Genetic Testing of a Puerto Rican Family Trio with Oculocutaneous Albinism Type 1B Reveals a Misdiagnosis of Hermansky-Pudlak Syndrome

Hermansky‐Pudlak syndrome (HPS) is a rare autosomal recessive disorder where the biogenesis of lysosomal‐related organelles is affected. Clinical manifestations depend on the type of HPS, and frequently include a hemorrhagic diathesis, oculocutaneous albinism and a lysosomal storage disease. Some types of HPS manifest with pulmonary fibrosis, granulomatous colitis, neutropenia, immunodeficiency and neurological symptoms. Up to date, 10 types of HPS have been reported, each arising from mutations in different genes. In Puerto Rico, HPS is caused primarily by founder mutations in the HPS1 and HPS3 genes. The present study aims to determine the genetic defects in a Puerto Rican family trio that does not harbor the HPS1 and HPS3 founder mutations. The proband presented with ocular albinism, reduced number on platelet dense bodies, neutropenia, and gastroesophageal reflux disease, which led clinicians to diagnose her with HPS. Exome sequencing was performed for the family trio using blood samples, where single nucleotide variants in several HPS genes as well as the Tyrosinase gene (TYR) were found. The proband carries three TYR gene amino acid changes: G47D, S192Y, and R402Q. The pathological G47D mutation has been previously detected in Puerto Rican oculocutaneous albinism type 1 (OCA1) patients who were homozygous for these mutations. The proband’s father carries the G47D and S192Y variants, but the R402Q is a de novo mutation in the proband. The R402Q amino acid change is frequently found in Caucasians (MAF=.252) and Puerto Ricans (MAF=0.183) and makes TYR a temperature‐sensitive enzyme. The TYR gene mutations detected would imply that the proband has very low TYR activity. Both the S192Y and the R402Q variants have been proposed to have combinatory variant effects with other more severe OCA1 mutations. Our findings suggest that the combination of common and pathological TYR alleles may be the cause of the proband’s albinism, and that the other clinical manifestations may be unrelated or due to the other mutations found in HPS genes. This study supports previous work that proposed that the common S192Y and R402Q TYR alleles combined with a deleterious mutation can cause OCA1B, but their clinical relevance still need to be investigated further since there is also evidence that homozygosity for R402Q does not cause OCA. The clinical relevance of supposedly benign HPS gene SNPs also deserves further studies. Support or Funding Information This research was supported in part by RCMI grants U54 MD007600 and U54MD007587 (National Institute on Minority Health and Health Disparities), RISE grant R25GM061838 and PR INBRE grant P20GM103475 (National Institute of General Medical Sciences).