Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH

Table 4 Burden of de novo variants in pediatric-onset PAH (n = 124 child-parent trios)

	Variant type*	Observed	Expected by chance	Enrichment	p value	Estimated # of risk variants
All genes (18,939 genes)	SYN	42	38.3	1.1	0.51	N/A
	LGD	14	11.8	1.2	0.46	N/A
	MIS	93	84.7	1.1	0.36	N/A
	D-Mis	30	17.3	1.73	0.005	N/A
	LGD + D-Mis	44	28.9	1.52	0.009	15
HLE or HHE** (5756 genes)	SYN	18	14.01	1.28	0.28	N/A
	LGD	10	4.69	2.13	0.03	N/A
	MIS	40	31.68	1.26	0.15	N/A
	D-Mis	19	7.25	2.62	2.0e−4	12
	LGD + D-Mis	29	11.85	2.45	2.5e−5	17

* SYN, synonymous; LGD, likely gene-disrupting; MIS, missense; D-Mis, deleterious missense based on REVEL > 0.5
**HLE, high lung expression (murine E16.5 lung stromal cells); HHE, high heart expression (murine E14.5 heart)

ISSN: 1756-994X