Molecular diagnosis of phenylketonuria in 157 Chinese families and the results of prenatal diagnosis in these families.
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ABSTRACT:
SUBMITTER: Xiao Y
PROVIDER: S-EPMC8280003 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionGenetic epilepsy is a large group of clinically and genetically heterogeneous neurological disorders characterized by recurrent seizures, which have a clear association with genetic defects. In this study, we have recruited seven families from China with neurodevelopmental abnormalities in which epilepsy was a predominant manifestation, aiming to elucidate the underlying causes and make a precise diagnosis for the cases.MethodsWhole-exome sequencing (WES) combined with Sanger sequencing was used to identify the causative variants associated with the diseases in addition to essential imaging and biomedical examination.ResultsA gross intragenic deletion detected in MFSD8 was investigated via gap-polymerase chain reaction (PCR), real-time quantitative PCR (qPCR), and mRNA sequence analysis. We identified 11 variants in seven genes (ALDH7A1, CDKL5, PCDH19, QARS1, POLG, GRIN2A, and MFSD8) responsible for genetic epilepsy in the seven families, respectively. A total of six variants (c.1408T>G in ALDH7A1, c.1994_1997del in CDKL5, c.794G>A in QARS1, c.2453C>T in GRIN2A, and c.217dup and c.863+995_998+1480del in MFSD8) have not yet been reported to be associated with diseases and were all evaluated to be pathogenic or likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines.MethodsBased on the molecular findings, we have associated the intragenic deletion in MFSD8 with the mutagenesis mechanism of Alu-mediated genomic rearrangements for the first time and provided genetic counseling, medical suggestions, and prenatal diagnosis for the families. In conclusion, molecular diagnosis is crucial to obtain improved medical outcomes and recurrence risk evaluation for genetic epilepsy.
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Project description:BackgroundOculocutaneous albinism (OCA) is a group of heterogeneous genetic disorders characterized by abnormal melanin synthesis in the hair, skin, and eyes. OCA exhibits obvious genetic and phenotypic heterogeneity. Molecular diagnosis of causal genes can be of help in the classification of OCA subtypes and the study of OCA pathogenesis． METHODS: In this study, Sanger sequencing and whole exome sequencing were used to genetically diagnose 20 nonconsanguineous Chinese OCA patients. In addition, prenatal diagnosis was provided to six OCA families.ResultsVariants of TYR, OCA2, and HPS1 were detected in 85%, 10%, and 5% of affected patients, respectively. A total of 21 distinct variants of these three genes were identified. Exons 1 and 2 were the hotspot regions of the TYR variants, and c.895C > A and c.896G > A were the hotspot variants. We also found seven novel variants: c.731G > A, c.741C > A, c.867C > A, and c.1037-2A > T in TYR, c.695dupT and c.1054A > G in OCA2, and c.9C > A in HPS1. Genetic tests on six fetuses revealed three carrier fetuses, two normal fetuses, and one affected fetus. The follow-up results after birth were consistent with the results of prenatal diagnosis (one fetus terminated during pregnancy was not followed up).ConclusionsThis study expands our understanding of the genotypic spectrum of the Chinese OCA population. The findings indicate that prenatal diagnosis can provide important information for genetic counseling.
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Project description:BackgroundVariants in the ATP binding cassette protein subfamily D member 1 (ABCD1) gene are known to cause X-linked adrenoleukodystrophy (X-ALD). This study focused on the characteristics of ABCD1 variants in Chinese X-ALD families and elucidated the value of genetic approaches for X-ALD.Methods68 male probands diagnosed as X-ALD were screened for ABCD1 variants by the Sanger sequencing of polymerase chain reaction (PCR) products and multiplex ligation-dependent probe amplification (MLPA) combined with long-range PCR. Prenatal diagnosis was performed in 20 foetuses of 17 probands' mothers. Descriptive statistics were used to summarise the gene variants and prenatal diagnosis characteristics and outcomes.ResultsThis study allowed the identification of 61 variants occurring in 68 families, including 58 single nucleotide variants or small deletion/insertion variants and 3 large deletions. Three probands with no variants detected by next-generation sequencing were found to have variants by PCR-sequencing. Prenatal diagnosis found that 10 of the 20 foetuses had no variants in ABCD1.ConclusionPCR primers that do not amplify the pseudogenes must be used for PCR-sequencing. MLPA combined with long-range PCR can detect large deletions and insertions, which are usually undetectable by PCR-sequencing. Prenatal diagnosis could help to prevent the birth of infants with X-ALD.
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Project description:Waardenburg syndrome (WS) is an auditory‑pigmentary disorder with varying combinations of sensorineural hearing loss and abnormal pigmentation. The present study aimed to investigate the underlying molecular pathology and provide a method of prenatal diagnosis of WS in Chinese families. A total of 11 patients with WS from five unrelated Chinese families were enrolled. A thorough clinical examination was performed on all participants. Furthermore, patients with WS underwent screening for mutations in the following genes: Paired box 3 (PAX3), melanogenesis associated transcription factor (MITF), SRY‑box 10, snail family transcriptional repressor 2 and endothelin receptor type B using polymerase chain reaction sequencing. Array‑based comparative genomic hybridization was used for specific patients whose sequence results were normal. Following identification of the genotype of the probands and their parents, prenatal genetic diagnosis was performed for family 01 and 05. According to the diagnostic criteria for WS, five cases were diagnosed as WS1, while the other six cases were WS2. Genetic analysis revealed three mutations, including a nonsense mutation PAX3 c.583C>T in family 01, a splice‑site mutation MITF c.909G>A in family 03 and an in‑frame deletion MITF c.649_651delGAA in family 05. To the best of the authors' knowledge the mutations (c.583C>T in PAX3 and c.909G>A in MITF) were reported for the first time in Chinese people. Mutations in the gene of interest were not identified in family 02 and 04. The prenatal genetic testing of the two fetuses was carried out and demonstrated that the two babies were normal. The results of the present study expanded the range of known genetic mutations in China. Identification of genetic mutations in these families provided an efficient way to understand the causes of WS and improved genetic counseling.
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Project description:BackgroundRelative haplotype dosage (RHDO) approach has been applied in noninvasive prenatal diagnosis (NIPD) of Duchenne muscular dystrophy (DMD). However, the RHDO procedure is relatively complicated and the parental haplotypes need to be constructed. Furthermore, it is not suitable for the diagnosis of de novo mutations or mosaicism in germ cells. Here, we investigated NIPD of DMD using a relative mutation dosage (RMD)-based approach-cell-free DNA Barcode-Enabled Single-Molecule Test (cfBEST), which has not previously been applied in the diagnosis of exon deletion.MethodsFive DMD families caused by DMD gene point mutations or exon deletion were recruited for this study. After the breakpoints of exon deletion were precisely mapped with multiple PCR, the genotypes of the fetuses from the five DMD families were inferred using cfBEST, and were further validated by invasive prenatal diagnosis.ResultsThe cfBEST results of the five families indicated that one fetus was female and did not carry the familial molecular alteration, three fetuses were carriers and one was male without the familial mutation. The invasive prenatal diagnosis results were consistent with those of the cfBEST procedure.ConclusionThis is the first report of NIPD of DMD using the RMD-based approach. We extended the application of cfBEST from point mutation to exon deletion mutation. The results showed that cfBEST would be suitable for NIPD of DMD caused by different kinds of mutation types.
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Project description:BackgroundTo offer 4-year clinical prenatal diagnosis experience of Duchenne muscular dystrophy (DMD).MethodsDenaturing high-performance liquid chromatography (DHPLC) and Sanger sequencing were used for molecular diagnosis of 237 DMD families.ResultsIn the study, deletions, duplications, complex rearrangement and small mutations accounted for 47.3%, 8.4%, 1.7% and 42.6% of 237 families, respectively. Sixty-six different deletion patterns were identified in 112 families. Fourteen different duplication patterns were identified in 20 families and 4 complex rearrangements were identified. About 87.1% different small mutation patterns were identified, including 37.6% different nonsense mutation patterns, 24.8% different frameshift mutation patterns, 7.9% different missense mutation patterns, and 16.8% different splice site mutation patterns. There was no significant difference in the age of onset and mutation patterns (P > .05). The follow-up examinations revealed that the pregnancies of 14 cases were interrupted. Two cases were preterm births, 151 cases were delivered at term, 63 cases continued to pregnancy, and 7 cases were lost to follow-up.ConclusionDHPLC and Sanger sequencing technique are efficient, sensitive, and specific in screening for DMD gene mutations. And pre-pregnancy DMD gene examination is an important step to assess mutation type of family with suspected DMD and guides exactly prenatal diagnosis in high-risk families.
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Project description:BackgroundPhenylketonuria (PKU) is a metabolic disease that can cause severe and irreversible brain damage without treatment.MethodsHere we developed a non-invasive prenatal diagnosis (NIPD) technique based on haplotypes via paired-end molecular tags and weighting algorithm and applied it to the NIPD of PKU to evaluate its accuracy and feasibility in the early pregnancy. A custom-designed hybridization probes containing regions in phenylalanine hydroxylase (PAH) gene and its 1 Mb flanking region were used for target sequencing on genomic and maternal plasma DNA (7-13 weeks of gestation) to construct the parental haplotypes and the proband's haplotype. Fetal haplotype was then inferred combined with the parental haplotypes and the proband's haplotype. The presence of haplotypes linked to both the maternal and paternal mutant alleles indicated affected fetuses. The fetal genotypes were further validated by invasive prenatal diagnosis in a blinded fashion.ResultsThis technique has been successfully applied in twenty-one cases. Six fetuses were diagnosed as patients carrying both of the mutated haplotypes inherited from their parents. Eleven fetuses were carriers of one heterozygous PAH variants, six of which were paternal and five of which were maternal. Four fetuses were absence of pathogenic alleles. All results were consistent with the prenatal diagnosis through amniotic fluid.ConclusionsThe results showed that our new technique applied to the genotyping of fetuses with high risk for PKU achieves an accurate detection at an early stage of pregnancy with low fetal fraction in cell free DNA.
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Project description: Not available
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Project description:Phenylketonuria (PKU) is an inherited autosomal recessive disorder of phenylalanine metabolism, mainly caused by a deficiency of phenylalanine hydroxylase (PAH). The incidence of various PAH mutations differs among race and ethnicity. Here we report a spectrum of PAH mutations complied from 796 PKU patients from mainland China. The all 13 exons and adjacent intronic regions of the PAH gene were determined by next-generation sequencing. We identified 194 different mutations, of which 41 are not reported before. Several mutations reoccurred with high frequency including p.R243Q, p.EX6-96A > G, p.V399V, p.R241C, p.R111*, p.Y356*, p.R413P, and IVS4-1G > A. 76.33% of mutations were localized in exons 3, 6, 7, 11, 12. We further compared the frequency of each mutation between populations in northern and southern China, and found significant differences in 19 mutations. Furthermore, we identified 101 mutations that are not reported before in Chinese population, our study thus broadens the mutational spectrum of Chinese PKU patients. Additionally, 41 novel mutations will expand and improve PAH mutation database. Finally, our study offers proof that NGS is effective, reduces screening times and costs, and facilitates the provision of appropriate genetic counseling for PKU patients.
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Project description:Mowat-Wilson syndrome (MWS) is a complex developmental disorder. We report the first prenatal diagnosis provided for a family in mainland China after identifying the causal mutation for the proband. Special focus on MWS-related organs during prenatal ultrasound scan is described which is extremely important for genetic counseling of parents.
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