Whole-exome sequencing analysis of Waardenburg syndrome in a Chinese family.
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ABSTRACT:
SUBMITTER: Chen D
PROVIDER: S-EPMC5489998 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:OBJECTIVE: Nance-Horan syndrome (NHS) is a rare X-linked disorder characterized by congenital nuclear cataracts, dental anomalies, and craniofacial dysmorphisms. Mental retardation was present in about 30% of the reported cases. The purpose of this study was to investigate the genetic and clinical features of NHS in a Chinese family. METHODS: Whole exome sequencing analysis was performed on DNA from an affected male to scan for candidate mutations on the X-chromosome. Sanger sequencing was used to verify these candidate mutations in the whole family. Clinical and ophthalmological examinations were performed on all members of the family. RESULTS: A combination of exome sequencing and Sanger sequencing revealed a nonsense mutation c.322G>T (E108X) in exon 1 of NHS gene, co-segregating with the disease in the family. The nonsense mutation led to the conversion of glutamic acid to a stop codon (E108X), resulting in truncation of the NHS protein. Multiple sequence alignments showed that codon 108, where the mutation (c.322G>T) occurred, was located within a phylogenetically conserved region. The clinical features in all affected males and female carriers are described in detail. CONCLUSIONS: We report a nonsense mutation c.322G>T (E108X) in a Chinese family with NHS. Our findings broaden the spectrum of NHS mutations and provide molecular insight into future NHS clinical genetic diagnosis.
| S-EPMC4129093 | biostudies-literature
Project description:BackgroundTraboulsi syndrome is a rare disorder characterized by ectopia lentis and facial dysmorphism (large beaked nose), which was only reported in 18 individuals to date. It is caused by homozygous/compound heterozygous variants in the aspartate/asparagine-β-hydroxylase (ASPH) gene, which hydroxylates the aspartic acid and asparagine in epidermal growth factor-like domains of various proteins.MethodsWhole-exome and Sanger sequencing were used to identify the disease-causing gene of the patient in a consanguineous Chinese family. Domain analysis was applied to predict the impact of the variant on ASPH protein.ResultsThrough exome and Sanger sequencing, we identified a novel homozygous ASPH variant (NM_004318.4:c.1910del/NP_004309.2: p.(Asn637MetfsTer15)) in the patient, which may lead to blockage of the ASPH function through truncating the AspH oxygenase domain of the ASPH protein and/or nonsense-mediated decay of the ASPH transcript. This is the first report of Traboulsi syndrome in a Chinese patient who was combined with ventricular septal defect, lung bullae, and recurrent spontaneous pneumothorax.ConclusionOur results revealed the clinical characteristics of the first Chinese patient with Traboulsi syndrome. Additionally, our study expands the mutational spectrum of Traboulsi syndrome and provides information for clinical genetic counseling to this family.
| S-EPMC7963421 | biostudies-literature
Project description:BACKGROUND AND OBJECTIVES:Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes. RESULTS:In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. NPHS1, PLCE1, NPHS2, and SMARCAL1 were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome. CONCLUSIONS:Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.
| S-EPMC5753307 | biostudies-other
Project description:BackgroundRoberts syndrome (RBS) is a rare autosomal recessive disorder caused by variations in the ESCO2 gene; however, prenatal diagnosis of RBS has never been reported in Chinese families. Additionally, fetal-specific phenotypic characteristics associated with ESCO2 variants have not been reported.Case presentationA fetus in a healthy, nonconsanguineous Chinese family with multiple serious congenital malformations was diagnosed prenatally. Two consecutive fetuses in this family presented with tetraphocomelia, growth restriction, cleft lip and palate bilaterally, and other abnormalities. The main phenotypic characteristics of this case were strongly suspected to be associated with RBS. Finally, whole exome sequence analysis revealed the insertion of a homozygous base pair in exon 6 of the ESCO2 gene (NM_001017420.3, c.1111insA, NP_001017420.1, p.Thr371fs). Both of the couples were heterozygous carriers for this variant.ConclusionWe are the first to report a prenatal case of RBS diagnosed in a Chinese family. Here, we have confirmed that the rare variant is a definite pathogenic variant, and we provide detailed phenotypic characteristics for the prenatal diagnosis of RBS due to this causative variant.
| S-EPMC8800352 | biostudies-literature
Project description:BACKGROUND:Joubert syndrome (JS, OMIM: 213300) is a recessive developmental disorder characterized by cerebellar vermis hypoplasia and a distinctive mid-hindbrain malformation called the "molar tooth sign" on axial magnetic resonance imaging. To date, more than 35 ciliary genes have been identified as the causative genes of JS. METHODS:Whole exome sequencing was performed to detect the causative gene mutations in a Chinese patient with JS followed by Sanger sequencing. RT-PCR and Sanger sequencing were used to confirm the abnormal transcript of centrosomal protein 104 (CEP104, OMIM: 616690). RESULTS:We identified two novel heterozygous mutations of CEP104 in the proband, which were c.2364+1G>A and c.414delC (p.Asn138Lysfs*11) (GenBank: NM_014704.3) and consistent with the autosomal recessive inheritance mode. CONCLUSION:Our study reported the fourth case of JS patients with CEP104 mutations, which expands the mutation spectrum of CEP104 and elucidates the clinical heterogeneity of JS.
| S-EPMC6900356 | biostudies-literature
Project description:In the present study we attempted a parent-child trio, whole exome sequencing (WES) approach to study Apert's syndrome. Clinical characteristics of the child were noted down and WES was carried out using Ion Torrent System that revealed the presence of previously reported P253R mutation in FGFR2 gene. Presence of two SNPs rs1047057 and rs554851880 in FGFR2 gene with an allelic frequency of 0.5113 and 0.001176 respectively and 161 complete damaging mutations were found. This study is the first reported case of exome sequencing approach on an Apert's syndrome patient aimed at providing better genetic counselling in a non-consanguineous relationship.
| S-EPMC6147108 | biostudies-literature
Project description:BackgroundMutations in PKHD1 cause autosomal recessive Caroli disease, which is a rare congenital disorder involving cystic dilatation of the intrahepatic bile ducts. However, the mutational spectrum of PKHD1 and the phenotype-genotype correlations have not yet been fully established.MethodsWhole exome sequencing (WES) was performed on one twin sample with Caroli disease from a Chinese family from Shandong province. Routine Sanger sequencing was used to validate the WES and to carry out segregation studies. We also described the PKHD1 mutation associated with the genotype-phenotype of this twin.ResultsA combination of WES and Sanger sequencing revealed the genetic defect to be a novel compound heterozygous genotype in PKHD1, including the missense mutation c.2507 T>C, predicted to cause a valine to alanine substitution at codon 836 (c.2507T>C, p.Val836Ala), and the nonsense mutation c.2341C>T, which is predicted to result in an arginine to stop codon at codon 781 (c.2341C>T, p.Arg781*). This compound heterozygous genotype co-segregates with the Caroli disease-affected pedigree members, but is absent in 200 normal chromosomes.ConclusionsOur findings indicate exome sequencing can be useful in the diagnosis of Caroli disease patients and associate a compound heterozygous genotype in PKHD1 with Caroli disease, which further increases our understanding of the mutation spectrum of PKHD1 in association with Caroli disease.
| S-EPMC3977808 | biostudies-literature
Project description:Paramyotonia congenita (PC) is a rare autosomal dominant neuromuscular disorder characterized by juvenile onset and development of cold-induced myotonia after repeated activities. The disease is mostly caused by genetic mutations of the sodium channel, voltage-gated, type IV, alpha subunit (SCN4A) gene. This study intended to systematically identify the causative genetic variations of a Chinese Han PC family. Seven members of this PC family, including four patients and three healthy controls, were selected for whole exome sequencing (WES) using the Illumina HiSeq platform. Sequence variations were identified using the SoftGenetics program. The mutation R1448C of SCN4A was found to be the only causative mutation. This study applied WES technology to sequence multiple members of a large PC family and was the first to systematically confirm that the genetic change in SCN4A is the only causative variation in this PC family and the SCN4A mutation is sufficient to lead to PC.
| S-EPMC4535863 | biostudies-literature
Project description:IntroductionGout is a worldwide chronic disease generally caused by high serum levels of uric acid. Using whole exome sequencing, we aimed to explore genetic alterations in hereditary gout.Patients' concernsThere were 9 direct descendants diagnosed with gout in total in this family. The patients concerned about the high incidence and inheritance of gout.DiagnosisThe youngest propositus was diagnosed as gout in our hospital. Diagnoses of other patients in this family were made on the foundation of history and clinical tests.InterventionsSix direct descendants and 3 healthy spouses in 1 family were recruited in our study. Whole-exome sequencing was conducted in all participants.OutcomesWhole-exome sequencing and genetic analysis revealed 2 putative rare inherited deleterious variants, which were detected only in direct descendants. Twelve gout and uric acid (UC)-related nucleotide sequence variants previously reported by GWAS were detected among all subjects.ConclusionsIn the case of this family, the GWAS identified gout and UC-related nucleotide sequence variants may increase the risk of developing gout, but penetrance was not complete. The rare sequence variants in low-density lipoprotein receptor-related protein 1 (LRP1) and oncoprotein induced transcript 3 (OIT3) may have contributed to inheritance of gout within the 5 generations of family members in this study.
| S-EPMC7310917 | biostudies-literature
Project description:PurposeMacrozoospermia is a rare sperm morphologic abnormality associated with male infertility and is characterized by a high percentage of spermatozoa with large irregular heads. The aim of this study was to identify the genetic cause of an infertile male with macrozoospermia from a consanguineous family.MethodsWhole-exome sequencing (WES) was performed using peripheral blood genomic DNA from the patient and his parents.ResultsWES analysis of the patient with macrozoospermia from a consanguineous family allowed the identification of a novel homozygous missense variant in the AURKC gene (c.269G>A). Bioinformatics analysis also suggested this variant a pathogenic mutation. Quantitative real-time PCR analysis showed that the mRNA level of AURKC is significantly decreased in the patient compared with his father. Moreover, no embryos were available for transfer after ICSI.ConclusionsThese results further support the important role of AURKC in male infertility and guide the practitioner in optimal decision making for patients with macrozoospermia.
| S-EPMC6439091 | biostudies-literature