Ehlers Danlos syndromesGene: IPO8
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
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.
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
gene: IPO8 was added gene: IPO8 was added to Ehlers Danlos syndromes. 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