1. NGS panel - Genetic testing for albinism

Albinism

March 09, 2017

Clinical features

Albinism is an inherited genetic condition that reduces the amount of melanin pigment formed in the eyes, skin, and/or hair. The most common form of albinism is oculocutaneous albinism (OCA), a group of autosomal recessive disorders caused by a reduction of melanin biosynthesis in the melanocytes resulting in hypopigmentation of the hair, skin, and eyes1. The different types of OCA are caused by mutations in different genes and it is recognized as nonsyndromic OCA (genes TYR, OCA2, TYRP1, and SLC45A2) and syndromic OCA (genes HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, PLDN, LYST, MYO5A, RAB27A, and MLPH)2. Apart from these genes, other genes are also involved in causing OCA, including genes participating in melanogenesis and encoding melanosomal proteins (SLC24A5, C10orf11, KIT, and others) (please see Table 1).

Albinism affects 1 in 20,000 individuals world-wide3, but the prevalence of individual subtypes varies among different ethnic backgrounds: OCA1 is the most common subtype found in Caucasians and accounts for about 50% of cases worldwide, while OCA2 accounts for 30% of cases worldwide and is most common in Africa, where it is estimated to affect 1 in 10,0003. OCA3 affects approximately 1 in 8500 individuals from southern Africa4, or 3% of cases worldwide, and OCA4 accounts for 17% of cases and in Japan is diagnosed in 1 of 4 persons affected with OCA4.

Clinical ocular findings in all types of OCA are similar, including the following:

  • various degrees of congenital nystagmus
  • hypopigmentation of iris and iris translucency
  • reduced pigmentation of the retinal pigment epithelium
  • foveal hypoplasia
  • reduced visual acuity
  • a degree of color vision impairment.

Furthermore, OCA1 is characterized by white hair, very pale skin, and light-colored irises. OCA2 is less severe than type 1, with creamy white color skin and light yellow, blond, or light brown hair. OCA3 includes a form of albinism called “rufous oculocutaneous albinism”, which usually affects dark-skinned people. Affected individuals have reddish-brown skin, ginger or red hair, and hazel or brown irises. OCA4 has signs and symptoms similar to those seen with type 21.

TYR gene mutations are the most common genetic cause of albinism; they are identified in ~ 60% albinism patients. TYR is located on chromosome 11q14.3 and it encodes enzyme tyrosinase. Tyrosinase catalyzes multiple steps in melanin synthesis, and mutations in TYR can cause complete or partial loss of melanin1,2. The most common mutations in TYR reported so far include T373K, N371Y, M370T, and P313R in OCA1, and R305W in OCA2-affected cases2. Numerous genetic studies of OCA-affected families indicate high frequency of not only TYR, but other gene mutations, for example: OCA2 (17%), TYRP1 (1%), SLC45A2 (7%), GPR143 (5%), and SLC24A5 (<0.5%)5.

There is no cure for albinism to date, but treatment for albinism can relieve symptoms and prevent sun damage. Treatment may include protective sunglasses, clothing, and sunscreen to protect the skin from UV rays as well as surgery on the muscles of the eyes to correct abnormal eye movements1,2.

Based on the most recent literature, CENTOGENE experts have designed an Albinism panel that includes all relevant genes that have been reported in the most common mutation databases as OCA-related genes (Table 1). Thus, CENTOGENE offers the Albinism panel (genes: AP3B1, BLOC1S3, BLOC1S6, C10ORF11, DTNBP1, EDN3, EDNRB, GPR143, HPS1, HPS3, HPS4, HPS5, HPS6, KIT, LYST, MC1R, MITF, MLPH, MYO5A, OCA2, PAX3, RAB27A, SLC24A5, SLC45A2, SNAI2, SOX10, TYR, TYRP1) including full gene sequencing and deletion/duplication analysis of selected genes (EDNRB, PAX3, EDN3, SNAI2, SOX10, KIT, OCA2, GPR143, TYR, MITF). In addition, tests for any of the genes in the Albinism panel can also be ordered individually, for full gene sequencing and deletion/duplication analysis.


Differential diagnosis

The differential diagnosis of albinism disorders – depending on the major symptoms in the initial case – includes the following diseases5:

  • Hermansky-Pudlak syndrome
  • Chediak-Higashi syndrome
  • Griscelli syndrome
  • Waardenburg syndrome type II
  • Ichthyosis.

Diagnostic strategy

To confirm/establish the diagnosis, we offer full Albinism panel sequencing and deletion/duplication gene testing. We also offer a broad selection of NGS panels that are designed for the molecular diagnostics of related conditions/phenotypes.

Thus, CENTOGENE offers the following testing strategy for Albinism panel gene testing:

Step 1: Albinism panel full gene sequencing – covers the entire coding region, exon/intron boundaries and 200 bp of the gene promoter for all the genes included in the Albinism panel.

Step 2: Deletion/duplication analysis/mutational scanning of selected Albinism panel genes (EDNRB, PAX3, EDN3, SNAI2, SOX10, KIT, OCA2, GPR143, TYR, and MITF).

Step 3: If no mutation is identified after analysis with the Albinism panel, we can offer whole exome sequencing, based on NGS technology and confirmation of the sequencing results.


Referral reasons

The following individuals are candidates for this particular gene testing:

  • Individuals with a family history of disease and presentation of the most common symptoms
  • Individuals without a positive family history, but with symptoms resembling this disease
  • Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Test utility

Sequencing, deletion/duplication of this gene and related genes should be performed in all individuals suspected for this particular phenotype. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management.

Genetic counseling can provide a patient and/or family with the natural history of the condition, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.


Overview of all relevant genes that have been reported as OCA-related

Gene OMIM Protein Function
AP3B1 603401 ADAPTOR-RELATED PROTEIN COMPLEX 3 Organelle biogenesis associated with melanosomes
BLOC1S3 609762 BIOGENESIS OF LYSOSOME-RELATED ORGANELLES COMPLEX 1, SUBUNIT 3 Required for normal biogenesis of specialized organelles of the endosomal-lysosomal system, such as melanosomes and platelet dense granules
BLOC1S6 604310 BIOGENESIS OF LYSOSOME-RELATED ORGANELLES COMPLEX 1, SUBUNIT 6 Required for normal biogenesis of specialized organelles of the endosomal-lysosomal system, such as melanosomes and platelet dense granules
DYNBP1 607145 DYSBINDIN A key component of biogenesis of lysosome-related organelles complex-1, which regulates the trafficking of proteins in the lysosomal pathway
C10ORF11 614537 CHROMOSOME 10 OPEN READING FRAME 11 A gene that is important for melanocyte differentiation and function
EDN3 131242 ENDOTHELIN 3 Plays an important role in neural crest cells, including menalocytes/td>
EDNRB 131244 ENDOTHELIN RECEPTOR B Endothelin receptor type B together play an important role in neural crest cells, including melanocytes
GPR143 300808 G PROTEIN-COUPLED RECEPTOR 143 G protein-coupled receptor exclusively expressed by melanocytes and retinal pigment epithelium
HPS1 604982 HPS1 HPS genes encodes proteins called melanosomes that produce and distribute melanin
HPS3 606118 HPS3 HPS genes encodes proteins called melanosomes that produce and distribute melanin
HPS4 606682 HPS4 HPS genes encodes proteins called melanosomes that produce and distribute melanin
HPS5 607521 HPS5 HPS genes encodes proteins called melanosomes that produce and distribute melanin
HPS6 607522 HPS6 HPS genes encodes proteins called melanosomes that produce and distribute melanin
KIT 164920 KIT ONCOGENE Regulates development of melanocytes and other cell types
LYST 606897 LYSOSOMAL TRAFFICKING REGULATOR Provides instructions for making a protein known as the lysosomal trafficking regulator
MC1R 155555 MELANOCORTIN 1 RECEPTOR Provides instructions for making a protein called the melanocortin 1 receptor, that plays an important role in normal pigmentation
MITF 1156845 MICROPHTHALMIA-ASSOCIATED TRANSCRIPTION FACTOR MITF plays a role in the development of various cell types, including neural crest-derived melanocytes and optic cup-derived retinal pigment epithelial cells
MLPH 606526 MELANOPHILIN Provides instructions for making a protein called melanophilin, found in melanocytes
MYO5A 160777 MYOSIN VA Melanophilin interacts with proteins produced from the MYO5A and RAB27A genes to form a complex that transports melanosomes to the outer edges of melanocytes
OCA2 611409 OCA2 This protein is located in melanocytes, where it plays a role in normal vision.
PAX3 606597 PAIRED BOX GENE 3 Plays a critical role in the formation of tissues and organs during embryonic development, including development of melanocytes
RAB27A 603868 RAS-ASSOCIATED PROTEIN 27A Melanophilin interacts with proteins produced from the MYO5A and RAB27A genes to form a complex that transports melanosomes to the outer edges of melanocytes
SLC24A5 609802 SOLUTE CARRIER FAMILY PROTEIN 24 (SODIUM/POTASSIUM/CALCIUM ) The human SLC24A5 gene has a role in skin pigmentation
SLC45A2 606202 SOLUTE CARRIER FAMILY 45; MEMBRANE-ASSOCIATED TRANSPORTER PROTEIN BRCA1/BRCA2 panel
SNAI2 602150 NEURAL CREST TRANSCRIPTION FACTOR SLUG Plays a role in the formation of tissues during embryonic development, including pigment-producing cells called melanocytes
SOX10 602229 SRY-BOX 10 SOX10 protein is essential for the formation of nerves in the intestine and melanocytes
TYR 606933 TYROSINASE Tyrosinase catalyzes the conversion of tyrosine to melanin
TYRP1 115501 TYROSINASE-RELATED PROTEIN 1 The TYRP1 gene provides instructions for making an enzyme called tyrosinase-related protein 1

More information on CENTOGENE´s Albinism panel can be found in our genetic test catalogue.