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Primary immunodeficiency

Gene: IPO8

Amber List (moderate 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)

Comment on list classification: New gene added by Boaz Palterer (University of Florence). This gene is associated with a phenotype in Gene2Phenotype but not OMIM. As immune dysregulation is not seen in all affected individuals (PMID:34010604) and PMID:34010605 did not investigate the immune status of their cohort this gene has been given an Amber rating until further cases are available.
Created: 19 Jul 2021, 9:36 a.m. | Last Modified: 19 Jul 2021, 9:36 a.m.
Panel Version: 2.444
Zornitza Stark also left a Green review of this gene on the Thoracic aortic aneurysm and dissection (Version 1.8) panel:

"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
Zornitza Stark (Australian Genomics), 11 Jun 2021"
Created: 16 Jun 2021, 1:40 p.m. | Last Modified: 16 Jun 2021, 1:41 p.m.
Panel Version: 2.434
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, 1:39 p.m. | Last Modified: 16 Jun 2021, 1:39 p.m.
Panel Version: 2.434

Boaz Palterer (University of Florence)

Green List (high evidence)

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
Created: 24 May 2021, 10:30 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
cardiovascular anomalies; joint hyperlaxity; dysmorphic features; developmental delay; immune dysregulation; allergy

Publications

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
Phenotypes
  • cardiovascular anomalies
  • joint hyperlaxity
  • dysmorphic features
  • developmental delay
  • immune dysregulation
  • allergy
Tags
watchlist Q3_21_expert_review
OMIM
605600
Clinvar variants
Variants in IPO8
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

19 Jul 2021, Gel status: 2

Added Tag

Ivone Leong (Genomics England Curator)

Tag Q3_21_expert_review tag was added to gene: IPO8.

19 Jul 2021, Gel status: 2

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: ipo8 has been classified as Amber List (Moderate Evidence).

19 Jul 2021, Gel status: 0

Added Tag

Ivone Leong (Genomics England Curator)

Tag watchlist tag was added to gene: IPO8.

16 Jun 2021, Gel status: 0

Set publications

Ivone Leong (Genomics England Curator)

Publications for gene: IPO8 were set to 34010604; 34010605

16 Jun 2021, Gel status: 0

Set publications

Ivone Leong (Genomics England Curator)

Publications for gene: IPO8 were set to 34010604

24 May 2021, Gel status: 0

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

Boaz Palterer (University of Florence)

gene: IPO8 was added gene: IPO8 was added to Primary immunodeficiency. Sources: Literature Mode of inheritance for gene: IPO8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IPO8 were set to 34010604 Phenotypes for gene: IPO8 were set to cardiovascular anomalies; joint hyperlaxity; dysmorphic features; developmental delay; immune dysregulation; allergy Penetrance for gene: IPO8 were set to unknown Review for gene: IPO8 was set to GREEN