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.
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
CENTOGENE offers advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on the PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and provides sequencing of entire gene at a more uniform coverage.
To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for albinism using NGS Panel Genomic targeted towards this specific phenotype:
Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Albinism panel. Copy Number Variants analysis derived from NGS data is also included
Step 2: If no mutation is identified after analysis of the Albinism panel, based on the approval and consent, we further recommend to continue the bioinformatics analysis of the data obtained by whole genome sequencing to cover genes that are either implicated in an overlapping phenotype or could be involved in a similar pathway but not strongly clinically implicated based on the current information in literature.
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).
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
|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.