Hypopigmentation Panel

Inherited pigmentation disorders were among the first traits studied in humans as the phenotype is easy recognizable. These disorders are due to a deficiency of the pigment melanin, which is produced by melanocytes through a process called melanogenesis and catalyzed by at least one or several enzymes with the most prominent enzyme being tyrosinase. The marked variation in basal human skin color and tanning response even within a particular ethnic group is due to differences in amount and/or cellular distribution of melanin rather than differing melanocyte numbers. Abnormal melanogenesis results in hypopigmentation of the skin, eyes, and hair (Dessinioti et al. 2009. PubMed ID: 19555431; Baxter and Pavan. 2013. PubMed ID: 23799582).

The hereditary disorders of pigmentation such as Oculocutaneous albinism (OCA), Hermansky-Pudlak Syndrome (HPS), Waardenburg syndrome (WS) may originate due to pathogenic variants in genes involved in the complex pathway of melanocyte development, function and the migration of the melanocyte precursor melanoblast (Dessinioti et al. 2009. PubMed ID: 19555431; Baxter and Pavan. 2013. PubMed ID: 23799582).

If the hypopigmentation phenotype is mainly restricted to the eyes and optic system, it is referred to as ocular albinism (OA) (Gargiulo et al. 2011. PubMed ID: 20861488). The reduction or complete absence of melanin pigment in the developing eye leads to foveal hypoplasia and misrouting of the optic nerves (Oetting and King. 1999. PubMed ID: 10094567). The eye and optic system abnormalities that are common to all types of albinism are nystagmus, photophobia, strabismus, moderate to severe impairment of visual acuity, reduced iris pigment with iris translucency, reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination, refractive errors, and altered visual evoked potentials (VEP). The degree of skin and hair hypopigmentation varies with the type of OCA, but the ocular phenotype does not change (Lewis. 1993. PubMed ID: 20301410). To date, four types of non-syndromic OCA (type I-IV, based on gene involved) have been described, and their prevalence varies among different populations (Lewis. 1993. PubMed ID: 20301345).

HPS is characterized by tyrosinase-positive OCA, significant reduction in visual acuity often complicated by nystagmus, and bleeding diathesis resulting in bruising and sporadic and prolonged bleeding (Hermansky and Pudlak. 1959. PubMed ID: 13618373). HPS patients may develop granulomatous colitis, with onset usually in their teens, and/or pulmonary fibrosis, with onset typically in their thirties or forties (Gahl et al. 1998. PubMed ID: 9562579). Similar characteristics are found with the related Chediak-Higashi Syndrome (CHS). Both HPS and CHS are storage pool disorders. The cellular origin of disease is attributed to abnormal storage granules such as melanosomes, platelet-dense granules, and lysosomes. Granule cargo includes pigment proteins, signaling molecules, and enzymes, and defects in granule biogenesis, structure, or function affect myriad downstream events. Micrographs of platelets from HPS patients often reveal a striking lack of dense granules, whereas granulocytes of CHS patients contain giant, aberrant storage granules.

WS is an auditory-pigmentary disorder characterized by congenital sensorineural hearing loss and pigmentary abnormalities of the hair, including a white forelock and pigmentary changes of the iris such as heterochromia. WS is classified into four main types depending on the clinical symptoms and is associated with causative variants in several genes (Pingault et al. 2010. PubMed ID: 20127975).

OCA is genetically heterogeneous and exhibits autosomal recessive (AR), and X-linked (XL) inheritance. So far, 13 genes have been implicated in different forms of OCA. All kinds of causative variants (missense, nonsense, splicing, small as well as gross deletions and duplications, complex genomic rearrangements) have been reported in OCA (Human Gene Mutation Database). The major AR nonsyndromic forms OCA I and II are caused by genetic variations in TYR and OCA2 genes, respectively. The other nonsyndromic AR forms OCA III and IV involve TYRP1 and SLC45A2 genes, respectively (Simeonov et al. 2013. PubMed ID: 23504663).

TYR-encoded Tyrosinase and TYRP1-encoded tyrosinase-related protein catalyze the initial steps in melanin production. The P-protein encoded by OCA2 and the solute carrier 45 subunit A2 encoded by SLC45A2 are transporters localized in the melanosome membrane (Preising et al. 2011. PubMed ID: 21541274). Pathogenic variants in GPR143 are associated with XL ocular albinism. GPR143-encoded protein is a G protein-coupled receptor (GPCR) involved in intracellular signal transduction system and in the regulation of melanosome biogenesis and growth (Schiaffino and Tacchetti. 2005. PubMed ID: 16029416; Mayeur et al. 2006. PubMed ID: 16646960). Recently, pathogenic variants in two new genes, LRMDA and SLC24A5, have also been also associated with non-syndromic AR OCA (Grønskov et al. 2013. PubMed ID: 23395477; Wei et al. 2013. PubMed ID: 23364476).

Clinical findings of hypopigmentation of the skin and hair, in addition to the characteristic ocular symptoms are present in many syndromic disorders. Examples include Hermansky-Pudlak syndrome (HPS) (Schreyer-Shafir et al. 2006. PubMed ID: 17041891), Chediak Higashi Syndrome (CHS) (Kaya et al. 2011. PubMed ID: 21488161), Griscelli syndrome(GS) (Ménasché et al. 2000. PubMed ID: 10835631; Pastural et al. 1997. PubMed ID: 9207796) and Waardenburg syndrome (WS) (Morell et al. 1997. PubMed ID: 9158138). The causative variants in HSP6, LYST, MYO5A, AP3D1, EPG5 and RAB27A are associated with the syndromic forms of AR OCA. MITF and MC1R have been reported to have a digenic inheritance with TYR and OCA2 (Morell et al. 1997. PubMed ID: 9158138; Preising et al. 2011. PubMed ID: 21541274).

See individual gene test descriptions for more information on molecular biology of gene products.

A molecular screening of the TYR, OCA2, TYRP1, SLC45A2 genes in 121 unrelated non-Hispanic/Latino White Oculocutaneous albinism (OCA) patients identified pathogenic variants in TYR (69%), OCA2 (18%), SLC45A2 (6%), and no apparent pathological variants in 7% of patients (Hutton and Spritz. 2008. PubMed ID: 18463683). These results indicate the heterogeneity of this disorder. Another study in Chinese OCA patients identified pathogenic variants in TYR (36%), OCA2 (25%), TYRP1(2%), SLC45A2 (11%) and GPR143 (6%) (Morice-Picard et al. 2014. PubMed ID: 23985994). Clinical sensitivity for other genes is currently unknown due to limited cases.

Most Puerto Ricans affected with Hermansky-Pudlak Syndrome harbor either a 16bp duplication in HPS1 or a 3.9kb deletion in HPS3 (Anikster et al. 2001. PubMed ID: 11455388; Santiago Borrero et al. 2006. PubMed ID: 16417222). In non-Puerto Ricans, HPS1 pathogenic variants account for ~50% of cases (Oh et al. 1998. PubMed ID: 9497254) with the remaining cases being distributed as follows: AP3B1/(HPS2) ~1%, HPS3 ~13%, HPS4 ~12%, HPS5 ~9%, HPS6 ~7%, DTNBP1/(HPS7) ~1%, BLOC1S3/(HPS8) ~1%, BLOC1S6/(HPS9) only two patients to date.

With the exception of the 3.9kb deletion in the HPS3 gene that is common among Puerto Ricans (Anikster et al. 2001. PubMed ID: 11455388), large deletions and duplications are not common among the remaining Hermansky-Pudlak Syndrome genes. Large deletions have been reported in only the HPS2 (Jung et al. 2006. PubMed ID: 16537806) and HPS6 genes ( Huizing et al. 2002. PubMed ID: 11809908).

Pathogenic variants in in multiple genes are known to cause Waardenburg Syndrome (WS) (Pingault et al. 2010. PubMed ID: 20127975).

WSI and III: Molecular genetic testing by sequencing of PAX3 detects more than 90% of disease-causing variants. Partial and full gene deletions have been documented.

WSII: Molecular genetic testing by sequencing of MITF detects more than 90% of disease-causing variants. Since extensive studies evaluating the role of SNAI2 point pathogenic variants have not been carried out, the clinical sensitivity of our sequencing test for this gene is currently unknown. Partial and full gene deletions represent a significant proportion of SOX10 causative variants and have also been described for MITF and SNAI2.

WSIV: The clinical sensitivity of our sequencing assay for the END3, EDNRB and SOX10 genes for WSIV is currently unknown. Partial and full gene deletions have been documented for EDNRB and SOX10.

PAX3 is the only gene in which pathogenic variants are known to cause WS type 1 and type 3. Molecular genetic testing by deletion/duplication analysis of PAX3 detects about 6% of disease-causing variants. Gross deletions and duplications have also been reported in the TYR, OCA2, SLC45A2, GPR143, HPS6, LYST, RAB27A genes. (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.4% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

We also test for the GPR143 deep intronic variant c.885+748G>A.

This panel does not include the common OCA2 deletion common in African countries.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).