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.

IndividualClinical descriptionNucleotide
change
Protein changePresence in
population*
Family
segregation
Predicted effectOther mutation
P1P, mother with H, sister and
grandmother have E
c.95C>Tp.P32L0.0001NADamagingNone
F1-I-1Severe E, (cauterized age 10)c.299C>Tp.P100L0.0002YesDamagingNone
F1-II-4Severe E, Tc.299C>Tp.P100L0.0002YesDamagingNone
F1-III-1E, Tc.299C>Tp.P100L0.0002YesDamagingNone
F1-III-2E, C (ruptured)c.299C>Tp.P100L0.0002YesDamagingNone
P4E, Tc.299C>Tp.P100L0.0002NADamagingNone
P5E, T, P,c.676A>Gp.K226E0.00009NADamaging§None
F2-I-2E, T, GI-T, P, H, liver shuntsc.836G>Tp.R279LAbsentYesDamagingENG
F2-II-1E, T, GI-T, multiple Pc.836G>Tp.R279LAbsentYesDamagingENG

*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.