Phenotype and variant spectrum in the LAMB3 form of amelogenesis imperfecta

Amelogenesis imperfecta (AI) is a heterogeneous group of inherited disorders characterized by abnormal formation of dental enamel, either in isolation or as part of a syndrome. Heterozygous variants in laminin subunit beta 3 (LAMB3) cause AI with dominant inheritance in the absence of other cosegregating clinical features. In contrast, biallelic loss-of-function variants in LAMB3 cause recessive junctional epidermolysis bullosa, characterized by life-threatening skin fragility. We identified 2 families segregating autosomal dominant AI with variable degrees of a distinctive hypoplastic phenotype due to pathogenic variants in LAMB3. Whole exome sequencing revealed a nonsense variant (c.3340G>T, p.E1114*) within the final exon in family 1, while Sanger sequencing in family 2 revealed a variant (c.3383-1G>A) in the canonical splice acceptor site of the final exon. Analysis of cDNA from family 2 revealed retention of the final intron leading to a premature termination codon. Two unerupted third molar teeth from individual IV:5 in family 2 were subject to computerized tomography and scanning electron microscopy. LAMB3 molar teeth have a multitude of cusps versus matched controls. LAMB3 enamel was well mineralized but pitted. The architecture of the initially secreted enamel was abnormal, with cervical enamel appearing much less severely affected than coronal enamel. This study further defines the variations in phenotype-genotype correlation for AI due to variants in LAMB3, underlines the clustering of nonsense and frameshift variants causing AI in the absence of junctional epidermolysis bullosa, and highlights the shared AI phenotype arising from variants in genes coding for hemidesmosome proteins.