Table 1. Rare DROSHA variants identified in HHT patients.

Sequencing was performed by Sanger sequencing. All nucleotide substitutions are heterozygous. F, family; P, proband; E, epistaxis; T, telangiectasia; GI-T, gastrointestinal telangiectasia; C, cerebral arteriovenous malformation (AVM); H, hepatic AVM; and P, pulmonary AVM. The presence of P32L (rs202053700; frequency, 0.0001), P100L (rs199846087; frequency, 0.0002), and K226E (rs762758438; frequency, 0.00009) was significantly lower in the Exome Aggregation Consortium (ExAC) database (which spans 60,706 unrelated individuals) compared to HHT patients using Fisher’s exact test at P < 0.01. NA, not available.

Individual	Clinical description	Nucleotide change	Protein change	Presence in population*	Family segregation	Predicted effect	Other mutation
P1	P, mother with H, sister and grandmother have E	c.95C>T	p.P32L	0.0001	NA	Damaging†	None
F1-I-1	Severe E, (cauterized age 10)	c.299C>T	p.P100L	0.0002	Yes	Damaging‡	None
F1-II-4	Severe E, T	c.299C>T	p.P100L	0.0002	Yes	Damaging‡	None
F1-III-1	E, T	c.299C>T	p.P100L	0.0002	Yes	Damaging‡	None
F1-III-2	E, C (ruptured)	c.299C>T	p.P100L	0.0002	Yes	Damaging‡	None
P4	E, T	c.299C>T	p.P100L	0.0002	NA	Damaging‡	None
P5	E, T, P,	c.676A>G	p.K226E	0.00009	NA	Damaging§	None
F2-I-2	E, T, GI-T, P, H, liver shunts	c.836G>T	p.R279L	Absent	Yes	Damaging¶	ENG||
F2-II-1	E, T, GI-T, multiple P	c.836G>T	p.R279L	Absent	Yes	Damaging¶	ENG

^*Presence in population refers to the presence of the variant in the ExAC database.

^†Mutation is predicted to be damaging by SIFT.

^‡Mutation is predicted to be damaging by SIFT, PolyPhen-2, and Mutation Taster.

^§Mutation is predicted to be damaging by Mutation Taster.

^¶Mutation is predicted to be damaging by PolyPhen-2 and Mutation Taster.

^||Affected individuals in family 2 that carries a mosaic ENG c.1311+1G>A splice site mutation.