BACKGROUND: Oculocutaneous albinism (OCA) is a genetically heterogeneous condition that is associated with reduced or absent melanin pigment in the skin, hair, and eyes, resulting in reduced vision, high sensitivity to light, and rapid and uncontrolled eye movements. To date, seventeen genes have been associated with OCA including syndromic and non-syndromic forms of the condition.
METHODS: Whole exome sequencing (WES) was performed to identify pathogenic variants in nine Pakistani families with OCA, with validation and segregation of candidate variants performed using Sanger sequencing. Furthermore, the pathogenicity of the identified variants was assessed using various in-silico tools and 3D protein structural analysis software.
RESULTS: WES identified biallelic variants in three genes explaining the OCA in these families, including four variants in TYR, three in OCA2, and two in HPS1, including two novel variants c.667C > T: p.(Gln223*) in TYR, and c.2009 T > C: p.(Leu670Pro) in HPS1.
CONCLUSIONS: Overall, this study adds further knowledge of the genetic basis of OCA in Pakistani communities and facilitates improved management and counselling services for families suffering from severe genetic diseases in Pakistan.

To analyse the genetic aetiology of a child with oculocutaneous albinism and to explore the effects of two mutation sites on the function of the OCA2 protein at the mRNA and protein levels via the use of recombinant carriers in vitro. Whole-exome sequencing (WES) and Sanger sequencing were used to analyse the pathogenic genes of the child and validate the mutations in the parents. pEGFP and phage vectors carrying wild-type and mutant OCA2 were constructed using the coding DNA sequence (CDS) of the whole gene-synthesized OCA2 as a template and transfected into HEK293T cells, after which expression analysis was performed. The child in this study was born with white skin, hair, eyelashes, and eyebrows and exhibited nystagmus. Genetic analysis indicated that the child carried two heterozygous mutations: c.1079C > T (p.Ser360Phe) of maternal origin and c.1095_1103delAGCACTGGC (p.Ala366_Ala368del) of paternal origin, conforming to an autosomal recessive inheritance pattern. In vitro analysis showed that the expression of the c.1079C > T (p.Ser360Phe) mutant did not significantly change at the mRNA level but did increase at the protein level, suggesting that the mutation may lead to enhanced protein stability, and the c.1095_1103delAGCACTGGC (p.Ala366_Ala368del) mutation resulted in the loss of three amino acids in exon 10, producing a truncated protein. In vitro expression analysis also revealed that the expression of the mutant gene was significantly downregulated at both the mRNA and protein levels, suggesting that the mutation can simultaneously produce truncated proteins and lead to protein degradation. This case study enriches the phenotypic spectrum of OCA2 gene disease. In vitro expression analysis confirmed that both mutations affect protein expression, providing a theoretical basis for analysing the pathogenicity of these two mutations.

BACKGROUND: Oculocutaneous albinism (OCA) is a group of autosomal recessive hereditary disorders that affect melanin biosynthesis, resulting in abnormalities in hair, skin, and eyes. Retinopathy of prematurity (ROP) is a proliferative retinopathy mainly observed in premature infants with low birth weight and early gestational age, but it can also affect full-term infants or children with normal weight, particularly in developing countries. The coexistence of ROP and OCA is rare. There is limited documentation regarding treatment approaches, with few studies reporting positive outcomes with laser treatment due to the absence of melanin pigment. This study discusses the treatment challenges in a female infant diagnosed with ROP and OCA, and underscores the importance of genetic analysis in guiding therapeutic decisions for this rare comorbid condition.
METHODS: The study presents a case of ROP occurring concurrently with OCA. Genetic testing revealed two variants, c.727C > T (p.R243C) and c.1832 T > C (p.L611P), in the OCA2 gene, inherited from the patient\'s mother and father, respectively. The identified mutations were consistent with a diagnosis of OCA2, classified as a subtype of OCA. The patient initially received intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection, followed by laser photocoagulation therapy for a recurrent event. A favorable outcome was observed during the 2-month follow-up period.
CONCLUSIONS: The co-occurrence of ROP and OCA is a rare phenomenon, and this is the first recorded case in the Chinese population. The current case supports the use of laser as the primary treatment modality for ROP in OCA2 patients with partial pigmentation impairment. Furthermore, genetic analysis can aid in predicting the effectiveness of laser photocoagulation in this patient population.

Melanosomal pH is important for the synthesis of melanin as the rate-limiting enzyme, tyrosinase, is very pH-sensitive. The soluble adenylyl cyclase (sAC) signaling pathway was recently identified as a regulator of melanosomal pH in melanocytes; however, the melanosomal proteins critical for sAC-dependent regulation of melanosomal pH were undefined. We now systematically examine four well-characterized melanosomal membrane proteins to determine whether any of them are required for sAC-dependent regulation of melanosomal pH. We find that OA1, OCA2, and SLC45A2 are dispensable for sAC-dependent regulation of melanosomal pH. In contrast, TPC2 activity is required for sAC-dependent regulation of melanosomal pH and melanin synthesis. In addition, activation of TPC2 by NAADP-AM rescues melanosomal pH alkalinization and reduces melanin synthesis following pharmacologic or genetic inhibition of sAC signaling. These studies establish TPC2 as a critical melanosomal protein for sAC-dependent regulation of melanosomal pH and pigmentation.

A 48-year-old male with oculocutaneous albinism (OCA) presented with bilateral diminution of vision. Ocular examination revealed bilateral central corneal thinning, scarring with ectasia, depigmented irides, transillumination defects, and pseudophakia. Examination of the right eye also revealed a hyperoleon, emulsified silicon oil in the vitreous cavity, and an attached retina, while the left eye had a total rhegmatogenous retinal detachment (RRD). This case describes a unique set of challenges (the presence of an ectatic scarred cornea and a hypopigmented fundus) and sodium fluorescein dye as an adjunct in the surgical management of a complex RRD. A review of literature highlighting the association of keratoconus and RRD in OCA is also presented in this report.

UNASSIGNED: To report a case of unsuccessful transscleral cyclophotocoagulation in a patient with OCA1A tyrosinase-negative oculocutaneous albinism.
UNASSIGNED: A 35-year-old Asian female with molecularly diagnosed OCA1A (tyrosinase-negative) oculocutaneous albinism and unilateral severe mixed mechanism glaucoma underwent transscleral cyclophotocoagulation on two separate occasions to treat elevated intraocular pressure. The intraocular pressure remained markedly elevated approximately 1 month following two separate treatments of transscleral cyclophotocoagulation while using high energy settings. The poor efficacy of both cyclophotocoagulation treatments was most likely due to a lack of melanin in the setting of oculocutaneous albinism.
UNASSIGNED: Cyclophotocoagulation in patients with oculocutaneous albinism is less likely to yield a desired lowering of intraocular pressure due to the absence of melanin.

Oculocutaneous albinism (OCA) is genetically transmitted. In this paper we advocate for this disease to be included in the NTD list of the WHO. OCA type 2 is the most common form of albinism in sub-Saharan Africa, with a prevalence of 1 in 7900 among the Bamileke of Cameroon, 1 in 3900 in South Africa and 1 in 1100 among the Ibos of Nigeria, as compared to a prevalence of 1 in 10,000 among African Americans and 1 in 36,000 among White Americans and Europeans. The medical problems related to ophthalmological aspects (poor visual acuity, ametropia, nystagmus, photophobia) and dermatological aspects of albinism (sensitivity to UV rays from the sun and development of skin cancers) are well known. However, their management is often challenging for persons with albinism in sub-Saharan Africa because of their financial burden and the difficulty of accessing medical specialists. In many African countries, persons with albinism are also very often the subject of social, cultural, medical, moral and economic discrimination, which can limit their access to education, employment and community life. They are considered \'white Africans\', intermediary and incomplete, with innate powers for good and evil. This particularity has made persons with albinism the targets of mutilations and/or ritual attacks for the purposes of using their body parts in the preparation of charms to bring good luck, health or prosperity. On 13 June 2013, as a result of lobbying by the Canadian NGO Under the Same Sun and African albinism associations, United Nations bodies including UNESCO and the WHO (World Health Organization) responded and a Resolution addressing the discrimination and attacks was voted in. The date has since become International Albinism Awareness Day and is celebrated on a different theme each year with great energy and impact, especially by French, English and Portuguese speaking albinism associations across sub-Saharan Africa. In 2015 the Human Rights Council created the position of Independent Expert on Albinism to better collect and analyse data on the rights of persons with albinism around the world, and especially in countries where ritual attacks occur. The data collected by albinism associations and the authorities thus go directly to the UN Human Rights Directorate. Despite this international attention to the attacks on persons with albinism, one of the biggest threats is skin cancer, which very often leads to early death. In 2022, the WHO launched a strategic framework for the control and management of neglected skin-related neglected tropical diseases - an additional reason to include oculocutaneous albinism as an NTD. Although the focus is currently limited to dermatoses of an infectious nature, we argue here for the integration of oculocutaneous albinism among NTDs because the deadliness of these carcinomas in sub-Saharan Africa is well-known and has been examined in a number of medical publications. Here, we propose that oculocutaneous albinism in sub-Saharan Africa be classified as an NTD to help people with albinism have access to health, economic, social and cultural rights.

BACKGROUND: Oculocutaneous albinism type 4 (OCA4) is a rare autosomal recessive disorder characterized by a reduction of pigmentation in skin, hair, and eyes, and OCA4 is mainly seen in the SLC45A2 gene variants.
OBJECTIVE: To report a Chinese patient suspected of oculocutaneous albinism and identify the causing mutation.
METHODS: Genomic DNA was extracted from the peripheral blood samples of the patient, his parents, and elder brother. Whole exome sequencing was performed in the family, and Sanger sequencing was then used to verify the mutations.
RESULTS: Compound heterozygous variants, c.1304C>A (p.S435Y) and c.301C>G (p.R101G) in SLC45A2 gene, were detected in the proband, which were inherited from his father and mother respectively. Based on the ACMG guidelines, we can interpret the c.1304C>A (p.S435Y) variant as a suspected pathogenic variant and the c.301C>G (p.R101G) variant as a clinically significant unspecified variant. The diagnosis of OCA4 is confirmed.
CONCLUSIONS: We firstly reported this case of OCA4 with the compound heterozygous variants in the SLC45A2 gene. Our findings further enrich the reservoir of SLC45A2 mutations in OCA4.

Oculocutaneous albinism (OCA) is a rare inherited disorder characterized by a partial or complete reduction of melanin biosynthesis that leads to hypopigmentation in the skin, hair and eyes. The OCA1 subtype is caused by mutations in TYR. The purpose of this study was to investigate the genetic and clinical ophthalmic characteristics of TYR mutations in patients with OCA. Herein, 51 probands with a clinical diagnosis of OCA were enrolled. Whole-exome sequencing and comprehensive ophthalmic examinations were performed. Overall, TYR mutations were detected in 37.3% (19/51) in the patients with OCA. Fifteen patients had compound heterozygous variants, and four cases had homozygous variants. Eleven different pathogenic variants in TYR were detected in these 19 patients, with missense, insertion, delins and nonsense in 71.1% (27/38), 15.8% (6/38), 2.6% (1/38), and 10.5% (4/38), respectively. Clinical examinations revealed that 84.2% (16/19) of patients were OCA1A, and 15.8% (3/19) were OCA1B. Most TYR probands (52.6%, 10/19) had moderate vision impairment, 15.8% (3/19) had severe visual impairment, 10.5% (2/19) exhibited blindness, only 5.3% (1/19) had mild visual impairment and 15.8% (3/19) were not available. Photophobia and nystagmus were found in 100% (19/19) of the patients. In addition, grade 4 foveal hypoplasia was detected in 100% (12/12) of the patients. In conclusion: The TYR patients exhibited severe ocular phenotypes: the majority (93.8%, 15/16) of them had a moderate vision impairment or worse, and 100% (12/12) had severe grade 4 foveal hypoplasia. These novel findings could provide insight into the understanding of OCA.

UNASSIGNED: We report a case of Hermansky-Pudlak Syndrome type 7 (HPS-7) caused by a homozygous variant in the dystrobrevin-binding protein 1 gene (DTNBP1) and highlight the genetic challenges associated with this rare disorder.
UNASSIGNED: Case report. Literature review was performed by searching PubMed on May 2023, without language or date restriction, using the following terms: Hermansky-Pudlak syndrome, Hermansky-Pudlak syndrome type 7, and dystrobrevin-binding protein 1 gene.
UNASSIGNED: We report a case of a 69-year-old Portuguese female who presented for ophthalmic evaluation with long-standing severe visual impairment, pronounced photophobia, right-eye esotropia, and bilateral pendular nystagmus. Anterior segment examination revealed iris transillumination defects, while the ocular fundus showed hypopigmentation and the absence of the foveal reflex. The patient had a history of oculocutaneous albinism (OCA) and recurrent epistaxis. Her family history was positive for first-degree consanguineous parents and a deceased sister at young age who also exhibited OCA and recurrent epistaxis. Genetic testing identified a homozygous pathogenic nonsense variant in the DTNBP1, c.307C>T p.(Gln103*). The patient\'s clinical features and genetic testing support the diagnosis of HPS-7. The identified variant has been previously reported in the literature, in adult patients of Portuguese descent.
UNASSIGNED: This work highlights the genetic complexity of HPS-7 and emphasizes the importance of genetic testing in the diagnosis of this rare disorder. The identification of a rare pathogenic variant expands our understanding of HPS-7 genetics and suggests a possible founder effect in the Portuguese population.