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. 2024 Jul 12;12(7):e2493. doi: 10.1002/mgg3.2493

After an initial Hermansky–Pudlak syndrome clinical diagnosis, molecular testing reveals variants for oculocutaneous albinism type 1B: A case report

Joseline Serrano‐González 1, Ingrid Montes‐Rodríguez 2, Jessicca Y Renta 1, Ricardo Rojas 1, Carmen L Cadilla 1,✉
PMCID: PMC11240142  PMID: 38994739

Abstract

Background

Albinism is a heterogeneous condition in which patients present complete absence, reduction, or normal pigmentation in skin, hair and eyes in addition to ocular defects. One of the heterogeneous forms of albinism is observed in Hermansky–Pudlak syndrome (HPS) patients. HPS is characterized by albinism and hemorrhagic diathesis due to the absence of dense bodies in platelets.

Methods

In this report, we describe a case of a pair of Puerto Rican siblings with albinism that were clinically diagnosed with HPS during childhood. Since they did not harbor the founder changes in the HPS1 and HPS3 genes common in Puerto Ricans, as adults they wanted to know the type of albinism they had. We performed exome sequencing, validation by PCR, and cloning of PCR products followed by Sanger sequencing in the family members.

Results

We discovered no mutations that could explain an HPS diagnosis. Instead, we found the siblings were compound heterozygotes for 4 variants in the Tyrosinase gene: c.‐301C>T, c.140G>A (rs61753180; p.G47D), c.575C>A (rs1042602; p.S192Y), and c.1205G>A (rs1126809; p.R402Q). Our results show that the correct diagnosis for the siblings is OCA1B.

Conclusion

Our study shows the importance of molecular testing when diagnosing a rare genetic disorder, especially in populations were the disease prevalence is higher.

Keywords: albinism, Hermansky–Pudlak syndrome, hypomorphic alleles

Puerto Ricans siblings diagnosed with Hermansky–Pudlak syndrome showed tyrosinase gene mutations consistent with OCA1B. Molecular testing should be performed in early childhood for genetically heterogenous diseases in geographical locations where rare syndromic albinism forms are very frequent.

graphic file with name MGG3-12-e2493-g003.jpg

1. INTRODUCTION

Hermansky–Pudlak syndome (HPS) is a rare autosomal recessive genetic disorder that affects the biogenesis and trafficking of lysosomal‐related organelles (LRO) (Hermansky & Pudlak, 1959). To date, 11 subtypes of HPS have been reported each arising from variants in different genes (Ammann et al., 2016; Anikster et al., 2001; Badolato et al., 2012; Dell'Angelica et al., 1999; Li et al., 2003; Morgan et al., 2006; Oh et al., 1996; Pennamen et al., 2020; Suzuki et al., 2002; Zhang et al., 2003). Clinical manifestations depend on the affected gene and include hemorrhagic diathesis, oculocutaneous albinism, pulmonary fibrosis, granulomatous colitis, lysosomal accumulation of ceroid lipofuscin, neutropenia, and neurological problems. The clinical manifestations that are present across all the subtypes of HPS are oculocutaneous albinism, bleeding diathesis, nystagmus, and poor visual acuity (De Jesus‐Rojas & Young, 2020).

The Caribbean island of Puerto Rico has the highest prevalence of HPS cases in the world due to the presence of two founder changes: a 16 bp duplication in exon 15 of HPS1, and a 3.9 kb deletion in HPS3 (Anikster et al., 2001; Oh et al., 1996). The two sub‐types of HPS that have been described in Puerto Rico, type 1 and type 3, are responsible for approximately 60% of the albinism cases in this country (Santiago Borrero et al., 2006). The rest of the albinism cases in the island have been reported to harbor variants in the Tyrosinase (TYR) (gene ID: 7299; OMIM 606933) and P(OCA2) genes, responsible for oculocutaneous albinism (OCA) type 1 (OCA1) and type 2 (OCA2), respectively. Here, we report a Puerto Rican family with two siblings that were clinically diagnosed with HPS in 1993, but our exome sequencing and subsequent gene level variant screening results show associations with OCA1B. For over 30 years this family endured the implications of their HPS diagnosis like taking special care for dental and surgical procedures due to the profuse bleeding risk of HPS patients, the regular pulmonary assessment, and the stress of the possibility of having a child with the syndrome. This report evidences the importance of genetic testing in patients clinically diagnosed with any form albinism.

2. MATERIALS AND METHODS

2.1. Editorial policies and ethical considerations

The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of University of Puerto Rico Medical Sciences (protocol codes 2060199 and 2290033036R001; date of approval 12/22/2020, last continuing review approved 12/20/22). Written informed consent was obtained from all subjects involved in the study.

2.2. Case report

A Puerto Rican female was clinically diagnosed with HPS in early childhood. As an infant she was diagnosed with ocular albinism due to prominent nystagmus after a complete eye exam. During infancy she suffered from recurrent infections and at the age of 3 she was referred to a hematologist‐oncologist due to her constant easy bruising and prolonged bleeding. Because of her fair skin, light‐brown‐colored hair, ocular albinism, and neutropenia, the doctor suspected HPS and sent her blood for microscopical evaluation of her platelets. This analysis found smaller dense bodies than normal, and she was diagnosed with HPS. After some time, she was screened for the Puerto Rican founder variants in HPS1 and HPS3, which she did not harbor. When her brother was born with fair skin, platinum blond hair, and was later found to have ocular albinism, he was also clinically diagnosed with HPS.

Later on, as an adult, the proband's platelets were once again microscopically evaluated and this analysis showed lower number of dense bodies than normal, but higher number than in platelets from HPS patients, where they are absent. Both siblings now present with ocular albinism, fair skin and light brown‐colored hair. The proband's bleeding time is 7.5 min, frequent infections have decreased, and she occasionally suffers from gastroesophageal reflux disease. Her brother has ocular albinism but is an otherwise healthy male. Their father suffers from Meniere disease, bleeding problems (as described by the proband), and had colon and lymphatic cancer. Their mother suffers from oscillating thyroid function, pernicious anemia, and breast cancer. Family history did not include cases with HPS, but in both parental lines the siblings have relatives with albinism (Figure 1).

FIGURE 1.

FIGURE 1

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Familial pedigree on albinism. Both parental lines show relatives with some type of albinism: two paternal grandfather's cousins and a maternal grandmother's cousin. Symbols: square: male; circle: female; filled symbol: diamond: unknown/undetermined gender; filled symbol: affected individual; diagonal line through symbol: deceased.

2.3. Sample collection and processing

Blood samples were obtained from the proband and both of her parents. The proband's brother provided a saliva sample. DNA was isolated from whole blood using QIAamp DNA maxi kit (Qiagen, Hilden, Germany). DNA from the proband's brother was isolated from saliva using the Saliva DNA Isolation Kit (Norgen Biotek Corp., Thorold, ON).

2.4. Exome sequencing

Exome sequencing of the trio (proband, mother, and father) was performed using an Ion Proton sequencing system at the PROMICS Core of the UPR Comprehensive Cancer Center, using the Ion AmpliSeq Exome RDY Library preparation kit (Thermo Fisher Scientific) as recommended by the manufacturer. Briefly, 100 ng genomic DNA (gDNA) from each sample, 5X Ion AmpliSeq HiFi Mix and 12 separate exome primer pools were used for 10 cycles of the amplification step. The PCR products obtained were pooled before primer digestion using the FuPa reagent (Thermo Fisher Scientific). This was followed by a ligation step using Ion P1 and Ion Xpress Barcode adapters. The libraries were then purified and quantified using the Agilent High Sensitivity DNA kit on an Agilent 2100 Bioanalyzer (Agilent Technologies), prior to emulsion PCR on an Ion OneTouch System. The emulsion and enrichment steps were performed using the IonPI HiQ OT2 200 kit. The templated Ion Sphere particles were enriched using Ion OneTouch ES (Life Technologies, Carlsbad, CA, USA). Finally, the sequencing reactions were done on an Ion Proton Instrument (Life Technologies, Carlsbad, CA, USA) using the IonPI HiQ Sequencing 200 kit and the Ion PI chip V3 (Thermo Fisher Scientific). We sequenced two libraries per chip and obtained approximately 13–15 Gb of DNA sequence per sequencing run/sample. Reads were mapped against the UCSC Human reference genome GRCh37/hg19 and the Ion Torrent pipeline was used to identify the variants (Life technologies, Carlsbad, CA).

To search for the variants that could be the cause of the proband's phenotype, we focused on the genes related to HPS and the TYR gene. We filtered variants by selecting missense variants and those variants for which the proband did not share the genotype with both parents. The proband's brother sample was collected after exome sequencing of the trio and analyzed by PCR and Sanger sequencing. Aliquots of 100 ng of DNA from each sample were used for amplification. To avoid annotation errors, selected genetic variants were validated through exon sequencing, and both direct PCR product and plasmid Sanger sequencing, including the proband's brother DNA sample. Automated Sanger sequencing was carried out at the UPR Molecular Biology Core in an ABI 3130 system using dye terminator chemistry. Sequence electrophoregrams were visualized using SnapGene Viewer (Dotmatics).

2.5. Tyrosinase variants phasing

To determine the chromosomal origin of the c.575C>A (rs1042602; p.S192Y) variant, we cloned the TYR exon 1 PCR products using Zero Blunt TOPO PCR Cloning Kit for Sequencing by Invitrogen (Waltham, MA). Blunt‐End PCR products were generated using the Platinum SuperFi thermostable proofreading polymerase (Invitrogen, Thermo Scientific) and cloned into the pCR4Blunt‐TOPO vector with increased incubation times (Table S1). Ligation products were chemically transformed into One Shot Chemically Competent Escherichia coli and transformants were selected through kanamycin resistance. Plasmids were extracted using the QIAprep Miniprep Kit (Qiagen, Hilden, Germany), and sequenced using M13 sequencing primers. To detect the TYR promoter variant c.‐301C>T, we performed Sanger Sequencing of PCR products, as described above.

3. RESULTS

3.1. Exome sequencing

Exome sequencing was performed in the family trio (proband, mother, and father). The results revealed several missense variants in HPS‐associated genes (Table S2). De novo changes in the proband were found in the HPS1 and HPS5 genes, for which the proband was heterozygous. Variants in AP3B1 (for HPS type 2), and HPS4 present in the proband where also found in one or both parents. Using the 1000 Genomes Browser phase 3 Puerto Rican population (PUR), the allele frequencies of Puerto Rican individuals with the same gene haplotypes that the proband had were the following: 34.61% for HPS4, 8.54% for HPS1, 3.85% for the combination of HPS4 and HPS1 haplotypes, and 8.65% for HPS5. PUR allele frequencies for the AP3B1 gene region were not available. In addition to the HPS‐associated genes, we decided to look for variants in the TYR gene because of the family history with albinism and the proband's phenotype. We found a pathogenic variant, c.140G > A (rs61753180; p.G47D) (Oetting et al., 1991, 1993; Oetting & King, 1993), and two additional missense variants, i.e., c.575C>A (rs1042602; p.S192Y) and c.1205G>A (rs1126809; p.R402Q). Although the variant c.1205G>A in the mother's DNA was not detected by semiconductor sequencing, later on it was found by Sanger Sequencing in the validation process. The frequency of the proband's TYR haplotype was 0.0% among the PUR data sample in the 1000 Genomes Browser phase 3. For the c.575C>A and c.1205G>A variants, the haplotype frequency in PUR is 7.69%.

3.2. Tyrosinase variants phasing

We confirmed by Sanger Sequencing that the siblings were heterozygous for the TYR variants c.140G>A (rs61753180; p.G47D), c.575C>A (rs1042602; p.S192Y), and c.1205G>A (rs1126809; p.R402Q). We also found that they were homozygous for the promoter variant c.‐301C>T [rs4547091] (Figure 2a). Variant phasing of TYR exon 1 showed that both siblings have the variant c.140G > A in a different chromosome than c.575C>A. Since the c.140G>A was inherited from the paternal chromosome, then the c.575C>A is derived from the maternal chromosome (Figure 2b). The PUR haplotype frequencies for c.[‐301C; 140A] and c.[‐301C; 575A; 1205A] are 0.48% and 1.92%, respectively.

FIGURE 2.

FIGURE 2

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Sequencing electropherograms for Tyrosinase variants and haplotype diagram for albinism patients in this study. (a) The Sanger Sequencing electropherograms for the sibling's TYR gene affected regions where the variants were detected are shown (TOP row: Proband, BOTTOM row: Affected brother). The siblings are homozygous for the c.‐301C>T ref. allele C [rs4547091], and heterozygous for the other three variants: c.140G>A (rs61753180; p.G47D), c.575C>A (rs1042602; p.S192Y), and c.1205G>A (rs1126809; p.R402Q) (b) Chromosomal representation of TYR gene haplotypes in the affected siblings. Sanger sequencing of TYR PCR products showed that both siblings have the haplotype [c.‐301C, c.140A] in the paternal chromosome, and the haplotype [c.‐301C, c.575A, c.1205A] in the maternal chromosome.

4. CONCLUSION

Exome sequencing results did not support an HPS diagnosis since the proband was either heterozygous for HPS gene variants or the corresponding genotypes were found on her unaffected parents (Table S2). We decided to look into other albinism‐related genes because of the proband's ocular albinism and the family history (Figure 1). In the TYR gene, the proband and her father are carriers of a pathogenic variant commonly found in OCA1A Puerto Rican patients, the c.140G>A (rs61753180; p.G47D, [Oetting et al., 1993; Santiago Borrero et al., 2006]) which has a PUR minor allele frequency (MAF) of 0.005. The G47D missense variant may affect substrate or cofactor binding to TYR (Oetting & King, 1993). Exome sequencing also revealed the presence of two other coding variants in the TYR gene: c.575C>A (rs1042602; p.S192Y; PUR MAF = 0.308) and c.1205G > A (rs1126809; p.R402Q; PUR MAF = 0.183) in exons 1 and 4, respectively (Table S1). The affected family members were heterozygous for the S192Y variant, which affects one of the copper‐binding regions of the enzyme (Oetting & King, 1993). The proband and her mother are both carriers for the thermosensitive variant R402Q which reduces the enzymatic activity of TYR by almost 75% at 37°C compared to normal activity at 31°C (Jagirdar et al., 2014). Because of the thermosensitive effect of R402Q on TYR, many studies have linked this variant with OCA (Campbell et al., 2019; Chiang et al., 2008; Fukai et al., 1995; Grønskov et al., 2019; Hutton & Spritz, 2008; Kalahroudi et al., 2014; Monfermé et al., 2019; Norman et al., 2017; Wang & Chiang, 2019) and have strongly suggested that this variant is considered pathogenic when found in compound heterozygosity with another deleterious variant in TYR, leading to mild forms of albinism (Lasseaux et al., 2018). The effect of the variants S192Y and R402Q in cis and found in trans with a pathogenic variant deserves more studies, but sufficient evidence suggests their association to OCA1 (Lasseaux et al., 2018; Sergouniotis et al., 2023). In addition, the R402Q and S192Y variants have been shown to contribute to foveal morphology among the normal vision population (Ayala et al., 2021). For the promoter variant c.‐301C>T (PUR MAF = 0.567), one study found that it modulates the penetrance of the c.1205A allele (Michaud et al., 2022). In vitro studies show that the TYR gene expression is lower for the ‐301C allele because it decreases the transcription activity by affecting the binding of the orthodenticle homeobox 2 (OTX2) transcription factor (Liu et al., 2019; Reinisalo et al., 2012). Therefore, if the ref. allele for the promoter variant c.‐301C is homozygous with the c.1205A allele, the risk of albinism is high (Michaud et al., 2022). Another study confirmed this finding and also included evidence that the c.‐301C and c.575A alleles are in high linkage disequilibrium, and that the TYR haplotype c.[575A; 1205A] arose from recombination events within intron 3 (Loftus et al., 2023). The TYR c.[−301C;575C>A;1205G>A] haplotype frequency in people with European‐like ancestries is estimated to be about 1% and its presence either in the homozygous state or in trans to a TYR‐like pathogenic or pathogenic variant like G47D, is considered sufficient to establish the genetic diagnosis, especially in people who have relatively mild forms of albinism (Sergouniotis et al., 2023).

The affected siblings share the same genotype for all TYR variants (Figure 2a). Phasing revealed that the variant S192Y was on the maternal chromosome together with the R402Q, locating them in trans with the G47D (Figure 2b) and both chromosomes carry the reference allele for the promoter variant c.‐301C. This is the first case report in the literature that includes the c.‐301C allele and the pathogenic variant G47D in trans with the commonly found S192Y and R402Q variants. Although the allelic heterogeneity of the presented variants do not allow us to predict the exact allelic combination responsible for the albinism in the siblings, it is clear that both TYR copies are compromised. These results taken together with the phenotypic traits of poor visual acuity, nystagmus, and hypopigmentation is consistent with an OCA1B diagnosis. These results highlight the clinical and molecular complexity involved when diagnosing albinism.

In conclusion, the molecular genetics of albinism exhibits locus and genetic heterogeneity. Performing the most comprehensive genetic testing helps physicians in making the correct diagnosis in patients with albinism, which has become of great importance over time since there are life threatening syndromes that include this phenotype. Genetic testing always should be accompanied by genetic counseling to ensure that the patients understand the molecular mechanisms that cause their phenotype and the preventive care needed to ensure a healthy life. This case report not only demonstrates the necessity of performing genetic testing in patients, but also the importance of including the regulatory regions, haplotype analysis and consideration of population genetics data.

AUTHOR CONTRIBUTIONS

Joseline Serrano‐González: Methodology, validation, formal analysis, investigation, writing—original draft preparation, and visualization. Ingrid Montes‐Rodríguez: Methodology. Jessicca Y. Renta: Methodology. Ricardo Rojas: Methodology. Carmen L. Cadilla: Conceptualization, resources, writing—review and editing, supervision, project administration, and funding acquisition.

FUNDING INFORMATION

This research was funded in part by an RCMI grant U54MD007600 (National Institute on Minority Health and Health Disparities), as well as grants R25GM061838, U54GM133807 and P20GM103475 from the National Institute of General Medical Sciences.

CONFLICT OF INTEREST STATEMENT

The authors declare that there are no conflicts of interest.

ETHICS STATEMENT

The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of University of Puerto Rico Medical Sciences (protocol code 2060199 and new code 2290033036R001 and date of approval 12/22/2020).

PATIENT CONSENT STATEMENT

Written informed consent was obtained from all subjects involved in the study.

Supporting information

Table S1.

Table S2.

MGG3-12-e2493-s001.docx (16.4KB, docx)

ACKNOWLEDGMENTS

We thank Dr. Carmelo Carmona‐Rivera (Systemic Autoimmunity Branch, NIAMS, NIH, MD, USA) and Dr. Lluís Montoliu (CNB‐CSIC, CIBERER‐ISCIII, Madrid, Spain), for their insight on this case report. Lilliam Villanueva and Sahily González of the UPR Molecular Biology Core Laboratory for their technical assistance with automated Sanger Sequencing. This research was funded in part by RCMI grant U54MD007600 (National Institute on Minority Health and Health Disparities), as well as grants R25GM061838, U54GM133807 and P20GM103475 from the National Institute of General Medical Sciences.

Serrano‐González, J. , Montes‐Rodríguez, I. , Renta, J. Y. , Rojas, R. , & Cadilla, C. L. (2024). After an initial Hermansky–Pudlak syndrome clinical diagnosis, molecular testing reveals variants for oculocutaneous albinism type 1B: A case report. Molecular Genetics & Genomic Medicine, 12, e2493. 10.1002/mgg3.2493

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table S1.

Table S2.

MGG3-12-e2493-s001.docx (16.4KB, docx)

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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