Amelogenesis imperfecta

Gene: PEX6

Green List (high evidence)

PEX6 (peroxisomal biogenesis factor 6)
EnsemblGeneIds (GRCh38): ENSG00000124587
EnsemblGeneIds (GRCh37): ENSG00000124587
OMIM: 601498, Gene2Phenotype
PEX6 is in 22 panels

2 reviews

Claire Smith (University of Leeds)

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.
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

Rebecca Foulger (Genomics England curator)

Comment on phenotypes: Expanded phenotypes to include the Peroxisome biogenesis disorders after review by Claire Smith.
23 Oct 2017, 11:53 a.m.
Comment when marking as ready: Marked PEX6 as ready: 23rd October 2017.
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.
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.
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).
19 Oct 2017, 3:35 p.m.

History Filter Activity

2 Feb 2018, Gel status: 3

Panel promoted to version 1.0

Sarah Leigh (Genomics England Curator)

This panel has been promoted after review by Claire Smith (Leeds) and further personal consultation with Dr Smith

23 Oct 2017, Gel status: 4

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for PEX6 were set to Heimler Syndrome 2, 616617 (includes amelogenesis imperfecta); Peroxisome biogenesis disorder 4A (Zellweger), 614862; Peroxisome biogenesis disorder 4B, 614863

23 Oct 2017, Gel status: 4

Gene classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

This gene has been classified as Green List (High Evidence).

23 Oct 2017, Gel status: 4

Gene classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

This gene has been classified as Green List (High Evidence).

19 Oct 2017, Gel status: 2

Gene classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

This gene has been classified as Amber List (Moderate Evidence).

19 Oct 2017, Gel status: 1

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for PEX6 were set to Heimler Syndrome 2, 616617 (includes amelogenesis imperfecta)

19 Oct 2017, Gel status: 1

Set publications

Rebecca Foulger (Genomics England curator)

Publications for PEX6 were set to 27302843; 26387595; 16530715

12 Jun 2017, Gel status: 1

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for PEX6 were set to ; Heimler Syndrome 2, 616617 (includes amelogenesis imperfecta)

12 Jun 2017, Gel status: 1

Set publications

Rebecca Foulger (Genomics England curator)

Publications for PEX6 were set to 27302843

8 Jun 2017, Gel status: 1

Set Mode of Inheritance, Added New Source

Rebecca Foulger (Genomics England curator)

PEX6 was added to Amelogenesis Imperfectapanel. Source: UKGTN Model of inheritance for gene PEX6 was set to BIALLELIC, autosomal or pseudoautosomal

8 Jun 2017, Gel status: 0

Added New Source

Rebecca Foulger (Genomics England curator)

PEX6 was added to Amelogenesis Imperfectapanel. Sources: Eligibility statement prior genetic testing

8 Jun 2017, Gel status: 0

Created

Rebecca Foulger (Genomics England curator)

PEX6 was created by rfoulger