Comprehensive analysis of spectral distribution of a large cohort of Chinese patients with non‐syndromic oculocutaneous albinism facilitates genetic diagnosis

Zhong, Zaimin; Gu, Li; Zheng, Xiujie; Ma, Nengjun; Wu, Zehua; Duan, Juan; Zhang, Jun; Chen, Jianjun

doi:10.1111/pcmr.12790

Cited by 20 publications

(22 citation statements)

References 28 publications

(84 reference statements)

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“…However, researchers were unable to conclude the molecular diagnosis for approximately 27% of participants (Lasseaux et al, 2018). Another study reported 31 new mutations in a cohort of 114 individuals with albinism and also reported 14% participants without identified mutations (Zhong et al, 2019). Despite a smaller group of subjects, our study identified one novel mutation and two rare variants, as cause of OCA.…”

Section: Discussioncontrasting

confidence: 55%

“…In our cohort, the variant c389_391delAGA was identified in siblings (C6 and C7) whose ancestry analysis clustered them with Ad Mixed American instead of African population, this is in agreement with the TOPMed freeze 5 panel study. A second mutation, c.1037-7T > A, which was previously reported as causing OCA1 (Park et al, 1997;Grønskov et al, 2009;Lasseaux et al, 2018;Zhong et al, 2019), segregated in trans with c.389_391delAGA. Both mutations were identified in individuals (C6 and C7) who presented ophthalmologic manifestations and hair and skin hypopigmentation consistent with the albinism phenotype (Figure 1).…”

Section: Discussionmentioning

confidence: 87%

“…For three individuals with the classic OCA phenotype, we could not conclude molecular diagnosis. In OCA, a lack of associated genes or only one mutant allele in patients with clinical diagnosis of OCA has been frequently reported in the literature (Grønskov et al, 2009;Gargiulo et al, 2011;Montoliu et al, 2014;Lasseaux et al, 2018;Zhong et al, 2019). Pathogenic variations may be in intragenic, intronic, or regulatory regions that were not covered by the techniques we used.…”

Section: Discussionmentioning

confidence: 99%

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Non-syndromic Oculocutaneous Albinism: Novel Genetic Variants and Clinical Follow Up of a Brazilian Pediatric Cohort

et al. 2020

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Oculocutaneous albinism (OCA) is a genetic disorder characterized by skin, hair, and eye hypopigmentation due to a reduction or absence of melanin. Clinical manifestations include vision problems and a high susceptibility to skin cancer. In its non-syndromic form, OCA is associated with six genes and one chromosomal region. Because OCA subtypes are not always clinically distinguishable, molecular analysis has become an important tool for classifying types of OCA, which facilitates genetic counseling and can guide the development of new therapies. We studied eight Brazilian individuals aged 1.5-18 years old with clinical diagnosis of OCA. Assessment of ophthalmologic characteristics showed results consistent with albinism, including reduced visual acuity, nystagmus, and loss of stereoscopic vision. We also observed the appearance of the strabismus and changes in static refraction over a 2-year period. Dermatologic evaluation showed that no participants had preneoplastic skin lesions, despite half of the participants reporting insufficient knowledge about skin care in albinism. Wholeexome and Sanger sequencing revealed eight different mutations: six in the TYR gene and two in the SLC45A2 gene, of which one was novel and two were described in a population study but were not previously associated with the OCA phenotype. We performed two ophthalmological evaluations, 2 years apart; and one dermatological evaluation. To the best of our knowledge, this is the first study to perform clinical followup and genetic analysis of a Brazilian cohort with albinism. Here, we report three new OCA causing mutations.

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Section: Discussioncontrasting

confidence: 55%

Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

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Non-syndromic Oculocutaneous Albinism: Novel Genetic Variants and Clinical Follow Up of a Brazilian Pediatric Cohort

et al. 2020

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“…OCA is a group of autosomal recessive disorders characterized by the loss of or a reduction in pigmentation in the eyes, hair, and skin. Populations of all ethnic backgrounds can be affected by OCA, with an estimated global prevalence of 1 : 17,000 [6][7][8][9]. Very rarely, OCA may be accompanied by systematic defects such as Hermansky-Pudlak and Chediak-Higashi syndromes [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Nonhuman Primate Model of Oculocutaneous Albinism with TYR and OCA2 Mutations

Yang

et al. 2020

Research

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Human visual acuity is anatomically determined by the retinal fovea. The ontogenetic development of the fovea can be seriously hindered by oculocutaneous albinism (OCA), which is characterized by a disorder of melanin synthesis. Although people of all ethnic backgrounds can be affected, no efficient treatments for OCA have been developed thus far, due partly to the lack of effective animal models. Rhesus macaques are genetically homologous to humans and, most importantly, exhibit structures of the macula and fovea that are similar to those of humans; thus, rhesus macaques present special advantages in the modeling and study of human macular and foveal diseases. In this study, we identified rhesus macaque models with clinical characteristics consistent with those of OCA patients according to observations of ocular behavior, fundus examination, and optical coherence tomography. Genomic sequencing revealed a biallelic p.L312I mutation in TYR and a homozygous p.S788L mutation in OCA2, both of which were further confirmed to affect melanin biosynthesis via in vitro assays. These rhesus macaque models of OCA will be useful animal resources for studying foveal development and for preclinical trials of new therapies for OCA.

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“…We and others have shown that over 50% of OCA patients with molecular diagnosis have a mutation in TYR (OCA1) encoding tyrosinase while around 2-3% have a defective TYRP1 (OCA3) encoding tyrosinase related 1 protein 1,5–8 . Both enzymes are well known to control pigment synthesis 9 .…”

Section: Introductionmentioning

confidence: 99%

Dopachrome tautomerase variants in patients with oculocutaneous albinism

Pennamen

Tingaud‐Sequeira

Gažová

et al. 2020

Preprint

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PurposeAlbinism is a clinically and genetically heterogeneous condition. Despite analysis of the nineteen known genes, ∼30% patients remain unsolved. We aimed to identify new genes involved in albinism.MethodsWe sequenced a panel of genes with known or predicted involvement in melanogenesis in 230 unsolved albinism patients.ResultsWe identified variants in the Dopachrome tautomerase (DCT) gene in two patients. One was compound heterozygous for a 14 bp deletion in exon 9 and c.118T>A p.(Cys40Ser). The second was homozygous for c.183C>G p.(Cys61Trp). Both patients had mild hair and skin hypopigmentation, and classical ocular features. CRISPR/Cas9 was used in C57BL/6J mice to create mutations identical to the missense mutations carried by the patients, along with one loss-of-function indel mutation. When bred to homozygosity the three mutations revealed hypopigmentation of the coat, milder for Cys40Ser compared to Cys61Trp or the frameshift mutation. Histological analysis identified significant hypopigmentation of the retinal pigmented epithelium (RPE) indicating that defective RPE melanogenesis could be associated with eye and vision defects. DCT loss of function in zebrafish embryos elicited hypopigmentation both in melanocytes and RPE cells.ConclusionsDCT is the gene for a new type of oculocutaneous albinism that we propose to name OCA8.

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Comprehensive analysis of spectral distribution of a large cohort of Chinese patients with non‐syndromic oculocutaneous albinism facilitates genetic diagnosis

Cited by 20 publications

References 28 publications

Non-syndromic Oculocutaneous Albinism: Novel Genetic Variants and Clinical Follow Up of a Brazilian Pediatric Cohort

Non-syndromic Oculocutaneous Albinism: Novel Genetic Variants and Clinical Follow Up of a Brazilian Pediatric Cohort

Nonhuman Primate Model of Oculocutaneous Albinism with TYR and OCA2 Mutations

Dopachrome tautomerase variants in patients with oculocutaneous albinism

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