Interstitial Lung Disease

Gene: SMAD9

Green List (high evidence)

Agree with reviewers below.
In addition publication PMID: 21898662 - missense variant in 7yo girl with PAH. Expression of the 'mutant' protein in a reporter construct generated reduced basal activity and impaired responses to ligand stimulation compared to wildtype.

Created: 5 Nov 2021, 1:21 a.m. | Last Modified: 5 Nov 2021, 1:21 a.m.

Panel Version: 0.154

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Childhood PAH

Publications

• PMID: 21898662

Green List (high evidence)

Alt gene name SMAD8
gnomAD: pLI = 0. Most frequent NMD-pred PTC has 6 hets in the population, currently a VUS in ClinVar.

PMID: 29844917 - NMD PTC in a 14 year old patient with brain arteriovenous malformation, resulted in reduced phosphorylation of downstream SMAD4. Zebrafish knockdown model showed abnormal cerebral artery-to-vein connection.

PMID: 21920918 - NMD PTC in a patient with heritable pulmonary arterial hypertension. Functional studies on patient cells showed no significant effect in inducing miR-21, miR-27a or miR-100. ID1 (no OMIM) expression was significantly increased.

PMID: 19211612 - NMD PTC in a patient, paternally inherited (also affected with pulmonary arterial hypertension). Functional studies show the protein could not interact with SMAD4, and reduced transcriptional activation activity.

Created: 11 Feb 2021, 1:08 a.m. | Last Modified: 11 Feb 2021, 1:08 a.m.

Panel Version: 1.0

Alt gene name SMAD8
gnomAD: pLI = 0. Most frequent NMD-pred PTC has 6 hets in the population, currently a VUS in ClinVar.

PMID: 29844917 - NMD PTC in a 14 year old patient with brain arteriovenous malformation, resulted in reduced phosphorylation of downstream SMAD4. Zebrafish knockdown model showed abnormal cerebral artery-to-vein connection.

PMID: 21920918 - NMD PTC in a patient with heritable pulmonary arterial hypertension. Functional studies on patient cells showed no significant effect in inducing miR-21, miR-27a or miR-100. ID1 (no OMIM) expression was significantly increased.

PMID: 19211612 - NMD PTC in a patient, paternally inherited (also affected with pulmonary arterial hypertension). Functional studies show the protein could not interact with SMAD4, and reduced transcriptional activation activity.

Created: 11 Feb 2021, 1:08 a.m. | Last Modified: 11 Feb 2021, 1:08 a.m.

Panel Version: 1.0

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Pulmonary hypertension, primary, 2 MIM#615342

Publications

• PMID: 29844917
• 21920918
• 19211612

Green List (high evidence)

Pulmonary arterial hypertension is the main feature of the condition caused by this gene.
Sources: Expert list

Created: 23 Jan 2020, 12:29 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Pulmonary hypertension, primary, 2 MIM#615342