Background

Albinism is a group of conditions associated with reduced levels of melanin pigment that result in developmental visual system anomalies; skin and hair manifestations are also present in the majority of cases. Significant phenotypic variability has been described among affected individuals. The pigmentation of the skin, the hair and the uveal layer of the eye, for example, can range from very reduced to (almost) normal. The ophthalmic features, which are the hallmark of the condition, are also variable and can include nystagmus, reduced best-corrected visual acuity, photoaversion, iris transillumination, foveal hypoplasia and chiasmal misrouting of the optic nerves.1

At least 20 genetically distinct forms of albinism have been described. These can be caused by variants in genes encoding: melanogenic enzymes (TYR, TYRP1 and DCT); channels regulating melanosomal pH (OCA2 and SLC45A2) or calcium homeostasis within melanin-containing cells (SLC24A5); subunits of multiprotein complexes that are involved in melanosome maturation and/or trafficking of melanogenic enzymes (Hermansky-Pudlak syndrome [HPS] group of genes).² Most forms of albinism are inherited as autosomal recessive traits apart from GPR143-related albinism, which is an X-linked recessive condition. Although it is possible that additional albinism-associated genes remain to be discovered, alterations in such genes are expected to explain only a very small fraction of cases. Indeed, pathogenic variants in two genes that have been recently implicated in albinism, DCT and BLOC1S5, were detected in only 2 of 1500 (0.13%) albinism cases each.^{3 4}

Obtaining a precise genetic diagnosis in people with albinism:

• Allows timely identification of the subset of affected individuals who are at risk of developing major complications (lung fibrosis, prolonged bleeding and/or granulomatous colitis in individuals with certain subtypes of HPS; immunodeficiency and neurodegeneration in individuals with Chediak-Higashi syndrome [CHS]). In these cases, early diagnosis can drive evidence-based changes in care management and result in improved outcomes (a relevant example can be found in the Cases section: proband 1).

• Helps rule out differential diagnoses in individuals presenting with non-specific features such as nystagmus and/or foveal hypoplasia.

• Facilitates accurate genetic counselling and can inform reproductive planning in affected individuals and families.

To reach a genetic diagnosis, integration of phenotypic and genomic information is required; family context and dynamic changes in pigmentation should also be taken into account. In this article, we discuss clinical genetic testing in individuals who have features of albinism and propose a molecular diagnostic decision tree.

Approach to genetic testing in albinism

An initial aim of genetic testing in individuals suspected of having albinism is the identification of single-nucleotide variants (SNVs) and copy number variants (CNVs) impacting albinism-related genes. Additional analysis of other genes — such as FRDM7, SLC38A8 and PAX6 — is recommended; although these genes have been implicated in distinct conditions that do not generally feature hypopigmentation, the associated phenotypic spectra include characteristic ophthalmological manifestations of albinism. Notably, infants whose presentation is linked to changes in these three genes may have lightly pigmented skin/hair due to their familial/genomic background; this can increase the apparent overlap between these conditions and albinism.5

High-throughput DNA sequencing approaches are typically used for genetic variant detection. These approaches can be complemented by high-resolution array CGH (comparative genomic hybridization) analyses that focus on CNVs, which are thought to represent >10% of pathogenic alleles.5 It is noted that bioinformatic tools that mine sequencing data are increasingly replacing array CGH-based workflows.

Like other rare genetic disorders, molecular diagnostic practice patterns for albinism rely heavily on a search for low-frequency (rare), highly penetrant genetic variants. This reflects the wide acceptance of the rare disease – rare variant hypothesis which states that, if a disorder with a significant genetic component is rare, then the underlying genetic defect(s) will also be rare. However, in the past decade, a number of studies have challenged the universal nature of this paradigm and have highlighted the role of common genetic variation in rare phenotypes.6 7 In light of this and the findings of our recent work on albinism,8 we propose a three-step approach to the analysis of genetic data from patients with suspected albinism, i.e. individuals with at least one of the key ophthalmic features of the condition (for example prominent foveal hypoplasia) (figure 1).

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Figure 1

Schematic showing the proposed workflow for downstream analysis of genetic variants detected in individuals who have features of albinism.The focus of this decision tree is diagnostic genetic testing. Predictive testing, either in the context of a specific family or in broader settings requires a customised approach. Notably, as genotypes that include albinism-associated TYR haplotypes are unlikely to be fully penetrant, accurate risk prediction remains challenging.For brevity, this graph focuses on autosomal recessive forms of albinism and the X-linked, GPR143-related subtype is omitted.ACMG, American College of Medical Genetics and Genomics; heteroz, heterozygous; homoz, homozygous.

Cases

Three cases are discussed further to illustrate the utility of genetic testing in albinism (proband 1) and to highlight the value of the proposed molecular diagnostic approach (probands 2 and 3).

Proband 1 was diagnosed with oculocutaneous albinism in the first few months of life. He presented with nystagmus and was found to have iris transillumination, fundal hypopigmentation, and a featureless fovea. His skin and hair were moderately pigmented and there were no other concerns about his health/development. There was no family history of albinism or visual problems. Genetic testing was requested and revealed a homozygous HPS5 c.1507G>T (p.Glu503Ter) variant. Pathogenic variants in HPS5 are known to cause a form of HPS that is characterised by albinism and dysfunction of blood platelets (leading to prolonged bleeding). The infant was referred to the paediatric haematology department where he had platelet function analysis. This revealed prolonged PFA-100 closure time following stimulation with collagen and epinephrine (>300 s, reference range 79–205 s). This finding had significant implications as the child was due to have a routine urological procedure, which was safely performed with appropriate precautions. Notably, in our cohorts, approximately 1 in 20 individuals with suspected albinism is found to have biallelic pathogenic alterations in HPS-related or CHS-related genes.5 This case is also discussed in a previous report by our group where the benefits of genetic testing over more invasive and labour-intensive haematological approaches for the diagnosis of HPS are highlighted.15

Proband 2 was noted to have nystagmus soon after birth. There were no other medical concerns and there was no family history of relevance. The diagnosis of infantile nystagmus was made and the proband was followed up in his local ophthalmology unit for a number of years. An assessment in a tertiary ophthalmic genetic clinic was initiated in middle childhood, and the vision at that point was 0.3 LogMAR (Logarithm of the Minimum Angle of Resolution) in each eye. His irides were blue and there were no transillumination defects. Optical Coherence Tomography (OCT) imaging revealed foveal hypoplasia. It is noted that the broband’s hair were light brown and his skin colour was similar to that of close relatives. Genetic testing was initiated, revealing homozygosity for the TYR c.[−301C;575C>A;1205G>A] or (C;A;A) haplotype described previously. This genotype has been shown to confer a high ‘risk of albinism’ and should be considered pathogenic/predisposing.8

Proband 3 has a diagnosis of oculocutaneous albinism. Conventional genetic analysis focusing on rare variants revealed a heterozygous likely pathogenic variant in TYR c.823G>T (p.Val275Phe) [rs104894314]; this was found to be inherited from the proband’s mother (figure 2). When the common, functionally-relevant TYR c.1205G>A (p.Arg402Gln) variant was included in the analysis, the proband appeared to have a genotype similar to that of his unaffected mother. Analysis of the common promoter variant TYR c.-301C>T, as well as of TYR c.575C>A (p.Ser192Tyr), and testing of samples from other family members highlighted that the proband carried the likely pathogenic TYR c.823G>T change in trans to the c.[−301C;575C;1205G>A] haplotype (figure 2). This rare haplotype is likely to be pathogenic/predisposing,8 and the fact that it is present in trans to a likely pathogenic change confirms the genetic diagnosis of albinism.

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Figure 2

Example of how the analysis of a common TYR promoter variant can help obtain a genetic diagnosis in people with albinism (see also Cases section: proband 3). It is highlighted that the TYR c.-301C allele is predicted to reduce TYR gene expression in fetal retinal pigment epithelia by altering an OTX2 binding site in the TYR promoter.16 17 In contrast, the TYR c.1205G>A missense change produces a temperature-sensitive enzyme that has reduced catalytic activity and a tendency to be retained in the endoplasmic reticulum.11 17–20 Notably, the TYR c.-301 position is unlikely to be targeted by many currently used genomic assays (including certain panel-based and exome sequencing tests), and expansion of the target enrichment design to include this region may be required.heteroz, heterozygous; homoz, homozygous.

Concluding remarks

We describe a framework for analysing genetic test results from individuals suspected of having albinism. The importance of incorporating selected common genetic variants in the analysis and the key role of haplotype phasing are highlighted.

Our work in particular clarifies the long-lasting debate about the impact of the TYR c.1205G>A (p.Arg402Gln) variant and its definition as a benign or pathogenic change.11–13 We argue that this variant can be considered to be pathogenic/predisposing in the context of specific haplotypes/genotypes, but not on its own.

In our setting, incorporating the two complex albinism-associated TYR haplotypes ([C;A;A] and [C;C;A]) in the analysis increased the diagnostic yield of genetic testing by 19%. This highlights the significant contribution of these changes to the genetic architecture of albinism.

It can be speculated that TYR c.1205G>A (p.Arg402Gln) is not the only missense TYR change whose effect can be modified by other variants. We expect that, in the future, genetic investigations for albinism will analyse key non-coding regions (including promoters and cis-regulatory elements) for all relevant genes. Notably, the concepts discussed here are likely to be relevant to the study of other rare disorders.