Thoracic aortic aneurysm or dissection

Gene: IPO8

Green List (high evidence)

IPO8 (importin 8)
EnsemblGeneIds (GRCh38): ENSG00000133704
EnsemblGeneIds (GRCh37): ENSG00000133704
OMIM: 605600, Gene2Phenotype
IPO8 is in 4 panels

2 reviews

Ivone Leong (Genomics England Curator)

Boaz Palterer also left a Green review on the Primary immunodeficiency panel (Version 2.434):

"Ziegler et al. reported 12 individuals from 9 unrelated kindreds with bi-allelic loss-of-function variants in IPO8 presenting with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation. IPO8 is involved in the TGFbeta/SMAD signaling, which is a known pathway in Loeys-Dietz syndrome. Functional data in a zebrafish model. Sources: Literature
Boaz Palterer (University of Florence), 24 May 2021"
Created: 16 Jun 2021, 1:41 p.m. | Last Modified: 16 Jun 2021, 1:41 p.m.
Panel Version: 1.11
Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Created: 16 Jun 2021, 1:28 p.m. | Last Modified: 16 Jun 2021, 1:28 p.m.
Panel Version: 1.10
Comment on publications: PMID: 34010604. 12 individuals from 9 families. 11/12 dilatation of the ascending aorta, 6/12 other abnormalities in great vessels (including ascending aortic aneurysm and carotid artery tortuosity), 6/10 heart malformations, 9/12 dysmorphic features (including proptossi, micrognathia, hypertelorism, frontal bossing and abnormal palate), 12/12 skeletal abnormalities (including hyperlaxity, recurrent joint dislocations, scoliosis, pectus and arachnodactyly), 8/12 skin hyperextensibility, 11/12 umbilical hernia, 7/12 developmental delay or intellectual disability (did not mention severity), 2/12 retinal detachment, 3/12 bilateral cataract (one patient had it at age of 45), 3/3 hyperIgE and IgG, 3/4 hypoIgA, 4/5 hypereosinophilia, 5/12 intestinal inflammation and 6/12 allergic symptoms. Patients were aged between 1 year - 62 years old).

PMID: 34010605. 7 individuals from 6 families. 7/7 dysmorphic features (including frontal bossing, hypertelorism, retrognathia and palate abnormalities), 7/7 skeletal findings (including arachnodactyly, joint hypermobility, scoliosis, pectus excavatum and pes planum), 7/7 developmental delay, 2/7 ID (1 mild ID and no severity for the other patient), 5/7 atrial septal defect, 4/7 ventricular septal defect, 6/7 cardiovascular abnormalities with aortic root and/orascending aortic aneurysm, 2/7 marked arterial tortuosity, 5/7 umbilical hernia, 2/7 bruise easily. Authors noted that despite patients having severe aneurysm phenotype none experienced arterial or aortic dissection and concluded that it may be because of the patients' young age (1 year - 19 years old). The study did not look at the immunological profile of the patients. The study also describes a knockout mouse model which recapitulates the human phenotype.
Created: 16 Jun 2021, 1:26 p.m. | Last Modified: 16 Jun 2021, 1:32 p.m.
Panel Version: 1.10

Zornitza Stark (Australian Genomics)

Green List (high evidence)

12 individuals from 9 unrelated families in a cohort submitted for publication with bi-allelic IPO8 variants. Variants were nonsense/splice and some missense. Patients displayed a phenotype reminiscent of Loeys Dietz syndrome that variably combined cardiovascular, neurologic, skeletal and immunologic abnormalities along with dysmorphic features. Western blot on patient cells (4 individuals) showed reduced IPO8 expression. Disruption of IPO8 homologue in zebrafish associated with cardiac anomalies. Transcriptome analysis in zebrafish showed that IPO8-deficient zebrafish had abnormal TGFbeta pathway expression.
Sources: Literature
Created: 11 Jun 2021, 9:42 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Loeys-Dietz syndrome-like; cardiovascular, neurologic, skeletal and immunologic abnormalities


Variants in this GENE are reported as part of current diagnostic practice


Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
  • Expert Review Green
  • Literature
  • Loeys-Dietz syndrome-like
  • cardiovascular, neurologic, skeletal and immunologic abnormalities
Clinvar variants
Variants in IPO8
Panels with this gene

History Filter Activity

16 Jun 2021, Gel status: 3

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: ipo8 has been classified as Green List (High Evidence).

16 Jun 2021, Gel status: 2

Removed Tag

Ivone Leong (Genomics England Curator)

Tag Q2_21_rating was removed from gene: IPO8.

16 Jun 2021, Gel status: 2

Created, Added New Source, Added Tag, Set mode of inheritance, Set publications, Set Phenotypes

Ivone Leong (Genomics England Curator)

gene: IPO8 was added gene: IPO8 was added to Thoracic aortic aneurysm or dissection. Sources: Expert Review Amber,Literature Q2_21_rating tags were added to gene: IPO8. Mode of inheritance for gene: IPO8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IPO8 were set to 34010604; 34010605 Phenotypes for gene: IPO8 were set to Loeys-Dietz syndrome-like; cardiovascular, neurologic, skeletal and immunologic abnormalities