Osteogenesis imperfecta
Gene: CREB3L1
See comments below, more evidence since initial classification in 2015.Created: 4 Jun 2019, 10:34 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Variants in this GENE are reported as part of current diagnostic practice
Comment on list classification: Following discussion in the GMS musculoskeletal specialist test group Webex on 2019-06-04 it was decided to make this green gene. There is more evidence since the last review.Created: 11 Jun 2019, 2:47 p.m.
4 cases now reported each in a publication (PMID: 24079343 - whole gene deletion, PMID: 28817112 - 3bp in-frame deletion (c.934_936delAAG [p.Lys312del], PMID: 29936144 - premature stop codon c.1284C>A; p.Tyr428*, PMID: 30657919 - homozygous missense variant (p.(Ala304Val))Created: 15 May 2019, 3:36 p.m.
This gene was part of an initial gene list collated by Duncan Baker, Sheffield Diagnostic Genetics Service, January 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: CREB3L1; Suggested initial gene rating: greenCreated: 3 Apr 2019, 4:08 p.m.
Following discussion with Dr Balasubramanian - rate green. PMID: 29936144 Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta. A homozygous CREB3L1 stop codon mutation in a boy with severe OI, had blue sclera and tooth agenesis. Markedly low levels of CREB3L1 mRNA were confirmed by qPCR in hOBs (16%) and FB (21%); however, collagen I levels were only reduced in hOBs (5-10%). Electron microscopy of hOBs showed pronounced alterations, with numerous myelin figures and diminished RER vs. normal ultrastructure of FB. Bone histomorphometry and qBEI were similar to collagen I OI, with low trabecular thickness and mineral apposition rate, and increased bone matrix mineralization. Raman microspectroscopy revealed low level of glycosaminoglycans. Clinical response to life-long bisphosphonate treatment was as expected in severe OI with steadily increasing bone mineral density, but despite this the boy suffered repeated childhood fractures. PMID: 30657919 A homozygous pathogenic missense variant broadens the phenotypic and mutational spectrum of CREB3L1-related osteogenesis imperfecta. Identified the first homozygous pathogenic missense variant (p.(Ala304Val)) in a patient with lethal OI, which is located within the highly conserved basic leucine zipper domain, four amino acids upstream of the DNA binding domain. In vitro structural modeling and luciferase assays demonstrate that this missense variant affects a critical residue in this functional domain, thereby decreasing the type I collagen transcriptional binding ability. In addition, overexpression of the mutant OASIS protein leads to decreased transcription of the SEC23A and SEC24D genes, which code for components of the coat protein complex type II (COPII), and aberrant OASIS signaling also results in decreased protein levels of SEC24D.Created: 3 Apr 2019, 4:14 p.m.
Two cases reports: PMID: 29936144 one patient homozygous for a stop mutation ( severe OI, had blue sclera and tooth agenesis), supported by functional assays.
PMID: 30657919 a homozygous pathogenic missense variant (p.(Ala304Val)) in a patient with lethal OI.Created: 22 Jan 2019, 11:28 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Osteogenesis imperfecta, type XVI 616229
Publications
Variants in this GENE are reported as part of current diagnostic practice
Comment on list classification: Based on report of a second novel variant in a consanguineous family, homozygotes displayed prenatal/perinatal lethal OI and the multiple heterozygotes had a mild phenotype (fractures, blue sclerae)(PMID: 28817112)Created: 12 Feb 2018, 2:12 p.m.
https://oi.gene.le.ac.uk/home.php?select_db=CREB3L1
A publication in 2017 (https://www.ncbi.nlm.nih.gov/pubmed/28817112) shows that a single amino acid deletion results in mild OI in heterozygous individuals and severe/lethal OI in homozygotes.Created: 8 Dec 2015, 12:34 p.m.
Publications
Single case report of homozygous whole gene deletion.Created: 9 Oct 2015, 10:06 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
osteogenesis imperfecta
Publications
Gene: creb3l1 has been classified as Green List (High Evidence).
Phenotypes for gene: CREB3L1 were changed from osteogenesis imperfecta to Osteogenesis imperfecta, type XVI 616229
Publications for gene: CREB3L1 were set to 24079343; 28817112
Source NHS GMS was added to CREB3L1.
This gene has been classified as Amber List (Moderate Evidence).
Publications for CREB3L1 were set to 24079343; 28817112
This proposed gene was validated and added to this panel
Model of inheritance for gene CREB3L1 was set to BIALLELIC, autosomal or pseudoautosomal
CREB3L1 was added to Osteogenesis Imperfecta panel. Source: Literature
CREB3L1 was added to Osteogenesis Imperfecta panel. Sources: Expert Review,Literature