Identification of a Novel Homozygous Nonsense Mutation in a Fetus with Bardet-Biedl Syndrome

Abstract Background: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive genetic disorder with clinical and genetic heterogeneity. BBS is more commonly reported in adults and children than in fetuses. Here, we reported the intrauterine phenotype and molecular characterizations of a fetus with BBS. Methods: Chromosome karyotype analysis, whole exome sequencing (WES), and a single nucleotide polymorphism array (SNP-array) were used to analyze the genetic etiology of a fetus with enlarged kidneys, enhanced echo, and oligohydramnios. Results: The results of chromosome karyotype analysis and SNP-array on the fetus were normal. WES, however, revealed homozygous mutation of c.1177C>T (p.Arg393*) on exon 12 of the BBS1 gene, and heterozygous variation of c.2704G>A (p.Asp902Asn) on exon 22 of the CC2D2A gene. According to ACMG guidelines, c.1177C> T was identified as a pathogenic mutation and c.2704G>A was identified as an uncertain significance. Sanger sequencing showed that there was heterozygous mutation of c.1177C>T and heterozygous variation of c.2704G>A in the parents of the fetus. Conclusions: WES identified a novel homozygous nonsense mutation c.1177C>T in the BBS1 gene of a Chinese fetus. The finding provides more insight into BBS1 mutations in Asian populations in general, and provides a basis for genetic counseling.

Download Full-text

Novel Homozygous Nonsense Mutation Associated with Bardet-Biedl Syndrome in Fetus with Congenital Renal Malformation

10.21203/rs.3.rs-1052435/v1 ◽

2021 ◽

Author(s):

Meiying Cai ◽

Xianguo Fu ◽

Liangpu Xu ◽

Na Lin ◽

Hailong Huang ◽

...

Keyword(s):

Nonsense Mutation ◽

Karyotype Analysis ◽

Genetic Disorder ◽

Snp Array ◽

Heterozygous Mutation ◽

Homozygous Mutation ◽

Bardet Biedl Syndrome ◽

Renal Malformation ◽

Homozygous Nonsense Mutation ◽

Chromosome Karyotype

Abstract Background: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive genetic disorder with clinical and genetic heterogeneity. BBS is more commonly reported in adults and children than in fetuses. Method: Here, a retrospective study of 210 fetuses with congenital renal malformation was performed. These fetuses were performed invasive prenatal diagnosis. Chromosome karyotype analysis, whole exome sequencing (WES), and a single nucleotide polymorphism array (SNP-array) were used.Results: We found the intrauterine phenotype of a fetus with enlarged kidneys, enhanced echo, and oligohydramnios, and the molecular characterizations of the fetus with BBS. The results of chromosome karyotype analysis and SNP-array on the fetus were normal. WES, however, revealed homozygous mutation of c.1177C>T (p.Arg393*) on exon 12 of the BBS1 gene, and heterozygous variation of c.2704G>A (p.Asp902Asn) on exon 22 of the CC2D2A gene. According to ACMG guidelines, c.1177C> T was identified as a pathogenic mutation and c.2704G>A was identified as an uncertain significance. Sanger sequencing showed that there was heterozygous mutation of c.1177C>T and heterozygous variation of c.2704G>A in the parents of the fetus. Conclusion: WES identified a novel homozygous nonsense mutation c.1177C>T in the BBS1 gene of a Chinese fetus with congenital renal malformation. The finding provides more insight into BBS1 mutations in Asian populations in general, and provides a basis for genetic counseling.

Download Full-text

Novel Homozygous Mutation (R329X) in the Hemojuvelin Gene Is Associated with Hypogonadotrophic Hypogonadism, Diabetes Mellitus and Heart Failure Duo to Juvenile Hemochromatosis.

Blood ◽

10.1182/blood.v114.22.5102.5102 ◽

2009 ◽

Vol 114 (22) ◽

pp. 5102-5102

Author(s):

Rong-Fu Zhou ◽

Jian Ouyang ◽

Xue-mei Guo ◽

Bing Chen ◽

Jing-yan Xu ◽

...

Keyword(s):

Diabetes Mellitus ◽

Heart Failure ◽

Nonsense Mutation ◽

Conflicts Of Interest ◽

Heterozygous Mutation ◽

Iron Level ◽

Homozygous Mutation ◽

Ferritin Concentration ◽

Hypogonadotrophic Hypogonadism ◽

Juvenile Hemochromatosis

Abstract Abstract 5102 Juvenile hemochromatosis (JH) is a rare autosomal recessive disorder characterized by the early onset of severe iron overload. A large variety of mutations within the genes encoding hepcidin (HAMP) and hemojuvelin (HJV) have been identified in patients with JH. But in the Chinese population, the prevalence of JH is quite low. No HJV mutation has been reported so far. Methods and results The proband was a 25-year-old young man of Asia decent presented with hypogonadotrophic hypogonadism, diabetes mellitus and heart failure but no family history of iron disorders. His serum iron level was 34μmol/L, with a transferrin concentration of 8.5g/L, serum ferritin concentration was 8140 μg/L. Echocardiography revealed that he had generalized cardiac enlargement, cardiac dysfunction, and severe mitral and tricuspidal insufficiency, pulmonary hypertension. Ultra-sonography showed diffuse hepatomegaly and splenomegaly, seroperitoneum and right hydrothorax. Liver biopsy showed severe diffuse hepatocellular siderosis and cirrhosis,hemosiderin pigmentation. To search for possible variants in the HJV gene, we performed PCR and direct sequencing in proband and his family. A homozygous nonsense mutation in exon 4 of HJV (R329X) was identified in the JH patient and heterozygous mutation of R329X in his father and mother. No mutations were found in other genes associated with adult or juvenile hemochromatosis including HFE, transferrin receptor-2 (TFR2), ferroportin (SLC40A1), hepcidin (HAMP). Conclusions A novel nonsense mutation (R329X) has been identified in the HJV gene for the first time in China. This mutation elevates ferritin levels and leads to JH associated with hypogonadotrophic hypogonadism, diabetes mellitus and severe cardiomyopathy. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Fetal Aberrant Right Subclavian Artery: Associated Anomalies, Genetic Etiology, and Postnatal Outcomes in a Retrospective Cohort Study

10.21203/rs.3.rs-1135174/v1 ◽

2021 ◽

Author(s):

Meiying Cai ◽

Xiangqun Fan ◽

Xuemei Chen ◽

Shiyi Xu ◽

Xiangguo Fu ◽

...

Keyword(s):

Genetic Analysis ◽

Subclavian Artery ◽

Karyotype Analysis ◽

Single Nucleotide Polymorphism Array ◽

Snp Array ◽

Normal Growth ◽

Aberrant Right Subclavian Artery ◽

Genetic Etiology ◽

Significant Difference ◽

Number Variation

Abstract Aberrant right subclavian artery (ARSA) is becoming more common in fetuses. However, there are relatively few studies on the genetic etiology of ARSA. We performed genetic analysis on fetuses with ARSA and followed up the pregnancy outcome to evaluate the prognosis of the fetuses, providing information for prenatal and eugenics consultations. A retrospective study was conducted on 112 pregnant women with fetuses diagnosed with ARSA from December 2016 to February 2021. Karyotype analysis and single-nucleotide polymorphism array (SNP-array) were performed in 112 fetuses. The 112 fetuses were divided into two groups: ARSA group, 48 (42.9%) and ARSA with other ultrasound abnormalities group, 64 (57.1%) cases. The total rate of pathogenic copy number variation (CNV) was 7.1% (8/112) using karyotype analysis (3/8) and SNP-array (5/8). The rate of pathogenic CNV in isolated ARSA and ARSA combined with other ultrasound abnormalities were 4.2% (2/48) and 9.4% (6/64), respectively. There was no significant difference between the two groups (P=0.463). The results of genetic analysis influence parents' decision to terminate the pregnancy. During follow-up, fetuses with ARSA without pathogenic CNV were found to have normal growth and development after birth. Therefore, prenatal genetic counseling and SNP-array should be recommended to better assess fetal prognosis.

Download Full-text

Nonlethal Raine Syndrome in a Newborn Boy Caused by a Novel FAM20C Variant

Molecular Syndromology ◽

10.1159/000513384 ◽

2021 ◽

pp. 1-5

Author(s):

Nazan Eras ◽

Yalcin Celik

Keyword(s):

Genetic Disorder ◽

Bone Dysplasia ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Homozygous Mutation ◽

Limited Information ◽

Sequencing Platform ◽

Gene Sequence Analysis ◽

Raine Syndrome

Raine syndrome (RS) is a rare genetic disorder characterized by osteosclerotic bone dysplasia caused by a homozygous mutation, compound heterozygous mutation, or microdeletion in the FAM20C gene. In the present study, the MiSeq next-generation sequencing platform was used to perform the FAM20C gene sequence analysis. A novel homozygous variant c.1255T>C (p.W419R) in the FAM20C gene was diagnosed, and a nonlethal RS phenotype was confirmed, thus contributing to the expansion of the nonlethal RS phenotype. Since there is limited information about rare diseases, we believe that these studies will contribute to the literature and to the understanding of how these disorders develop and progress.

Download Full-text

Whole exome sequencing reveals a homozygous nonsense mutation in HEXA gene leading to Tay-Sachs disease in Saudi Family

Pakistan Journal of Medical Sciences ◽

10.12669/pjms.36.6.2579 ◽

2020 ◽

Vol 36 (6) ◽

Author(s):

Muhammad Imran Naseer ◽

Angham Abdulrahman Abdulkareem ◽

Mohammed Mohammed Jan ◽

Adeel G. Chaudhary ◽

Mohammad H. Al-Qahtani

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Nonsense Mutation ◽

Sanger Sequencing ◽

Homozygous Mutation ◽

Tay Sachs Disease ◽

Whole Exome ◽

Hexa Gene ◽

Saudi Family ◽

Homozygous Nonsense Mutation

Objective: To study the causative variants in affected member of a Saudi family with Tay-Sachs disorder. This disorder includes paralysis, decreasing in attentiveness, seizures, blindness, motor deterioration progresses rapidly leading to a completely unresponsive state and a cherry-red spot visible on the eye. Methods: Whole exome sequencing (WES) and Sanger sequencing was performed to study the variant leading to the disease. Results: WES data analysis and Sanger sequencing validation, identifies a homozygous nonsense mutation c.1177C>T, p.Arg393Ter as a result in protein change. This mutation was also studied in 100 unrelated healthy controls. Conclusions: We detected homozygous mutation in HEXA gene that may lead to cause Tay-Sachs disorder. Moreover, explain the possibility that HEXA gene may play important role for multiple aspects of normal human neurodevelopment. doi: https://doi.org/10.12669/pjms.36.6.2579 How to cite this:Naseer MI, Abdulkareem AA, Jan MM, Chaudhary AG, Al-Qahtani MH. Whole exome sequencing reveals a homozygous nonsense mutation in HEXA gene leading to Tay-Sachs disease in Saudi Family. Pak J Med Sci. 2020;36(6):---------. doi: https://doi.org/10.12669/pjms.36.6.2579 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Download Full-text

Hypoplastic AI with Highly Variable Expressivity Caused by ENAM Mutations

Journal of Dental Research ◽

10.1177/0022034518763152 ◽

2018 ◽

Vol 97 (9) ◽

pp. 1064-1069 ◽

Cited By ~ 3

Author(s):

M. Koruyucu ◽

J. Kang ◽

Y.J. Kim ◽

F. Seymen ◽

Y. Kasimoglu ◽

...

Keyword(s):

Clinical Phenotype ◽

Tooth Enamel ◽

Genetic Disorder ◽

Donor Site ◽

Heterozygous Mutation ◽

Epithelial Tissue ◽

Homozygous Mutation ◽

Site Mutation ◽

Whole Exome ◽

Intron 4

Tooth enamel, the hardest tissue in the human body, is formed after a complex series of interactions between dental epithelial tissue and the underlying ectomesenchyme. Nonsyndromic amelogenesis imperfecta (AI) is a rare genetic disorder affecting tooth enamel without other nonoral symptoms. In this study, we identified 2 novel ENAM mutations in 2 families with hypoplastic AI by whole exome sequencing. Family 1 had a heterozygous splicing donor site mutation in intron 4, NM_031889; c.123+2T>G. Affected individuals had hypoplastic enamel with or without the characteristic horizontal hypoplastic grooves in some teeth. Family 2 had a nonsense mutation in the last exon, c.1842C>G, p.(Tyr614*), that was predicted to truncate the protein by 500 amino acids. Participating individuals had at least 1 mutant allele, while the proband had a homozygous mutation. Most interestingly, the clinical phenotype of the individuals harboring the heterozygous mutation varied from a lack of penetrance to a mild hypoplastic enamel defect. We believe that these findings will broaden our understanding of the clinical phenotype of AI caused by ENAM mutations.

Download Full-text

Faculty Opinions recommendation of Homozygous nonsense mutation in DSC3 resulting in skin fragility and hypotrichosis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.738390011.793578032 ◽

2020 ◽

Author(s):

Takashi Hashimoto

Keyword(s):

Nonsense Mutation ◽

Skin Fragility ◽

Homozygous Nonsense Mutation

Download Full-text

A novel homozygous nonsense mutation in the CA2 gene (c.368G>A, p.W123X) linked to carbonic anhydrase II deficiency syndrome in a Chinese family

Metabolic Brain Disease ◽

10.1007/s11011-021-00677-9 ◽

2021 ◽

Vol 36 (4) ◽

pp. 589-599

Author(s):

Yan Yang ◽

Nie Tang ◽

Ying Zhu ◽

Lei Zhang ◽

Xu Cao ◽

...

Keyword(s):

Carbonic Anhydrase ◽

Nonsense Mutation ◽

Deficiency Syndrome ◽

Carbonic Anhydrase Ii ◽

Chinese Family ◽

Carbonic Anhydrase Ii Deficiency ◽

Homozygous Nonsense Mutation

Download Full-text

A case report and mechanism analysis of a normal phenotype mosaic 47, XXY complicated by paternal iUPD (9) who had a normal PGD result

BMC Medical Genetics ◽

10.1186/s12881-019-0897-5 ◽

2019 ◽

Vol 20 (1) ◽

Author(s):

Dan Li ◽

Yun Wang ◽

Nan Zhao ◽

Liang Chang ◽

Ping Liu ◽

...

Keyword(s):

Case Report ◽

Karyotype Analysis ◽

Snp Array ◽

Uniparental Disomy ◽

Comparative Genomic ◽

Klinefelter’S Syndrome ◽

Mechanism Analysis ◽

Klinefelter's Syndrome ◽

Preimplantation Genetic Testing ◽

First Case

Abstract Background Uniparental disomy (UPD) refers to the situation in which two copies of homologous chromosomes or part of a chromosome originate from the one parent and no copy is supplied by the other parent. Case presentation Here, we reported a woman whose karyotype was 46, XX, t (1;17)(q42;q21), has obtained 5 embryos by intracytoplasmic sperm injection (ICSI) after one cycle of in vitro fertility (IVF). After microarray-based comparative genomic hybridization (array-CGH) for preimplantation genetic testing for chromosomal structural rearrangements (PGT-SR), two embryos were balanced, one balanced embryo was implanted and the patient successfully achieved pregnancy. Amniocentesis was performed at the 19th week of gestation for karyotype analysis and single nucleotide polymorphism (SNP)-array test. The result of karyotype analysis was: mos 47, XXY [19]/46, XY [81]; SNP-array results revealed 46, XY, iUPD (9) pat. After full genetic counseling for mosaic Klinefelter’s syndrome and paternal iUPD (9), the couple decided to continue pregnancy, and the patient gave birth to a healthy boy. The newborn is now 3.5 years old, and developed normally. This case will provide counseling evidences of paternal iUPD (9) for doctors. Conclusions This is the first case report of paternal iUPD9 with mosaic Klinefelter’s syndrome, and no abnormality has been observed during the 3.5-year follow-up. Further observation is required to determine whether the imprinted genes on the chromosomes are pathogenic and whether recessive pathogenetic genes are activated.

Download Full-text