Amelogenesis imperfecta

Gene: LAMB3

Comment when marking as ready: Marked as ready: October 31st 2017.

Created: 31 Oct 2017, 2:31 p.m.

Comment on mode of inheritance: Updated MOI from just AD to 'both AD and AR' based on Claire Smith's comments that AI is part of Junctional Epidermolysis Bullosa, where biallelic LAMB3 variants are causative. Both AR and AD MOI also agreed with Arianna Tucci.

Created: 31 Oct 2017, 2:29 p.m.

Comment when marking as ready: Marked as Ready: 18th October 2017.

Created: 18 Oct 2017, 11:44 a.m.

Comment on mode of pathogenicity: Updated M.O.P to 'Other' in-line with Claire's comments.

Created: 18 Oct 2017, 11:44 a.m.

Comment on list classification: Updated rating from Amber to Green: Green expert review plus on Leeds diagnostic panel. 3 unrelated cases supporting causation of AI in OMIM (plus further JEB cases where AI may be a presenting phenotype), and further LAMB3 variants curated in LOVD.

Created: 16 Aug 2017, 1:35 p.m.

Comment on phenotypes: Added junctional Epidermolysis bullosa phenotypes based on comment by Claire Smith that AI phenotype is part of Junctional Epidermolysis Bullosa. Also, OMIM clinical synopsis for JEB disorders includes 'Enamel hypoplasia' and 'Dental caries'.

Created: 16 Aug 2017, 9:42 a.m.

Green List (high evidence)

Currently on the Leeds AI diagnostic panel (Contact: Ruth Charlton). Only particular LAMB3 heterozygous variants cause AI. However AI is part of Junctional Epidermolysis Bullosa where biallelic LAMB3 variants are causative. The majority of AI-causing LAMB3 variants have not been reported in JEB patients. Most LAMB3 variants identified in AI patients are either frameshift or nonsense mutations predicted to escape NMD. The variants are consistent with a dominant gain of function disease mechanism, unlike the loss of function variants associated with recessively-inherited JEB. However, Prasad et al. (2016) did identify two AI patients carrying LAMB3 mutations that do not fit this pattern of pathogenesis, although family members for segregation purposes were lacking in these two cases and proof of causation was not ascertained. See LAMB3 LOVD: http://dna2.leeds.ac.uk/LOVD/genes/LAMB3

Created: 3 Aug 2017, 1:34 p.m.

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Amelogenesis imperfecta, type IA 104530; Epidermolysis bullosa, junctional, Herlitz type 226700; Epidermolysis bullosa, junctional, non-Herlitz type 226650

Publications

• PMID: 24494736
• 23632796
• 23958762
• 25769099
• 7706760
• 26502894
• 27220909

Mode of pathogenicity
Other