Genotype — Phenotype correlation in ABCA12 Mutations

In Harlequin Ichthyosis, 44 ABCA12 mutations were reported to date. Among them, most mutations are truncation mutations including nonsense mutations, frameshift mutations (deletion/ insertion mutations), and splice site mutations. Other mutations reported in HI families are missense mutations, exon deletions, and single amino acid deletions.

Most truncation or deletion mutations underlying HI are thought to lead to severe loss of ABCA12 protein function affecting important nucleotide-binding fold domains and/or transmembrane domains. Thus far, in HI patients, at least one mutation on each allele must be a truncation or deletion mutation within a conserved region to cause serious loss of ABCA12. Complete loss of ABCA12 function due to homozygous or compound heterozygous truncation mutations always results in the HI patient phenotype.

Genotype	Phenotype
[truncation]+[truncation]	HI
[truncation]+[exon or conserved amino acid deletion]	HI
[exon or conserved amino acid deletion]+[exon or conserved amino acid deletion]	HI, CIE
[truncation]+[missense]	HI, CIE
[missense]+[missense]	LI, CIE

Phenotype	Genotype
HI	[truncation]+[truncation]
	[truncation]+[exon or conserved amino acid deletion]
	[exon or conserved amino acid deletion]+[exon or conserved amino acid deletion]
	[truncation]+[missense mutation]
	[exon or conserved amino acid deletion]+[missense mutation]
LI	[missense]+[missense]
CIE	[missense]+[missense]
	[missense]+[truncation]
	[missense mutation]+[exon or conserved amino acid deletion]