Hypopigmentation Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10611 AP3B1 81479,81479 Order Options and Pricing
AP3D1 81479,81479
BLOC1S3 81479,81479
BLOC1S6 81479,81479
DTNBP1 81479,81479
EDN3 81479,81479
EDNRB 81479,81479
EPG5 81479,81479
GPR143 81479,81479
HPS1 81479,81479
HPS3 81479,81479
HPS4 81479,81479
HPS5 81479,81479
HPS6 81479,81479
KITLG 81479,81479
LRMDA 81479,81479
LYST 81479,81479
MC1R 81479,81479
MITF 81479,81479
MLPH 81479,81479
MYO5A 81479,81479
OCA2 81479,81479
PAX3 81479,81479
RAB27A 81479,81479
SLC24A5 81479,81479
SLC38A8 81479,81479
SLC45A2 81479,81479
SNAI2 81479,81479
SOX10 81479,81479
TYR 81404,81479
TYRP1 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10611Genes x (31)81479 81404, 81479 $890 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

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).

Genetics

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.

Clinical Sensitivity - Sequencing with CNV PGxome

A molecular screening of the TYR, OCA2, TYRP1, SLC45A2 genes in 121 unrelated non-Hispanic/Latino Caucasian 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).

Testing Strategy

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

This panel typically provides 99.7% 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.

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.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

All patients with hypopigmentation are candidates.

Diseases

Name Inheritance OMIM ID
Albinism, Ocular, With Sensorineural Deafness AD 103470
Albinism, Oculocutaneous, Type VII AR 615179
Chediak-Higashi Syndrome AR 214500
Foveal Hypoplasia 2, with or without Optic Nerve Misrouting and/or Anterior Segment Dysgenesis AR 609218
Griscelli Syndrome Type 1 AR 214450
Griscelli Syndrome Type 2 AR 607624
Griscelli Syndrome Type 3 AR 609227
Hermansky-Pudlak Syndrome 1 AR 203300
Hermansky-Pudlak Syndrome 10 AR 617050
Hermansky-Pudlak Syndrome 2 AR 608233
Hermansky-Pudlak Syndrome 3 AR 614072
Hermansky-Pudlak Syndrome 4 AR 614073
Hermansky-Pudlak Syndrome 5 AR 614074
Hermansky-Pudlak Syndrome 6 AR 614075
Hermansky-Pudlak Syndrome 7 AR 614076
Hermansky-Pudlak Syndrome 8 AR 614077
Hermansky-Pudlak Syndrome 9 AR 614171
Hyperpigmentation with or without Hypopigmentation AD 145250
Klein-Waardenberg's Syndrome AD, AR 148820
Nystagmus 6, Congenital, X-Linked XL 300814
Ocular Albinism, Type I XL 300500
Oculocutaneous Albinism Type 1A AR 203100
Oculocutaneous Albinism Type 1B AR 606952
Oculocutaneous Albinism Type 3 AR 203290
Oculocutaneous Albinism Type IV AR 606574
Skin/Hair/Eye Pigmentation, Variation In, 2 AR 266300
Skin/Hair/Eye Pigmentation, Variation In, 3 AR 601800
Skin/Hair/Eye Pigmentation, Variation In, 4 AR 113750
Tyrosinase-Positive Oculocutaneous Albinism AR 203200
Vici Syndrome AR 242840
Waardenburg Syndrome Type 1 AD 193500
Waardenburg Syndrome, Type 2D AR 608890
Waardenburg Syndrome, Type 2E AD 611584
Waardenburg Syndrome, Type 4A AD, AR 277580
Waardenburg Syndrome, Type 4B AD 613265
Waardenburg Syndrome, Type 4C AD 613266

Related Test

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PGxome®

Citations

  • Anikster et al. 2001. PubMed ID: 11455388
  • Baxter and Pavan. 2013. PubMed ID: 23799582
  • Dessinioti et al. 2009. PubMed ID: 19555431
  • Gahl et al. 1998. PubMed ID: 9562579
  • Gargiulo et al. 2011. PubMed ID: 20861488
  • Grønskov et al. 2013. PubMed ID: 23395477
  • Hermansky and Pudlak. 1959. PubMed ID: 13618373
  • Huizing et al. 2002. PubMed ID: 11809908
  • Human Gene Mutation Database (Bio-base).
  • Hutton and Spritz. 2008. PubMed ID: 18463683
  • Jung et al. 2006. PubMed ID: 16537806
  • Kaya et al. 2011. PubMed ID: 21488161
  • Lewis. 1993. PubMed ID: 20301410
  • Lewis. 1993. PubMed ID: 20301345
  • Mayeur et al. 2006. PubMed ID: 16646960
  • Ménasché et al. 2000. PubMed ID: 10835631
  • Morell et al. 1997. PubMed ID: 9158138
  • Morice-Picard et al. 2014. PubMed ID: 23985994
  • Oetting and King. 1999. PubMed ID: 10094567
  • Oh et al. 1998. PubMed ID: 9497254
  • Pastural et al. 1997. PubMed ID: 9207796
  • Pingault et al. 2010. PubMed ID: 20127975
  • Preising et al. 2011. PubMed ID: 21541274
  • Santiago Borrero et al. 2006. PubMed ID: 16417222
  • Schiaffino and Tacchetti. 2005. PubMed ID: 16029416
  • Schreyer-Shafir et al. 2006. PubMed ID: 17041891
  • Simeonov et al. 2013. PubMed ID: 23504663
  • Wei et al. 2013. PubMed ID: 23364476

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


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