OBJECTIVE: To analyze gene variants in a Chinese pedigree with oculocutaneous albinism (OCA). METHODS: Gene sequencing of the proband and his parents was performed using chip capture high-throughput sequencing and Sanger sequencing techniques, and PolyPhen-2, SIFT, MutationTaster, and FATHMM software were used to predict the function of new variants. At the same time,the pedigree and variant genes of 4 albinism patients from this pedigree were analyzed. RESULTS: Sequencing results showed that the proband's TYR gene (NM_000372) has c.230G>A (p.Arg77Gln) and c.120_121insG (p.Asp42GlyfsTer35) compound heterozygous variants. The proband's father carries c.230G>A heterozygous variant, and the mother carries c.120_121insG heterozygous variant, indicating that the proband's two variants are from his father and mother. The former is a known missense variant, which can cause abnormal or loss of the original function of the protein polypeptide chain. The latter c.120_121insG(p.Asp42GlyfsTer35) is an unreported frameshift variant of the TYR gene subregion (EX1; CDS1). PolyPhen-2, SIFT, MutationTaster and FATHMM predictions are all prompted as "harmful variants". This variant caused the amino acid encoded protein to terminate prematurely, producing a truncated protein, which eventually formed a 76-amino acid short-type TYR protein instead of the 529-amino acid wild-type TYR protein. Through the pedigree analysis, the four patients in the pedigree are all of the same type of compound heterozygous variants, and the disease-causing genes are all from the patient's parents. They belong to a special form of consanguineous marriage within 5 generations. CONCLUSION The compound heterozygous variants of c.230G>A (p.Arg77Gln) and c.120_121insG (p.Asp42GlyfsTer35) of the TYR gene may underlie the disease in this pedigree. The gene sequencing results enrich the variant spectrum of the TYR gene, and has facilitated molecular diagnosis for the patient.
Albinism, Oculocutaneous/genetics* ; Consanguinity ; Heterozygote ; Humans ; Mutation ; Pedigree

OBJECTIVE: To assess the value of non-invasive prenatal testing based on cfDNA barcode-enabled single-molecule test (cfBEST) for the prenatal diagnosis of oculocutaneous albinism type I in a family. METHODS: Prenatal genetic diagnosis was carried out by using the cfBEST-based method as well as invasive prenatal diagnosis through amniocentesis. The outcome of the pregnancy was followed up. RESULTS: Non-invasive prenatal testing based on cfBEST showed a fetal DNA concentration of 6.6%, with the proportion of c.929_930insC (p.Arg311Lysfs*7) and c.1037-7T>A mutations being 45.7% and 0%, respectively. The posterior frequency of the negative results was 1, suggesting that the fetus carried neither of the two mutations. The result was consistent with that of invasive prenatal diagnosis, and the follow-up found that the fetus was normal. CONCLUSION Non-invasive prenatal testing based on cfBEST can be used to detect maternal and fetal genotypes in maternal cell-free DNA, which is clinically feasible.
Albinism ; Albinism, Oculocutaneous/genetics* ; Amniocentesis ; Cell-Free Nucleic Acids ; Female ; Humans ; Pregnancy ; Prenatal Diagnosis

OBJECTIVETo provide prenatal diagnosis for two families affected with oculocutaneous albinism (OCA), in both of which only 1 pathogenic allele has been identified.

METHODSTo determine the clinical classification of OCA through DNA sequencing for TYR, P, TYRP1 and SLC45A2 genes in combination with phenotype analysis. Prenatal diagnosis was carried out by direct sequencing and intragenic SNPs family-based linkage analysis.

RESULTSIn the first family, only 1 heterozygous mutation c.1255C>T was found in the proband, which was inherited from her mother. Together with its clinical phenotype, the proband was suspected to have OCA2 Screening of amniotic fluid, however, has found no mutation. With family-based linkage analysis, the fetus was deemed to be an OCA2 carrier. In the second family, again only one heterozygous mutation c.1920_1949 del30bp and ins AACA was found in the proband, which was inherited from her father. Together with its clinical phenotype, the proband was suspected to have OCA2. Screening of amniotic fluid has revealed a heterozygous mutation c.1920_1949 del30bp and ins AACA. By family-based linkage analysis, the fetus was deemed to be an OCA2 carrier. Both fetuses had a normal phenotype at birth.

CONCLUSIONPrenatal genetic diagnosis has been provided for the first time for two families affected with OCA, in which only 1 pathogenic mutant allele was detected. The combined mutation detection and SNPs linkage analysis has turned out to be successful.

Albinism, Oculocutaneous ; genetics ; Female ; Genetic Linkage ; Humans ; Male ; Mutation ; Polymorphism, Single Nucleotide ; Prenatal Diagnosis

BACKGROUNDOculocutaneous albinism (OCA) is a heterogeneous and autosomal recessive disorder in all populations worldwide. The mutational spectra of OCA are population-specific. Some OCA patients carry mutations from different OCA genes. In this study, we investigated the frequency of digenic mutations in Chinese OCA patients.

METHODSGenomic DNAs were extracted from the blood samples of 184 clinically diagnosed OCA patients and 120 unaffected subjects. The amplified DNA segments of the exons and exon-intron boundaries were screened for mutations of TYR, OCA2, TYRP1, SLC45A2, and HPS1 by direct sequencing. To exclude the previously unidentified alleles from polymorphisms, samples from 120 unaffected controls were sequenced for the same regions of variations.

RESULTSIn all 184 patients, 134 had two pathologic mutations on one locus. Eleven cases had no apparent pathologic mutations in any of the genes studied. Among the remaining 39 patients who had only one pathologic mutation, five patients (2.7% in total) were found to carry the mutational alleles on a second locus in TYR, OCA2 or SLC45A2. Of the five digenic OCA patients, four patients were clinically diagnosed as OCA2 and one patient as OCA1. A previous unidentified allele p.G188D in SLC45A2 was identified, which was not present in the 120 unaffected controls.

CONCLUSIONSThe identification of the digenic OCA patients suggests the synergistic roles among TYR, OCA2 and SLC45A2 during melanin biosynthesis, which may cause OCA under digenic mutations. This information will be useful for gene diagnosis and genetic counseling of OCA in China.

Adult ; Albinism, Oculocutaneous ; genetics ; Antigens, Neoplasm ; genetics ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Male ; Membrane Transport Proteins ; genetics ; Mutation

BACKGROUNDThe mutation of the tyrosinase (TYR) gene results in oculocutaneous albinism type 1 (OCA1), an autosomal recessive genetic disorder. OCA1 is the most common type of OCA in the Chinese population. Hence, the TYR gene was tested in this study. We also delineated the genetic analysis of OCA1 in a Chinese family.

METHODSGenomic DNA was isolated from the blood leukocytes of a proband and his family. Mutational analysis at the TYR locus by DNA sequencing was used to screen five exons, including the intron/exon junctions. A pedigree chart was drawn and the fundus of the eyes of the proband was also examined.

RESULTSA novel missense mutation p.I151S on exon 1, and homozygous TYR mutant alleles were identified in the proband. None of the mutants was identified among the 100 normal control subjects. Genetic analysis of the proband's wife showed normal alleles in the TYR gene. Thus, the fetus was predicated a carrier of OCA1 with a normal appearance.

CONCLUSIONThis study provided new information about a novel mutation, p.I151S, in the TYR gene in a Chinese family with OCA1. Further investigation of the proband would be helpful to determine the effects of this mutation on TYR activity.

Adult ; Albinism, Oculocutaneous ; genetics ; Asian Continental Ancestry Group ; Female ; Genotype ; Humans ; Male ; Monophenol Monooxygenase ; genetics ; Mutation, Missense ; genetics ; Pedigree

OBJECTIVE: To identify the causative variants in 13 Chinese pedigrees affected with oculocutaneous albinism (OCA) so as to provide genetic counseling and prenatal diagnosis to them. METHODS: Thirteen unrelated pedigrees with clinically diagnosed OCA were collected and classified based on the manifestation of skin and eyes. With informed consent obtained from the participants, peripheral blood samples were collected from the probands and their family members for the extraction of genomic DNA. Candidate variants were screened by targeted capture and next generation sequencing, and the results were validated by Sanger sequencing. Prenatal diagnosis was provided to the families upon their subsequent pregnancies. RESULTS: Causative variants were detected in all probands, including 10 with compound heterozygotes or homozygotes for TYR gene variants and 3 with compound heterozygotes for OCA2 gene variants. Among these, two variants [TYR: c.650G>C (p.Arg217Pro) and OCA2: c.516-2A>T] were unreported previously. The pathogenicity of the novel TYR: c.650G>C (p.Arg217Pro) variant was verified through bioinformatic analysis and prediction of three dimensional structure of the protein. Prenatal diagnosis was provided to 6 fetuses with a high risk for OCA. Four fetuses were found to be carriers, one did not carry the variants of the proband, and one was affected with OCA. CONCLUSION Identification of the pathogenic variants in the 13 probands, including 2 novel ones, has expanded the mutational spectrum of OCA and enabled genetic counseling and prenatal diagnosis for the families.
Albinism, Oculocutaneous/genetics* ; China ; Female ; Genetic Testing ; Humans ; Membrane Transport Proteins/genetics* ; Monophenol Monooxygenase/genetics* ; Mutation ; Pedigree ; Pregnancy ; Prenatal Diagnosis

To summarize the clinical diagnosis and treatment process and genetic test results and characteristics of one child with Angelman syndrome (AS) complicated with oculocutaneous albinism type 2 (OCA2), and to review the literature. "Angelman syndrome" "P gene" and "Oculocutaneous albinism type 2" were used as keywords to search at CNKI, Wanfang, and PubMed databases (from creation to December 2019). Then all the patients were analyzed. The patient in this study was a girl aged 1 year. After birth, she was found to present as white body, yellow hair, and nystagmus. She could raise her head at the age of 2 months and turn over at the age of 7 months. The head circumference was 42 cm and she could not sit alone or speak at present. Trio-based exome sequencing revealed that the patient carried a homozygous mutation of c.168del (p.Gln58ArgfsTer44) in the P gene, and her father was heterozygous and her mother was wild-type. The detection of copy number variation showed deletion on the maternal chromosome at 15q11.2-13.1 region (P gene located in this region) in the patient. Until December 2019, a total of 4 cases in the 4 literature had been reported. Adding our case here, the 5 cases were summarized and found that all the cases showed white skin, golden hair, and shallow iris after birth. Comprehensive developmental delay was found around 6 months of age after birth, and the language remained undeveloped in 2 cases till follow-up into childhood. Seizures occurred in 4 patients. Two cases had ataxia. All the 5 cases had acquired microcephaly. Two cases had a family history of albinism. Electroencephalogram monitoring was completed in 3 cases and the results were abnormal. Genetic tests showed that all the 5 cases had deletion on maternal chromosome at 15q11-13 region. Four cases carried mutation of P gene on paternal chromosome. And 1 case was clinically diagnosed as OCA2 without P gene test. AS combined with OCA2 is relatively rare. OCA2 is easily diagnosed based on the obvious clinical manifestations after birth. When combined with clinical manifestations such as neurodevelopmental delay, it might indicate the possibility of AS that is hardly diagnosed clinically at an early stage. Genetic tests can reveal the cross-genetic phenomenon of AS and OCA2 and the complex of them can be eventually diagnosed.
Female ; Humans ; Albinism, Oculocutaneous/genetics* ; DNA Copy Number Variations ; Membrane Transport Proteins/genetics* ; Molecular Biology ; Mutation ; Infant

OBJECTIVETo identify the mutations of the tyrosinase gene (TYR) and P gene in patients with oculocutaneous albinism (OCA).

METHODSPolymerase chain reaction (PCR) and denaturing high performance liquid chromatography (DHPLC) were applied to detect the mutations in all exons of TYR gene and P gene. Then DNA sequencing and restriction endonuclease analysis were used to confirm the mutations detected by DHPLC. Novel mutations were screened in 100 unrelated persons with normal phenotypes to exclude the possibility of polymorphism.

RESULTSTwo mutations were detected in the P gene of the three patients and none in TYR gene. Heterozygous mutation of T450M in exon 13 of the P gene was detected in patient 1. Patient 2 had a heterozygous mutation of T450M in exon 13 and a heterozygous mutation of G775R in exon 23 of the P gene. Patient 3 had a heterozygous mutation of G775R as well. Restriction endonuclease analysis of the P gene exon 13 showed that the Oli I site had partly disappeared resulting from the heterozygous mutation T450M in patient 1 and patient 2, but not in 100 unrelated individuals. The heterozygous mutation T450M is a novel mutation.

CONCLUSIONGene diagnosis of OCA can be carried out effectively by combining PCR, DHPLC, DNA sequencing and restriction endonuclease analysis.

Albinism, Oculocutaneous ; genetics ; Base Sequence ; Catechol Oxidase ; genetics ; Child, Preschool ; DNA Mutational Analysis ; Exons ; genetics ; Female ; Hermanski-Pudlak Syndrome ; genetics ; Humans ; Monophenol Monooxygenase ; genetics ; Mutation ; Young Adult

OBJECTIVETo explore the patients' genotypes and the mutation spectrum of Tyrosinase (TYR) gene and the effects on protein structure and function in oculocutaneous albinism type 1 (OCA1).

METHODSThe polymerase chain reaction (PCR) and sequencing techniques were applied to amplify and analyze the regions of exon, exonintron and promoter of TYR gene of 15 OCA1 probands and some of their parents. The protein structure and function were forecasted and analyzed by bioinformatics software.

RESULTSSequencing result showed 11 kinds of mutations, including 5 missense mutations (W400L, R299H, E294K, R77Q and K142M), 3 nonsense mutations (R116X, R278X and G295X), 2 insertion mutation (929insC and 232insGGG) and 1 splice site mutation (IVS1-3C > G). The nosogenesis was related to the change of protein structure and function in four pathological mutations.

CONCLUSIONIt seemes that W400L is the frequent mutations, which accounted for about 30.0% in Chinese mainland OCA1 alleles. It is doable to make some reasonable interpretation about TYR gene nosogenesis by bioinformatics method.

Adolescent ; Adult ; Albinism, Oculocutaneous ; genetics ; Child ; Child, Preschool ; China ; DNA Mutational Analysis ; Female ; Genotype ; Humans ; Infant ; Infant, Newborn ; Male ; Monophenol Monooxygenase ; genetics ; Mutation ; Young Adult

OBJECTIVETo determine the genotype of a family affected with oculocutaneous albinism (OCA) and to provide genetic counseling and prenatal diagnosis.

METHODSTo determine the genotypes and mutational sites through PCR and sequencing for all exons and exon-intron junctions of 4 OCA genes in the proband and the P gene of her parents. Prenatal genotyping of the fetus was carried out using amniocentesis sample.

RESULTSThe patient was diagnosed with OCA2 based on a genotype of c.1327G>A/c.2360C>T. Her father was heterozygous for c.2360C> T, whilst her mother has none of the two mutations. c.1327G>A is therefore a maternal de novo mutation. Neither of the mutations was found in the fetus.

CONCLUSIONA maternally inherited de novo mutation c.1327G>A has been identified in the patient. In order to detect de novo mutations, full sequence analysis is necessary.

Adult ; Albinism, Oculocutaneous ; diagnosis ; genetics ; Base Sequence ; Child, Preschool ; Exons ; Female ; Genetic Linkage ; Haplotypes ; Humans ; Membrane Transport Proteins ; genetics ; Mutation ; Pedigree ; Polymorphism, Single Nucleotide ; Pregnancy ; Prenatal Diagnosis