Compound heterozygosity in type-II oculocutaneous albinism

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Oculocutaneous Albinism (OCA) is a group of genetically heterogeneous autosomal recessive (AR) disorders associated with mutations in genes controlling the biosynthesis of melanin. Classification of OCA has morphed from phenotypic to genotypic stratification. Other than OCA1A, which presents with a complete absence of melanin in the skin, hair, and eyes; other subtypes can present with wide phenotypic heterogeneity making differentiation challenging.¹ Hence, genetic analysis plays a crucial role in accurate diagnosis, prognosis, and genetic counselling.

A six-month-old girl, first child of a third-degree consanguineous marriage, presented with light-coloured skin and hair since birth. This presentation was not stark when compared to her parents. Parents also reported nystagmus since birth and occasional photosensitivity but no history of seizures, recurrent infections, breathlessness, bleeding tendencies, photophobia, or hearing difficulties. Birth and developmental history were uneventful. The phenotype of the father was normal; the mother exhibited blue-grey irides. A detailed pedigree [Figure 1] revealed light-coloured skin and eyes in one of the paternal cousins, in whom there was a subsequent darkening of skin colour.

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Figure 1:

Pedigree chart exhibiting third-degree consanguinity with affected proband and her paternal uncle. (Square: male; Round: female; Strike-through: deceased; Blacked out: affected.)

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Physical examination revealed diffuse hypopigmented skin [Figure 2a] that made naevus simplex over the occiput and glabella more prominent [Figure 2b]. Scalp hair and eyelashes were dark brown, eyebrows were light brown, and blue-grey irides. Hair shaft examination revealed a uniform reduction in pigmentation without melanin clumps or structural defects [Figure 2c], and ophthalmologic evaluation demonstrated bilateral nystagmus and hypopigmented fundus.

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Figure 2a:

Diffuse pigment dilution showing light skin over chest and abdomen.

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Figure 2b:

Generalised pigment dilution of face making glabellar naevus simplex more pronounced.

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Figure 2c:

Hair shaft examination showing diffuse reduction of pigment along the shaft with no structural abnormalities or melanin clumps [Light microscopy, 40x].

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After obtaining a written informed consent, clinical exome sequencing using next-generation sequencing (NGS) was performed that showed compound heterozygous mutations in the OCA2 gene. A novel 5’-splice-site variant in intron 10 (chr15:g.27990575C>T) and previously reported missense mutation in exon 19 (chr15:g.2792686G>C) were noted.

Splice-site mutation (c.1116+1G>A) affected the donor splice site downstream of exon 10 and was not reported in 1000 genome, gnomAD (v3.1, v2.1) and Topmed databases with the in-silico prediction of ‘damaging’ by MutationTaster2.

A missense mutation (c.2020C>G, p.Leu674Val) resulted in the amino acid substitution of valine with leucine at codon 674 at the citrate transporter domain of the OCA2 protein, which was previously reported in homozygous and compound heterozygous states.¹

No other pathogenic variants were noted in other genes governing pigmentation. No other contiguous micro-deletions leading to Angelman syndrome or Prader-Willi syndrome were noted either. These variants could not be confirmed with Sanger sequencing due to financial constraints. Nevertheless, family was counselled regarding inheritance patterns and need for Sanger sequencing should the next pregnancy be planned. Strict photo-protection and regular ophthalmological evaluation were also emphasised.

Table 1 highlights the various subtypes of albinism and other related disorders.^1-5

OCA2 is caused by a mutation in the OCA2 gene (located on 15q12-q13.1chromosome containing 838 amino acids over 30 exons), which encodes for the P-protein. P-protein contains 12 transmembrane domains, which are crucial for normal biogenesis of melanosomes by maintaining acidic pH and for processing and transporting TYR and TYRP1.⁶ Maternal and paternal micro-deletions on chromosome 15q can result in Angelman syndrome and Prader-Willi syndrome due to their proximity to the OCA2 gene.²

Patients with OCA2 present with minimal to near normal cutaneous pigmentation at birth as melanocytes retain some ability to synthesise melanin (tyrosinase-positive). Irides colour varies from blue to brown. Overall pigmentation may turn darker with age, and despite subsequent improvement, they may develop consequences secondary to chronic sun damage. Additionally, visual problems, although less severe than OCA1, can be highly debilitating and are an essential manifestation in early diagnosis of OCA2.⁶ Therefore, regular use of sunscreen, protective clothing, and periodic dermatological and ophthalmological evaluation is imperative.

Clinical heterogeneity in OCA and diversity within mutation of the OCA2 gene (homozygous or compound heterozygous), to possible overlap with Angelman syndrome or Prader-Willi syndrome establishes the pre-eminent roles of mutational analysis in albinism.

Compound heterozygosity entails the presence of two different mutated alleles at a particular gene locus and differs from homozygous mutations that necessitate acquiring two identical mutated alleles of a gene at similar loci, thus resulting in a more severe phenotype.⁷

All patient characteristics (including skin, hair, and eye colour) and mutations have been summarised in the supplementary table from a comprehensive PubMed search for ‘oculocutaneous albinism’, ‘compound heterozygous,’ and ‘OCA2 gene’.

Despite OCA2 being a milder phenotype of OCA, ophthalmological morbidity can be significant if ignored. Mutational analysis ensures a discussion regarding inheritance patterns, recurrence risk, reproductive options and helps clear doubts of worrying parents. With gene therapies making headway in genodermatoses, identification of the affected gene ensures specific treatment options in the future.