAH in (Rosenzweig 2008). Patient 13 and 14 in (Sztrymf 2008). Patient 3: age 18, no family history of PAH in (Wang 2010). Pt 30: age 34 in (Elliott 2006). Reported 4 times in (Girerd 2010).

Family UK21: two affected family members, age at onset ranged from 13-19.

Family PPH017: transmembrane domain, not found in 196 chromosomes (Deng 2000). Patient 12: age 48, family history of PAH (Rosenzweig 2008).

Family 71: transcript was subject to nonsense mediated decay.

Reported twice.

Patient 7913: diagnosis of PAH at 4 years of age, predicted mutant transcript would have Exon 04 spliced directly to Exon 08 and confirmed by RT-PCR, deletion of amino acids in the kinase domain, mutation was de novo (Harrison 2004). ID: 7913; Predicted consequence: In-frame deletion of 146 amino acids, kinase domain; confirmed de novo; pediatric (Aldred 2006).

Patient had taken fenfluramine for 2 months, affected amino acid is in the Kinase domain, not found in 130 healthy controls. Functional studies have suggested that p.Gly182Asp variant protein induces a transcriptional response following BMP4 stimulation in a manner indistinguishable from wild type BMPR2, although statistical analyses supporting this conclusion were not performed (Nasim 2008)

Patient 15 (Sztrymf 2008). Reported once, predicted to escape nonsense mediated decay (Girerd 2010).

Child 4: PAH diagnosis at 3 years and was reported to have ring chromosome 14 syndrome and congenital heart defect: complete atrial ventricular canal defect type C; this variant was not found in 196 healthy controls or 1,000 other PAH cases.

Patient 17.

Allele frequency of 5% among patients and 11% among controls (Sankelo 2005). Identified in 4 unrelated patients (Elliott 2006). Polymorphism with a frequency of 2.4% (Machado 2006). Frequency in PAH of 20% and 4% of controls (Ulrich 2009). Found in 8/90 patient samples, 8.8% (Smith unpublished). rs55722784

Patient 16, study included 223 patients.

Reported in a single patient, age 20 in (Wang 2009 and 2010).

Patient 18 in (Sztrymf 2008). Also reported in (Girerd 2010).

rs117575598

rs78779412

rs78796655

Patient 3: not found in 150 normal control chromosomes (Thomson 2000). Family ITA01: two affected family members, age at disease onset ranged from 7-18 (Machado 2001). Found in two sisters who had taken dexfenfluramine for 1 - 2 months, not found in 130 healthy controls (Humbert 2002). Reported 5 times in (Machado 2006). mutational hotspot located in the kinase domain (Wong 2005). Identified in Patients 19, 20, 21, and 22 in (Sztrymf 2008). Family 66: transcript was subject to nonsense mediated decay (Cogan 2006). Pt 87: age 87 (Elliott 2006). Reported 6 times in (Girerd 2010). Reported once in (Portillo 2009).

Case 5 & 6: reported in two unrelated individuals, patient ages were 27 and 19 at the time of the study (Morisaki 2004). Pt 137: age 30; Pt 162: age 14 in (Elliott 2006). Found on the same allele as c.690-91delAGinsT and Family 64: transcript was subject to nonsense mediated decay, protein change was reported as R225C (Cogan 2006). Reported twice in (Machado 2006). Found in a patient without a family history of PAH, internal case (Smith, unpublished).

Found in individuals not at risk for the disease, found in 3 families in (Machado 2001). Polymorphism with a frequency of 3% (Machado 2006).

Family US44: three affected family members, age at disease onset ranged from 4-46 in (Machado 2001). Patient 23 in (Sztrymf 2008). Reported once in (Girerd 2010).

Family PPH022: kinase domain (Deng 2000). Family 64: found on the same allele as c.673C>T; transcript was subject to nonsense mediated decay (Cogan 2006). Patient 14: age 36, family history of PAH (Rosenzweig 2008).

Family FRA04: two affected family members both 40 years old at disease onset (Machado 2001). Pt 111: age 47 in (Elliott 2006). Reported once in (Machado 2006).

Patient 4: age 26, no family history of PAH.

Reported once in (Machado 2006). Patient 24 in (Sztrymf 2008). Reported once in (Girerd 2010).

Patient 4: not found in 150 normal control chromosomes.

Found in a patient with a family history of PAH; variants may be on opposite chromosomes, internal case.

Family 135: transcript was subject to nonsense mediated decay.

No family history of PAH.

Patient 5: age 16, family history of PAH, no family studies were reported.

Family 124: transcript was subject to nonsense mediated decay.

Reported in a single patient in (Machado 2006). Frequency of 4% in control group; ESEfinder analysis: predicted to alternate the sequence of exonic splicing enhancers; RT-PCR analysis on the mRNA found that the mutation was also present in the transcript and did not influence the proper splicing (Ulrich 2009).

Patient 25 in (Sztrymf 2008). Reported in a single patient in (Girerd 2010).

Splice defect.

rs11390605, rs66469476, rs11464745

Patient 61: splice defect (Sztrymf 2008). Also reported in (Girerd 2010).

Patient 62: splice defect (Sztrymf 2008). Also reported in (Girerd 2010).

ID: 20046, predicted consequence: duplication of 38 amino acids, kinase domain; premature truncation within duplicated sequence.

Family 119: transcript was subject to nonsense mediated decay.

Reported once in (Machado 2006). Patient 26 and 27 in (Sztrymf 2008). Reported 3 times in (Girerd 2010).

Reported in a single patient, thromboembolic.

Patient 28 in (Sztrymf 2008). Single patient, predicted to escape nonsense mediated decay (Girerd 2010).

Patient ID: K5429A in (Koehler 2004). Reported 3 times in (Machado 2006). Patient 15: age 39, family history of PAH in (Rosenzweig 2008). Patients 29, 30, and 21 in (Sztrymf 2008). Patient 6 and 7: ages 14 and 33 neither had a family history of PAH (Wang 2010). Reported 4 times, predicted to escape nonsense mediated decay in (Girerd 2010).

Reported once, patient had taken Fenfluramine.

Splice site defect

Patient 8: inactivation of acceptor-splice site, age 30; position was reported as c.965-2A>C, no family history of PAH.

ID:5527, predicted consequence: in-frame deletion of 103 amino acids, kinase domain.

Pt 3: age 46.

Patient 5: paternal inheritance, not found in 150 normal control chromosomes in (Thomson 2000). Family US50: two affected family members, age at disease onset ranged from 28-32; Family US13: eight affected family members and two obligate carriers, age at disease onset ranged from 13-42, obligate carriers ages were 45 and 71 (Machado 2001). Family 6: variant affects the kinase domain in (Sankelo 2005). Reported once in (Wong 2005). Reported twice in (Machado 2006). Patient 114: age 30; Patient 116: age 54 (Elliott 2006). Reported as a mutational hotspot in the kinase domain in (Wang 2010). Patient 16: age 30, family history of PAH (Rosenzweig 2008). Reported once in (Portillo 2009). Also reported in (Girerd 2010).

Reported once in (Machado 2006) , (Girerd 2010) and (Sztrymf 2008).

Patient 33 in (Sztrymf 2008). Also reported in (Girerd 2010).

Family UK06: not found in 214 chromosomes from healthy controls, amino acid located in the kinase domain; protein change was reported as C347Y in (Lane 2000). Patient 9: age 24, family history of PAH (Wang 2010).

Patient 10: age 26, no family history of PAH.

Family US94: two affected family members, age at disease onset ranged from 39-42.

Family PPH010: kinase domain, not found in 196 chromosomes (Deng 2000). Reported once in (Machado 2006). Patient 34 in (Sztrymf 2008). Reported once, predicted to escape nonsense mediated decay in (Girerd 2010).

Found in individuals not at risk for the disease (Machado 2001). Polymorphism with a frequency of 1.1% (Machado 2006).

Pt 48: age 21.

Reported once, patient was reported to have pulmonary veno-occlusive disease.

Family 3771: this substitution is located in the donor splice-site of intron 8 (Rindermann 2003). Patient K3771A: reported once in (Koehler 2004). Family 67: Sequencing analysis of genomic DNA; RT-PCR studies showed deletion of exons 8-9, MLPA analysis was negative for an Exon 08-9 deletion, alteration of this nucleotide inactivated the donor splice-site resulting in an inflame deletion of codons 323-425, transcript was no subject to nonsense mediated decay (Cogan 2006).

Family US80: six affected family members, age at disease onset ranged from 24-53, inactivates Exon 09 acceptor site (Machado 2001). Reported once in (Machado 2006). Family 59: Sequencing analysis of genomic DNA; RT-PCR studies showed a deletion of Exon 09, MLPA analysis was negative for an Exon 09 deletion, acceptor site id disrupted resulting in a deletion of Exon 09 and a frameshift at codon 377 with the generation of PTC 47 codons downstream; transcript was subject to nonsense mediated decay (Cogan 2006). Pt 146: age 43 in (Elliott 2008).

Patient 22: age 50, no family history of PAH.

Patient 8: age12, no family history of PAH; authors reported p.Glu386Gln.

Not found in 200 healthy controls, age:14, mutation tracked with the disease and the patient's mother was diagnosed at 32 in (Fu 2008). Age 14, family history of PAH in (Wang 2010).

Patient MHH07: reported once, unclassified variant due to lack of functional data; located in the kinase domain.

Patient 35 in (Sztrymf 2008). Also reported in (Girerd 2010).

Patient 11: age 31, no family history of PAH.

Family US89: two affected family members both 26 years old at disease onset.

Patients ages 4 and 38 at time of disease onset; not found in unaffected family members (Uehara 2002). Case 7: patient's age was 40 at the time of the study in (Morisaki 2004). Proband 19: diagnosis at age 4 with mild dyspnea and positive family history and mutation tracked with disease, father diagnosed at age 34 and sister diagnosed at age 4 (Fujiwara 2008).

Patient 12: age 32, no family history of PAH.

Found in a patient who also had the mutation c.1250_1253del. p.Phe417X.

Patient 7: not found in 150 normal control chromosomes.

Patient 6: de novo, not found in 150 normal control chromosomes (Thomson 2000). Reported once in (Machado 2006). Pt 5: age 23 in (Elliott 2006).

Found in a patient who also had the mutation c.1245_1246dup. p.Ile416fs.

Family GER01: four affected family members, age at disease onset ranged from 9-40.

Case 8: patient's age was 27 at the time of the study in (Morisaki 2004). Reported twice in (Machado 2006).

Reported once in (Machado 2006). Patient 36 in (Sztrymf 2008). Also reported in (Girerd 2010).

Patient 17: age 30, family history of PAH in (Rosenzweig 2008).

Splice defect

Patient 63: splice defect, authors state that cDNA studies were done (Sztrymf 2008). Reported twice, splice defect, in (Girerd 2010). Reported as polymorphism with a frequency of 0.6% in (Machado 2006). Splice prediction suggests that this is pathogenic.

Pt 5: RT-PCR studies showed a tandem duplication of Exon 10, this causes a frame shift that leads to a premature stop codon in Exon 11 nucleotides 5-8; 34 years old at time of diagnosis (Cogan 2005). MLPA analysis (Family 5) showed duplication of Exon 10, mutant transcripts were not detected in RNA and were predicted to be subject to nonsense mediated decay (Cogan 2006). Predicted consequence, deletion of 45 amino acids, kinase domain; premature truncation in Exon 11. ID:5927, inherited from unaffected father and found in affected sister. ID: 21676; pediatric, inherited from an unaffected mother (Aldred 2006). Patient 65 and 66 in (Sztrymf 2008). Reported 7 times in (Girerd 2010).

Found in a patient with no family history of PAH, internal case.

Family CCG00386: PAH with suspected hereditary hemorrhagic telangiectasia with lung arteriovenous malformations (Rigelsky 2008).

Patient K4690A.

Family 61: this methionine is located within the kinase domain and is highly conserved.

Patient MHH09 in (Koehler 2004). Also reported in (Girerd 2010).

Predicted to escape nonsense mediated decay.

Case 9: patient was 32 at time of study.

Classified as suspected pathogenic because a study by Sankelo et al. did not list any evidence supporting a classification as benign and several frameshift mutations are classified as pathogenic in this codon as well as after. Family 12: de novo, variant affects the kinase domain; by studying both parents of two affected sibpairs authors stated that they were able to indirectly show that this variant was not the cause of their disease.

Patient MHH52: reported once; authors called this as an unclassified variant due to the lack of functional studies. However, it is likely to be pathogenic.

Patient 37 in (Sztrymf 2008). Reported twice in (Girerd 2010).

Patient K5943A in (Koehler 2004). Pt 52: age 43 in (Elliott 2006). Reported once in (Machado 2006).

Patient 38 in (Sztrymf 2008). Reported once in (Girerd 2010) and (Machado 2006).

Splice defect

Patient MHH10: variant causes deletion of Exon 10.

Polymorphism with a frequency of 2.7%.

Splice defect

ID: 6213; Deletion of 568 amino acids, kinase and cytoplasmic domains; altered termination codon and poly-A sites; inherited from unaffected mother. Patient 67 in (Sztrymf 2008). Reported 3 times in (Girerd 2010).

ID: 5181, deletion of 484 amino acids, kinase and cytoplasmic domains; premature truncation in Exon 013, found in unaffected mother. Partial deletion of 3' portion of the gene including Exon 12 with the patients age of 22, further classified in (Machado 2006). Also reported in (Girerd 2010).

Reported once in (Machado 2006). Also reported in (Girerd 2010).

Patient 8: not found in 150 normal control chromosomes (Thomson 2000). Patient had taken fenfluramine for 1 month, not found in 130 healthy controls (Humbert 2002). Patient 39 in (Sztrymf 2008). Reported once in (Girerd 2010).

Family NL01: not found in 214 chromosomes from healthy controls, amino acid located in the kinase domain.

Reported once in (Machado 2006). Pt 45: age 42 in (Elliott 2006).

Family PPH001, PPH008 & PPH021: kinase domain, not found in 196 control chromosomes (Deng 2000). Patient 8: 52 years old at time of study in (Morrell 2001). Variant was found in 3 affected family members and not in 11 others analyzed, ages 14, 29, and 37, not found in 240 health control chromosomes (Zhicheng 2004). Reported in 3 patients in the same family, disease onset at ages 35, 23, and 13, cDNA numbering was reported as c.491C>T in (Jing 2004). Patient K6361A in (Koehler 2004). Reported 3 times in (Machado 2006). Mutational hotspot in the kinase domain (Wong 2005). Patients 40, 41, 42, 43, and 44 in (Sztrymf 2008). Patients 5 and 6: ages 9 and 11; both had a family history of PAH in (Rosenzweig 2008). Patient 13: ages 20, no family history of PAH; also found in another patient age 37, with a family history of PAH in (Wang 2010). Reported 9 times in (Girerd 2010). Found in a patient with a family history of PAH, internal case (Smith, unpublished).

Family PPH019: Not found in either parent, kinase domain, not found in 196 control chromosomes (Deng 2000). Reported twice in (Machado 2006). Family 4: variant affects the kinase domain (Sankelo 2005). Mutational hotspot in the C-terminal domain (Wong 2005). Patient 18: age 28, family history of PAH in (Rosenzweig 2008). Patients 45, 46, and 47 in (Sztrymf 2008). Reported once in (Portillo 2009). Reported 3 times in (Girerd 2010).

rs2229778

Patient K5590A.

Child 5: PAH diagnosis at 2 years and was reported to have congenital heart defect: atrial septal defect, patent ductus arteriosus and partial anomalous pulmonary venous return; this variant was not found in 196 healthy controls or 1,000 other PAH cases.

Family GRE01: two affected family members, age at disease onset ranged from 19-50 (Machado 2001). Case 5559: found in a patient who also had R491Q, not found in 150 healthy controls (Machado 2005).

Polymorphism with a frequency of 0.25%.

Family UKSp16: Exon 01 and 12 analyzed for dosage, undetermined 3' deletion including Exon 12, one affected family member with an age of 22 at disease onset; family history of HHT.

Family V-1 and V-2: partial deletion of 3' of gene including Exon 12; family history of HHT.

Family SWE01: two affected family members both 34 years old at disease onset (Machado 2001). Patient MHH18 in (Koehler 2004).

Reported in 2 out of 14 patients, one with a closed atrial septal defect age 49 and one with a closed ventricular septal defect age 15.

Patient 48 in (Sztrymf 2008). Also reported once in (Girerd 2010).

Found in a patient with no family history of PAH, internal case.

Polymorphism found in the general population with an allele frequency of 0.5% (Morisaki 2004). Polymorphism with a frequency of 0.5% (Machado 2006).

PAH diagnosis at 19 years (Sugiyama 2004). Case 10: patient was 22 at time of study, variant was not found in unaffected father, protein change was reported as Thr652fs (Morisaki 2004).

Patient 9: not found in 150 normal control chromosomes.

rs111508874

rs75854140

Case 11: patient was 38 at time of study.

Family UK22: three affected family member, age at disease onset ranged from 30-57.

Patient 23: age 22, no family history of PAH.

Found in 5 unrelated patients, genotype frequency (A/G) 5% in a healthy population.

Polymorphism with a frequency of 5% (Machado 2006). Pt 15: age 58; Pt 23: age 33; Pt 35: age 47; Pt 96: age 26; Pt 151: age 151, no known relationship between patients (Elliott 2006). Found in 3 affected individuals, variant was called a polymorphism and was excluded from the study (Rosenzweig 2008). Frequency of 13% in chronic thromboembolic pulmonary hypertension as well and in 4% of controls (Ulrich 2009). Reported in 3 healthy controls, 2 with closed atrial septal defect and 1 with an untreated ventricular septal defect (Moller 2010). Found in 2/90 patient samples, 232%; one patient also had the pathogenic c.2617C>T, p.Arg873X variant (Smith unpublished). rs2228545

Polymorphism found in the general population with an allele frequency of 2.1% (Morisaki 2004 & Machado 2006). Classified as a polymorphism with a frequency 1/76 in a Chinese population (Wang 2010). rs3731697.

Patient 10, 11, and 12: de novo in patient 10, not found in 150 normal control chromosomes.

Family US79: two affected family members, age at disease onset ranged from 51-52.

Patient 7: age 11, family history of PAH.

rs1048127

Pt 88: transcript was subject to nonsense mediated decay.

Patient 49 in (Sztrymf 2008). Reported once in (Girerd 2010).

Patient 49 in (Sztrymf 2008). Reported once in (Girerd 2010).

Reported once in (Machado 2006). Pt 6: age 29 in (Elliott 2008).

Polymorphism found in the general population with an allele frequency of 0.5% (Morisaki 2004 and Machado 2006).

Family US55: not found in 214 chromosomes from healthy controls, this variant is likely to impede heteromeric receptor complex formation at the cell surface (Lane 2000). Family PPH015: (Deng 2000). Family UK11: three affected family members, age at disease onset ranged from 2-22 (Machado 2001). Pt 13: age 27, not found in 196 chromosomes in (Elliott 2006). Patient 19: age 28, family history of PAH in (Rosenzweig 2008).

Age 34, patient had a family history of PAH (Wang 2009 and 2010).

Family PPH018: not found in 196 chromosomes (Deng 2000). Pt 85: age 85; Pt 102: age 55, no known relationship between patients (Elliott 2006). Reported 3 times in (Machado 2006). Patient 20: age 56 in (Rosenzweig 2008). Patient 20: age 56, family history of PAH in (Rosenzweig 2008). Patients 50, 51, 52, 53, 54, and 55 in (Sztrymf 2008). Reported 6 times in (Girerd 2010). Found in a patient with no family history of PAH who also had the variant; internal case (Smith unpublished). rs137852748

Patient 56 in (Sztrymf 2008). Reported twice in (Girerd 2010).

Case 12: patient was 14 at time of study, variant was de novo.

rs148770894; reported in 0.1% of population

Polymorphism with a frequency of 0.6%. rs147960425.

Family US33: not found in 214 chromosomes from healthy controls, this variant is likely to impede heteromeric receptor complex formation at the cell surface (Lane 2000). Patient 13: not found in 150 normal control chromosomes in (Thomson 2000). Family US91: two affected family members, age at disease onset ranged from 27-32 (Machado 2001). Case 13 and 14: found in two unrelated individuals, patients were 38 and 47 at time of study in (Morisaki 2004). Reported 3 times in (Machado 2006). Mutational hotspot in the C-terminal domain (Wong 2005). Patient 14: age 18, no family history of PAH (Wang 2010). Reported once in (Girerd 2010). rs137852741.

Family 11: variant affects the C-terminal cytoplasmic domain, observed to locate correctly at the cell surface and SMAD mediated intracellular signaling was not impaired; this substitution led to constitutive activation of the SMAD independent P38MAPK pathway (Sankelo 2005). rs137852752.

Other findings: 27 years old, amfepramone chlorhydrate treatment for 4 and 5 weeks 3.5 and 1.5 years prior to onset; protein change was reported at position 766.

rs16839188

rs28572657

Case 15 and 16: reported in two unrelated individuals, patients ages were 33 and 22 at the time of the study.

rs1061157

Minor allele frequency of 0.21, 196 chromosomes tested (Deng 2000). Found in 7 unrelated patients (Elliott 2006). Found 15 unrelated families and in individuals not at risk for the disease (Machado 2001). Polymorphism found in the general population with an allele frequency of 2.1%, rs1061657 (Morisaki 2004 and Machado 2006). Allele frequency of 29% among patients and 15% among controls (Sankelo 2005). Classified as a polymorphism with a frequency 5/76 in a Chinese population (Wang 2010). Frequency in PAH patients was 20%, 20% in chronic thromboembolic pulmonary hypertension and in 38% of controls (Ulrich 2009). Found in 24 out of 90 patient samples, 26.6% (Smith unpublished). rs1061157

rs191901528

rs45528636

rs146027217. Average heterozygosity: 0.001, chromosome count: 4550.

Patient 23: diagnosis of limited cutaneous scleroderma spectrum with positive anticentromere and rheumatoid factor autoantibodies, Ashkenazi Jewish decent, patient's age was 59. rs148099152.

rs144848138