Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension

Zhu, Na; Pauciulo, Michael W.; Welch, Carrie L.; Lutz, Katie A.; Coleman, Anna W.; Gonzaga-Jauregui, Claudia; Wang, Jiayao; Grimes, Joseph M.; Martin, Lisa J.; He, Hua; Shen, Yufeng; Chung, Wendy K.; Nichols, William C.

doi:10.1186/s13073-019-0685-z

Table 2 Rare, predicted deleterious KLK1 and GGCX variants among 2572 PAH cases. Participants were heterozygous for the indicated variants

From: Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension

Participant ID	Gender	Age at dx (years)	PAH subclass	Ancestry	Gene**	Nucleotide change	Amino acid change	Variant type	MAF (ExAC)	CADD score	Revel score
08–022	F	60	IPAH	EUR	KLK1	c.46+1G>T	p.(=)	Splicing	–	24	–
10–096	F	68	IPAH	EUR	KLK1	c.60dup	p.Ile21Aspfs*12	Frameshift	4.29E−05	–	–
28–049	F	36	APAH-CHD	EUR	KLK1	c.60dup	p.Ile21Aspfs*12	Frameshift	4.29E−05	–	–
06–058	M	13	IPAH	EUR	KLK1	c.70C>T	p.Arg24Trp	D-Mis	8.47E−06	26	0.56
13–002	F	71	IPAH	EUR	KLK1	c.70C>T	p.Arg24Trp	D-Mis	8.47E−06	26	0.56
06–007	M	26	IPAH	EUR	KLK1	c.113G>A	p.Trp38*	Stop-gain	8.30E−06	35	–
12–061	F	51	IPAH	EUR	KLK1	c.469G>A	p.Gly157Ser	D-Mis	9.36E−05	29	0.72
14–018	M	61	IPAH	EUR	KLK1	c.469G>A	p.Gly157Ser	D-Mis	9.36E−05	29	0.72
17–075	F	82	APAH-CTD	EUR	KLK1	c.469G>A	p.Gly157Ser	D-Mis	9.36E−05	29	0.72
18–026	F	37	IPAH	EUR	KLK1	c.644G>A	p.Gly215Glu	D-Mis	–	30	0.85
19–013	F	51	IPAH	EUR	KLK1	c.650C>T	p.Pro217Leu	D-Mis	2.52E−05	29	0.60
19–033	F	37	IPAH	EUR	KLK1	c.689G>C	p.Trp230Ser	D-Mis	8.26E−06	25	0.50
06–014	M	35	FPAH	EUR	GGCX	c.137C>G	p.Ser46Cys	D-Mis	5.77E−05	23	0.70
04–020	F	36	IPAH	EUR	GGCX	c.G203G>C	p.Arg68Pro	D-Mis	–	35	0.96
12–207	F	43	IPAH	EUR	GGCX	c.G203G>C	p.Arg68Pro	D-Mis	–	35	0.96
32–003	M	81	IPAH	EUR	GGCX	c.248G>A	p.Arg83Gln	D-Mis	–	34	0.92
32–008	F	36	IPAH	AFR	GGCX	c.322C>T	p.Arg108Cys	D-Mis	1.65E−05	31	0.55
08–013	F	66	APAH-CTD	EUR	GGCX	c.646_647delinsCA	p.Val216Gln	In-frame	–	31	***
26–036	F	52	IPAH	EUR	GGCX	c.722 T>C	p.Phe241Ser	D-Mis	–	33	0.94
30–031	F	55	IPAH	EUR	GGCX	c.722 T>C	p.Phe241Ser	D-Mis	–	33	0.94
04–029	F	60	IPAH	EUR	GGCX	c.734 T>A	p.Leu245*	Stop-gain	–	40	–
04–087	F	54	IPAH	EUR	GGCX	c.763G>A	p.Val255Met	D-Mis	1.65E−05	34	0.86
34–005	M	66	IPAH	EUR	GGCX	c.763G>A	p.Val255Met	D-Mis	1.65E−05	34	0.86
11–004	F	24	IPAH	HIS	GGCX	c.763G>A	p.Val255Met	D-Mis	1.65E−05	34	0.86
22–108	F	40	APAH-HIV	AFR	GGCX	c.899C>T	p.Ser300Phe	D-Mis	2.53E−05	28	0.82
28–110	F	56	IPAH	AFR	GGCX	c.899C>T	p.Ser300Phe	D-Mis	2.53E−05	28	0.82
28–096	F	23	IPAH	EUR	GGCX	c.938_939del	p.Pro313Argfs*33	Frameshift	1.00E−04	–	–
08–046	F	53	APAH-Porto	EUR	GGCX	c.950G>A	p.Arg317Gln	D-Mis	1.67E−05	33	0.81
12–205	F	55	IPAH	EUR	GGCX	c.1017_1018insT	p.Ser340*	Stop-gain	–	–	–
15–008	F	14	APAH-CHD	EUR	GGCX	c.1075C>T	p.Arg359Cys	D-Mis	–	28	0.76
21–037	F	45	APAH-CTD	AFR	GGCX	c.1128C>G	p.Phe376Leu	D-Mis	–	27	0.85
06–039	F	28	IPAH	EUR	GGCX	c.1224C>A	p.His408Gln	D-Mis	8.24E−06	23	0.75
37–004	F	48	IPAH	EUR	GGCX	c.1249G>A	p.Asp417Asn	D-Mis	1.65E−05	26	0.72
30–034	F	49	APAH-CTD	HIS	GGCX	c.1304G>A	p.Arg435Gln	D-Mis	8.24E−06	29	0.67
14–029	M	48	IPAH	EUR	GGCX	c.1306C>T	p.Arg436*	Stop-gain	3.30E−05	41	–
37–010	F	77	APAH-CTD	EUR	GGCX	c.1306C>T	p.Arg436*	Stop-gain	3.30E−05	41	–
11–090	F	47	APAH	AFR	GGCX	c.1465G>A	p.Val489Met	D-Mis	2.47E−05	26	0.68
05–013	M	63	APAH-Porto	HIS	GGCX	c.1480 T>G	p.Ser494Ala	D-Mis	–	26	0.84
28–033	F	51	IPAH	EUR	GGCX	c.1758C>G	p.Tyr586*	Stop-gain	–	45	–
17–033	F	74	APAH-CTD	AFR	GGCX	c.1772C>T	p.Thr591Met	D-Mis	3.30E−05	29	0.83

*Rare, deleterious variants defined as gnomAD AF ≤ 1.00E−04 and REVEL > 0.5
**KLK1 transcript NM_002257.3 and GGCX transcript NM_000821.6
***REVEL score could not be computed for this 2-nt substitution because machine learning is based on 1-nt substitutions. Inclusion in the table was based on REVEL > 0.9 for single nt substitution and PROVEAN = deleterious for 2-nt substitution

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