Amelogenesis imperfecta

Gene: PEX1

Green List (high evidence)

Currently on the Leeds AI diagnostic panel (Contact: Ruth Charlton). Patients with PEX1 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 PEX1 variants that cause Heimler syndrome are hypomorphic, i.e. there is some protein produced, the variants are relatively mild in comparison with PEX1 variants causing Zellweger syndrome. It is likely that the majority of, if not all, Peroxisomal Biogenesis Disorder patients with PEX1 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. At least 6 families with AI and with PEX1 variants have been reported to date.

Created: 20 Oct 2017, 2:02 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Heimler syndrome 1 234580; Peroxisomal Biogenesis Disorder 1A (Zellweger syndrome) 214100; Peroxisomal Biogenesis Disorder 1A (NALD / IRD) 601539; amelogenesis imperfecta

Publications

• PMID:26387595
• 27302843
• 27633571

Comment when marking as ready: Marked as ready: October 23rd 2017. Green external review supports Green rating, and expanded phenotypes to include peroxisomal biogenesis disorders.

Created: 23 Oct 2017, 11:49 a.m.

PMID:26387595 (Ratbi et al 2015) report 8 families affected by HS (Heimler syndrome) and, by using a WES approach, identified biallelic mutations in PEX1 in 4 of them. The HS individuals were all characterized by a homogeneous phenotype of sensorineural hearing loss and amelogenesis imperfecta (AI). Families 2 and 8 were described previously (PMIDs: 2063923, 10636745).

Created: 19 Oct 2017, 3:51 p.m.

Comment on list classification: Updated rating from Red to Green, awaiting expert review. PEX1 is in the 'prior genetic testing' inclusion list, and on the UKGTN 21-gene AI panel. Sufficient cases in PMIDs 26387595 and 27633571 to support causation for Heimler syndrome (MIM:234580) which includes AI in secondary teeth.

Created: 19 Oct 2017, 2:55 p.m.

Comment on mode of inheritance: Biallelic MOI supported by OMIM and literature.

Created: 19 Oct 2017, 2:50 p.m.

PMID:27633571 (Ratbi et al 2016) report a second Moroccan family with Heimler syndrome. The female patient carried a novel homozygous missense variant (c.3140T>C p.Leu1047Pro) in PEX1, and phenotypes including AI in the secondary teeth.

Created: 19 Oct 2017, 2:44 p.m.

Heimler syndrome (HS, MIM:234580) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation.

Created: 19 Oct 2017, 2:43 p.m.