Amelogenesis imperfecta

Gene: PEX6

The mode of inheritance of this gene has been updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.

Created: 1 Feb 2023, 5:04 p.m. | Last Modified: 1 Feb 2023, 5:04 p.m.

Panel Version: 2.22

For Peroxisome biogenesis disorder 4B (OMIM:614863), Falkenberg et al (PMID: 29220678) has identified Allelic Expression Imbalance (AEI) as a mechanism responsible for the condition. Affected patients (7 unrelated cases) were monoallelic for rs61753230 (c.2578C>T, p.Arg860Trp) and rs144286892 (c.∗442_445 delTAAA), with these variants being on the same chromosome (cis). It would appear that rs144286892 causes the over expression of the allele that it is on, resulting in over expression of rs61753230. The unaffected parents analysed were monoallelic for rs61753230 and biallelic for rs144286892, resulting in overexpression of both rs61753230 and wild type alleles (PMID: 29220678). Experimental evidence revealed that rs61753230 has a dominant-negative effect on the function of the PEX1- PEX6 complex in peroxisomal matrix protein import (PMID: 29220678).

Created: 1 Apr 2022, 3:11 p.m. | Last Modified: 1 Apr 2022, 3:11 p.m.

Panel Version: 2.18

Comment on mode of inheritance: The Q1_22_MOI tag has been added to this gene. The mode of inheritance for PEX6 should be set to: BOTH monoallelic and biallelic, autosomal or pseudoautosomal in order to detect the dominant Peroxisome biogenesis disorder 4B. Incomplete penetrance has been noted, in order to highlight that unaffected parents may also carry rs61753230.

Created: 1 Apr 2022, 3:09 p.m. | Last Modified: 1 Apr 2022, 3:09 p.m.

Panel Version: 2.18

The review by Claire Smith (University of Leeds)(below), states that amelogenesis imperfecta maybe over looked in patients with Peroxisome biogenesis disorder 4A (Zellweger) (OMIM:614862) and Peroxisome biogenesis disorder 4B (OMIM:6148630), as these conditions are characterized by a severe phenotype and premature death in some cases. With this in mind the Peroxisome biogenesis disorder 4B (OMIM:614863) could be relevant to this panel and such the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal in order to detect variants resulting in allelic expression imbalance and dominant-negative effect (PMID: 29220678).

Created: 1 Apr 2022, 3:02 p.m. | Last Modified: 1 Apr 2022, 3:02 p.m.

Panel Version: 2.16

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Heimler syndrome 2, OMIM:616617

Publications

• 29220678

Mode of pathogenicity
Other

As a result of watchlist tag audit the watchlist tag was removed from PEX6- this is now a green gene. Previously noted that tag was removed but this was not actioned in the database.

Created: 13 Jan 2020, 11:30 a.m. | Last Modified: 13 Jan 2020, 11:30 a.m.

Panel Version: 2.0

Green List (high evidence)

Currently on the Leeds AI diagnostic panel (Contact: Ruth Charlton). Patients with PEX6 variants are often misdiagnosed with deafness or with Usher syndrome type II. Investigation of the enamel can discern Heimler syndrome from other syndromes of deaf-blindness. The PEX6 variants that cause Heimler syndrome are hypomorphic, i.e. there is some protein produced, the variants are relatively mild in comparison with PEX6 variants causing Zellweger syndrome. It is likely that the majority of, if not all, Peroxisomal Biogenesis Disorder patients with PEX6 variants have AI as literature has specifically said that due to the very serious nature of the other associated defects, or the early death of some patients, the enamel phenotype is often overlooked. Causative PEX6 variants include the relatively common c.1802G>A, p.(R601Q) variant, although it is unclear whether this particular variant is damaging enough to cause disease in a homozygous state since healthy homozygous individuals have been reported. At least 7 families with AI and with PEX6 variants have been reported to date.

Created: 20 Oct 2017, 1:57 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
OMIM:616617 Heimler syndrome 2; 614862 Peroxisomal Biogenesis Disorder (Zellweger syndrome); 614863 Peroxisomal Biogenesis Disorder

Publications

• PMID:26387595
• 27302843

Comment on phenotypes: Expanded phenotypes to include the Peroxisome biogenesis disorders after review by Claire Smith.

Created: 23 Oct 2017, 11:53 a.m.

Comment when marking as ready: Marked PEX6 as ready: 23rd October 2017.

Created: 23 Oct 2017, 11:02 a.m.

Comment on list classification: Updated rating from Amber to Green (and removed 'watchlist' tag) following Expert external review: sufficient cases (Claire Smith reports at least 7) to support causation.

Created: 23 Oct 2017, 11:02 a.m.

Comment on list classification: Updated rating from Red to Amber, awaiting external review. Heimler syndrome is characterised by phenotypes including AI in secondary teeth. PEX6 is included in the eligibility statement 'prior genetic testing' list, and features on the UKGTN 21-gene AI panel. However, only 2 cases (PMID:26387595) to support causation of Heimler syndrome so far. Therefore added 'watchlist' tag for further cases.

Created: 19 Oct 2017, 4:01 p.m.

PMID:26387595 (Ratbi et al 2015) ascertained eight families affected by HS (Heimler syndrome) and identified biallelic mutations in PEX6 in two of them. In family 5, the 2 affected individuals were compound heterozygous for a previously reported pathogenic c.821C>T (p.Pro274Leu) variant in PEX6 and an ultra-rare missense variant (c.1930C>T, p.Arg644Trp) on the other allele. In family 6, Sanger sequencing of monozygotic twins (previously reported in PMID:16530715) identified a missense variant (c.1802G>A, p.Arg601Gln) in PEX6 and a single-nucleotide deletion (c.1841del) predicted to result in a frameshift on the other allele. The HS individuals were all characterized by a homogeneous phenotype of sensorineural hearing loss and amelogenesis imperfecta (AI).

Created: 19 Oct 2017, 3:35 p.m.