Table 3.

Rare, predicted deleterious germline and somatic variants in candidate PAH risk gene TET2 amongst 2572 PAH Biobank cases.

TET2*
Patient ID	Mutation type	Nucleotide change	Amino acid change	MAF, gnomAD WES	VAF	CADD phred	REVEL score	PAH class	Gender	Genetic ancestry	Age (y) enrollment	Age (y) onset	Mean PAP, (mmHg)	Mean PCWP (mmHg)	CO (L/min)	PVR (WU)	Mean SAP (mmHg)	Mean SAP:PAP
03–057	Germ	c.1530_1531insCACCT	p.Lys513Thrfs22	.	31%	.	.	IPAH	F	EUR	74	65	38	14	4.2	5.71	NA	NA
03–100	Germ	c.2233C>T	p.Gln745✶	.	38%	37	.	IPAH	F	EUR	71	70	47	10	5.55	6.67	NA	NA
12–206	Germ	c.2872C>T	p.Gln958✶	1.22E-05	39%	41	.	IPAH	F	EUR	84	84	55	8	3.67	12.81	87	1.58
29–016†	Germ Soma	c.4081G>A c.5618T>C	p.Gly1361Ser p.Ile1873Thr	. 1.33E-05	49% 46%	34 26	0.57 0.61	IPAH	F	EUR	72	69	47	17	9.23	3.25	80	1.7
19–036	Germ Germ	c.4546C>T c.817C>T	p.Arg1516✶ p.Gln273✶	1.59E-05	54% 51%	40 36	.	IPAH	F	EUR	74	67	33	9	9.44	2.54	117	3.5
12–156	Germ	c.4893T>G	p.Tyr1631✶	.	36%	36	.	IPAH	M	EUR	84	83	40	12	3.3	8.48	88	2.2
13–025	Germ	c.3336delA	p.Asp1113Ilefs✶4	.	26%	.	.	APAH-Porto	M	EUR	67	66	36	13	4.8	4.79	NA	NA
08–055	Germ	c.4396C>T	p.Gln1466✶	.	47%	45	.	APAH-CTD	F	EUR	73	69	45	10	3.7	9.46	NA	NA
30–037	Soma	c.2862G>A	p.Trp954*	.	18%	39	.	APAH-CTD	M	Hispanic	48	47	46	5	6.53	6.28	116	2.52
23–014	Soma	c.5639T>C	p.Leu1880Pro	.	26%	26	0.62	APAH-CHD	F	EUR	86	79	46	4	5	8.4	NA	NA
Mean ± SD, TET2 carriers									3.5:1		73.3± 10.9	66.9 ± 10.7	43.3± 6.5	10.4 ± 3.6	5.5 ± 2.2	6.8 ± 3.1	97.6 ± 17.5	2.3 ± 0.8
n, TET2 carriers											10	10	10	10	10	10	5	5
Mean ± SD, cohort APAH+IPAH excluding TET2 carriers											52 ± 18	48 ± 19	50 ± 14	10 ± 4	4.5 ± 1.8	10.5 ± 7.0	90 ± 19	2.0 ± 0.7
n, cohort APAH+IPAH excluding TET2 carriers											2340	2340	2292	2232	1641	1595	1399	1397
p-Value											1.00E-05	1.00E-05	0.002	NS	NS	0.02	NS	NS

Variant filter: allele frequency <0.0001 and likely gene disrupting (stop/gain, frameshift or canonical splicing) or missense with REVEL score >0.5.

^*TET2 transcript: NM_001127208.2

^†Exceptions to the mosaic pipeline variant filter (MAF and alternate allele fraction); detected as known mutation hotspot in cancer.

Abbreviations: APAH-CHD, pulmonary arterial hypertension associated with congenital heart disease; APAH-CTD, pulmonary arterial hypertension associated with connective tissue diseases; APAH-Porto, pulmonary arterial hypertension associated with porto-pulmonary hypertension; FPAH, familial pulmonary arterial hypertension; Germ, germline; MAF, minor allele frequency; IPAH, idiopathic pulmonary arterial hypertension; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; SAP, systemic arterial pressure; Soma, somatic; WES, whole exome sequencing; VAF, variant allele frequency; WU, Wood unit. Unpaired t-test