Implementation of an optimized strategy for genetic testing of the Chinese patients with oculocutaneous albinism
Introduction
Oculocutaneous albinism (OCA) is an autosomal recessive disorder with a relatively high incidence in Chinese Han population as estimated as 1:18,000 [1]. It manifests as a reduction or complete loss of melanin in the skin, hair, and eyes, often accompanied with eye symptoms such as photophobia, strabismus, moderate to severe visual impairment, and nystagmus. OCA could be caused by mutations in non-syndromic OCA genes (TYR, OCA2, TYRP1 and SLC45A2) or syndromic OCA genes (HPS1, HPS2, HPS3, HPS4, HPS5, HPS6, HPS7, HPS8, LYST, MYO5A, RAB27A and MLPH) [2]. OCA1 is the predominant form which accounts for about 70% of the Chinese OCA patients, while OCA2, OCA4 and HPS1 are less common, reflecting a population-specific distribution of different subtypes of OCA [3].
OCA is clinically characterized as OCA1A, OCA1B or OCA2. OCA1A presents a complete lack of tyrosinase activity and produces a totally depigmented phenotype with affected individuals exhibiting white hair, white skin, and blue, brown or pink iris throughout life. OCA1B is characterized by reduction of tyrosinase activity. Individuals with OCA1B are born with white hair and then change to blond or yellow with age [4]. OCA2 is characterized by yellow, brown or golden hair at birth with or without darkening of hair color at later age. However, the clinically diagnosed subtypes of OCA could be mixed forms of molecularly diagnosed OCA subtypes, such as clinical OCA1 could be molecularly identified as OCA1, OCA2, OCA4 or HPS1, whereas clinical OCA2 could be OCA1, OCA2, OCA4, or HPS1 [3]. Hermansky-Pudlak syndrome (HPS) is a more severe form of OCA. Patients with HPS often die in their middle ages [5]. Therefore, the genetic testing of OCA is needed for routine diagnosis of OCA to better characterize the prognosis of OCA. Based on our previous genetic epidemiological studies of OCA in Chinese Han population, we have implemented an optimized strategy to molecularly screen the mutations on the known OCA genes.
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Study subjects
We recruited 52 unrelated OCA patients (Table 1) and 100 unaffected subjects from the Chinese Han population. The patients were from 19 different provinces of China in the Chinese Albinism Registry [6]. None of these patients have a family history of consanguinity. We followed the criteria for the differentiation of OCA1A, OCA1B and OCA2 as described [3]. Among the 52 OCA patients, thirty were clinically diagnosed as OCA1A or OCA1B, twenty were diagnosed as OCA2 and two OCA patients were not
The distribution of mutational OCA genes was slightly shifted
In a total of 52 OCA patients, 93.3% (48/52) of these patients were confirmed by molecular testing, with the remaining 7.7% (4/52) uncharacterized after mutational screening of the TYR, OCA2, TYRP1, SLC45A2 and HPS1 gene. Of the 48 molecularly diagnosed patients, 33 patients carried two mutational alleles; 15 carried one mutational allele. Of the identified patients, we found apparent pathologic TYR mutations in 50.0% patients (26/52), OCA2 mutations in 15.4% patients (8/52), SLC45A2 mutations
Discussion
OCA has been widely distributed in different populations. However, the spectra of disease genes and mutational alleles of the known OCA genes vary in different populations. The distributional pattern of TYR, OCA2, SLC45A2 and HPS1 in the Chinese population [3] is apparently different from other populations such as Japanese [13], non-Hispanic Caucasians [9], and Danes [14]. Nevertheless, TYR is the most common OCA gene in all these four populations. In this study, we have revised the spectrum of
Acknowledgements
This work was supported in part by National Natural Science Foundation of China (No. 30730049), National Basic Research Program of China (No. 2007CB947200), Ministry of Agriculture of China (2009ZX08009-158B) and Natural Science Foundation of Beijing (No. 7092040).
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