## 2 Harlequin Ichthyosis  
The discovery that _ABCA12_ gene mutations are associated with the skin disease harlequin ichthyosis (HI) is an example of where SNP microarray technology was used successfully to elucidate the genetic locus associated with this disease [9]. The inherited ichthyoses are a heterogeneous group of disorders characterised by skin scaling, often of the whole surface, and hyperkeratosis [10]. Syndromic (affecting multiple tissues) as well as nonshydromic forms of ichthyosis exist and mutations in multiple genes are associated with disease including _TGM1_ (OMIM *190195), _NIPAL4_ (OMIM *609383), _STS_ (OMIM *300747), _ALOX12B_ (OMIM *603741), _ALOXE3_ (OMIM *607206), _CYP4F22_ (OMIM *611495), and _FLG_ (OMIM *135940) amongst others (reviewed in [10]). Autosomal recessive congenital ichthyosis (ARCI) is comprised of three main groups: congenital ichthyosiform erythroderma (CIE), lamellar ichthyosis (LI) and HI [10]. HI (OMIM #242500) is the most severe form of ichthyosis and has a high perinatal mortality, with babies presenting at birth with hard scale plates with deep fissures, eclabium, and bilateral cortepion (reviewed in [9,11]). The discovery of the genetic cause of HI was hampered by availability of DNA from only affected family members or from small families due to the severity of the condition, thus genetic linkage studies were unfeasible [9]. To investigate the genetic basis of HI, [PERSON] _et al._ (2005) [9] used a SNP microarray to map a block of homozygosity on chromosome 2q35 and to identify a minimal region between HI patients from consanguineous parents, which contained the _ABCA12_ gene. ABCA12 belongs to the ATP-binding cassette (ABC) A family of transporters, some members of which have been implicated in lipid transport (reviewed in [12]). _ABC12_ was a promising gene candidate for HI because patient skin displayed aberrant lipid distribution [9] and missense mutations in _ABCA12_ were already known to be associated with another form of ARCI, LI [13]. PCR and Sanger sequencing of the _ABCA12_ gene in HI patients confirmed that recessive mutations were associated with HI [9,14]. Mutations in _ABCA12_ are now known to be associated with all three forms of ARCI (reviewed in [10]). However, unlike for LI and CIE, in which largely missense _ABCA12_ mutations are associated with disease [13,15,16], HI is usually associated with loss of function gene mutations including nonsense, frameshift, and splice site mutations, which severely disrupt the cellular functions of ABCA12 [9,17,18,19]. However, there are reports of patients who have ABCA12 missense mutations [9,11,18,20,21,22]. HI patients with homozygous loss of function mutations have an increased risk of mortality, indicating a survival advantage for patients with compound heterozygous mutations [11]. ABCA12 is thought to transport lipids via lamellar granules where they are processed and released to form lipid lamellae constituting the stratum corneum in the epidermis [14,23]. A reduction in the number, and structural abnormalities, of lamellar granules has been observed in HI patient skin [14,24,25]. In addition, characterisation of HI patient skin has shown a loss of nonpolar lipids [26] and abnormal glucosylceramide localization [14], and experiments with patient-derived keratinocytes showed aberrant glucosylceramide accumulation in lamellar granules [27], which is indicative of a lipid transport defect as a result of loss of ABCA12 function [14,26,27]. Similarly, _Abca12_ knockout mice models [28,29,30] and an _abca12_ knockout zebrafish model [31] showed features of aberrant lipid transport compared to controls (reviewed in [32]). HI skin also shows features of premature terminal differentiation and a decreased expression of certain proteases, which suggests that loss of ABCA12 disrupts keratinocyte differentiation and epidermal desquamation, resulting in the formation of an aberrant epidermal barrier [26].