Prenatal diagnosis for congenital afibrinogenemia caused by a novel nonsense mutation in the FGB gene in a Palestinian family

Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by the complete absence of detectable fibrinogen. We previously identified the first causative mutations for this disease, homozygous deletions of approximately 11 kb of the fibrinogen alpha chain gene (FGA). Subsequent analyses revealed that most afibrinogenemia alleles are truncating mutations of FGA, although mutations in all 3 fibrinogen genes, FGG, FGA andFGB have been identified. In this study, we performed the first prenatal diagnosis for afibrinogenemia. The causative mutation in a Palestinian family was a novel nonsense mutation in theFGB gene, Trp467Stop (W467X). Expression of the Trp467Stop mutant FGB cDNA in combination with wild-typeFGA and FGG cDNAs showed that fibrinogen molecules containing the mutant beta chain are not secreted into the media. The fetus was found to be heterozygous for the Trp467Stop mutation by direct sequencing and by linkage analysis, a result that was confirmed in the newborn by intermediate fibrinogen levels.

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Missense mutations in the human β fibrinogen gene cause congenital afibrinogenemia by impairing fibrinogen secretion

Blood ◽

10.1182/blood.v95.4.1336.004k16_1336_1341 ◽

2000 ◽

Vol 95 (4) ◽

pp. 1336-1341 ◽

Cited By ~ 75

Author(s):

Stefano Duga ◽

Rosanna Asselta ◽

Elena Santagostino ◽

Sirous Zeinali ◽

Tatjana Simonic ◽

...

Keyword(s):

Autosomal Recessive ◽

Autosomal Recessive Disorder ◽

Chain Gene ◽

Missense Mutations ◽

Wild Type ◽

Large Deletions ◽

Congenital Afibrinogenemia ◽

Low Levels ◽

A Chain ◽

Mutation Mechanisms

Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by bleeding that varies from mild to severe and by complete absence or extremely low levels of plasma and platelet fibrinogen. Although several mutations in the fibrinogen genes associated with dysfibrinogenemia and hypofibrinogenemia have been described, the genetic defects of congenital afibrinogenemia are largely unknown, except for a recently reported 11-kb deletion of the fibrinogen A-chain gene. Nevertheless, mutation mechanisms other than the deletion of a fibrinogen gene are likely to exist because patients with afibrinogenemia showing no gross alteration within the fibrinogen cluster have been reported. We tested this hypothesis by studying the affected members of two families, one Italian and one Iranian, who had no evidence of large deletions in the fibrinogen genes. Sequencing of the fibrinogen genes in the 2 probands detected 2 different homozygous missense mutations in exons 7 and 8 of the Bβ-chain gene, leading to amino acid substitutions Leu353Arg and Gly400Asp, respectively. Transient transfection experiments with plasmids expressing wild-type and mutant fibrinogens demonstrated that the presence of either mutation was sufficient to abolish fibrinogen secretion. These findings demonstrated that missense mutations in the Bβ fibrinogen gene could cause congenital afibrinogenemia by impairing fibrinogen secretion.

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Genetic Analysis of Afibrinogenemia and Hypofibrinogenemia: Novel Mutations in the FGB Gene in the Turkish Population

Acta Haematologica ◽

10.1159/000505174 ◽

2020 ◽

Vol 143 (6) ◽

pp. 529-532

Author(s):

Didem Torun Özkan ◽

Nazan Sarper ◽

Nejat Akar

Keyword(s):

Amino Acid ◽

Autosomal Recessive ◽

Adenine Nucleotide ◽

Gene Mutations ◽

Autosomal Recessive Disorder ◽

Turkish Population ◽

Chain Gene ◽

Congenital Afibrinogenemia ◽

Low Levels ◽

First Time

Introduction: Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by bleeding that varies from mild to severe and by complete absence or extremely low levels of plasma and platelet fibrinogen. Hypofibrinogenemia is characterized by fibrinogen levels <1.5 g/L. Objective: In this study, we analyzed fibrinogen beta chain gene mutations in Turkish afibrinogenemia and hypofibrinogenemia patients. Methods: We evaluated 20 afibrinogenemia and hypofibrinogenemia patients and 80 healthy controls. We have sequenced all exons of the FGB gene using the DNA isolated from the peripheral blood samples of patients and controls. Results and Conclusion: We found a nonsense mutation in exon 4 at nucleotide 630 that encoded serine amino acid, and in the same exon a missense mutation of T to C at nucleotide 647, resulting in a transition from leucine to proline (p.L198P) in a child with hypofibrinogenemia. These mutations have been shown for the first time in the same patient of Turkish descent. Furthermore, there was a novel heterozygous guanine-to-adenine nucleotide change in exon 3. This caused the change of arginine amino acid to threonine amino acid at position 136 (p.A136T) in a protein, which has not been described in the literature before.

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Congenital afibrinogenemia: identification and expression of a missense mutation in FGB impairing fibrinogen secretion

Blood ◽

10.1182/blood-2003-06-2141 ◽

2003 ◽

Vol 102 (13) ◽

pp. 4413-4415 ◽

Cited By ~ 22

Author(s):

Dung Vu ◽

Paula H. B. Bolton-Maggs ◽

Jeremy R. Parr ◽

Michael A. Morris ◽

Philippe de Moerloose ◽

...

Keyword(s):

Missense Mutation ◽

Gene Mutations ◽

Great Majority ◽

Autosomal Recessive Disorder ◽

Homozygous Deletion ◽

Chain Gene ◽

Missense Mutations ◽

Exon 2 ◽

Congenital Afibrinogenemia ◽

The Media

Abstract Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by complete absence of detectable fibrinogen. We previously identified the first causative mutations for this disease: a homozygous deletion of approximately 11 kb of the fibrinogen α-chain gene (FGA). Subsequent studies revealed that the great majority of afibrinogenemia mutations are localized in FGA, but mutations were also found in FGG and FGB. Apart from 3 missense mutations identified in the C-terminal portion of FGB, all fibrinogen gene mutations responsible for afibrinogenemia are null. In this study, a young boy with afibrinogenemia was found to be a compound heterozygote for 2 mutations in FGB: an N-terminal nonsense mutation W47X (exon 2) and a missense mutation (G444S, exon 8). Coexpression of the FGB G444S mutant cDNA in combination with wild-type FGA and FGG cDNAs demonstrated that fibrinogen molecules containing the mutant β chain are able to assemble but are not secreted into the media, confirming the pathogenic nature of the identified mutation. (Blood. 2003;102:4413-4415)

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Warmblood fragile foal syndrome causative single nucleotide polymorphism frequency in horses in Ireland

Irish Veterinary Journal ◽

10.1186/s13620-021-00206-1 ◽

2021 ◽

Vol 74 (1) ◽

Author(s):

Áine Rowe ◽

Sharon Flanagan ◽

Gerald Barry ◽

Lisa M. Katz ◽

Elizabeth A. Lane ◽

...

Keyword(s):

Autosomal Recessive ◽

Scientific Literature ◽

Genetic Test ◽

Low Frequency ◽

Autosomal Recessive Disorder ◽

Causative Mutation ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Hair Samples ◽

Heterozygous Carriers

Abstract Background Warmblood Fragile Foal Syndrome (WFFS) is an autosomal recessive disorder caused by a mutation in the procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1) gene. Homozygosity for the mutation results in defective collagen synthesis which clinically manifests as the birth of non viable or still born foals with abnormally fragile skin. While the mutation has been identified in non Warmblood breeds including the Thoroughbred, to date all homozygous clinically affected cases reported in the scientific literature are Warmblood foals. The objective of this study was to investigate the carrier frequency of the mutation in the Thoroughbred and sport horse populations in Ireland. Methods A test was developed at the UCD School of Veterinary Medicine using real-time PCR to amplify the PLOD1 gene c.2032G > A variant. A subset of the samples was also submitted to an external laboratory with a licensed commercial WFFS genetic test. Results Warmblood Fragile Foal Syndrome genotyping was performed on hair samples from 469 horses representing 6 different breeds. Six of 303 (1.98%) sport horses tested and three of 109 (2.75%) Thoroughbreds tested were heterozygous for the WFFS polymorphism (N/WFFS). The WFFS polymorphism was not identified in the Standardbred, Cob, Connemara, or other pony breeds. Conclusions The study identified a low frequency of the WFFS causative mutation in sport horses and Thoroughbreds in Ireland, highlighting the importance of WFFS genetic testing in order to identify phenotypically normal heterozygous carriers and to prevent the birth of nonviable foals.

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Hypomyelination and Congenital Cataract: Clinical, Imaging, and Genetic Findings in Three Tunisian Families and Literature Review

Neuropediatrics ◽

10.1055/s-0041-1728654 ◽

2021 ◽

Author(s):

Yosra Bouyacoub ◽

Cyrine Drissi ◽

Ichraf Kraoua ◽

Mariem Chargui ◽

Ibtihel Rebai ◽

...

Keyword(s):

Autosomal Recessive ◽

Congenital Cataract ◽

Direct Sequencing ◽

Autosomal Recessive Disorder ◽

Resonance Imaging ◽

Neurologic Impairment ◽

Tunisian Patients ◽

Myelin Deficiency ◽

The Brain ◽

Genotype Correlation

AbstractHypomyelination and congenital cataract (HCC) is characterized by congenital cataract, progressive neurologic impairment, and diffuse myelin deficiency. This autosomal recessive disorder is caused by homozygous variant in the FAM126A gene. Five consanguineous Tunisian patients, belonging to three unrelated families, underwent routine blood tests, electroneuromyography, and magnetic resonance imaging of the brain. The direct sequencing of FAM126A exons was performed for the patients and their relatives. We summarized the 30 previously published HCC cases. All of our patients were carriers of a previously reported c.414 + 1G > T (IVS5 + 1G > T) variant, but the clinical spectrum was variable. Despite the absence of a phenotype–genotype correlation in HCC disease, screening of this splice site variant should be performed in family members at risk.

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A G-to-A mutation in IVS-3 of the human gamma fibrinogen gene causing afibrinogenemia due to abnormal RNA splicing

Blood ◽

10.1182/blood.v96.7.2501 ◽

2000 ◽

Vol 96 (7) ◽

pp. 2501-2505 ◽

Cited By ~ 22

Author(s):

Maurizio Margaglione ◽

Rosa Santacroce ◽

Donatella Colaizzo ◽

Davide Seripa ◽

Gennaro Vecchione ◽

...

Keyword(s):

Amino Acid ◽

Rna Splicing ◽

Messenger Rna ◽

Stop Codon ◽

Premature Stop Codon ◽

Autosomal Recessive Disorder ◽

Chain Gene ◽

Hemorrhagic Diathesis ◽

Reading Frame ◽

Congenital Afibrinogenemia

Abstract Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by a hemorrhagic diathesis of variable severity. Although more than 100 families with this disorder have been described, genetic defects have been characterized in few cases. An investigation of a young propositus, offspring of a consanguineous marriage, with undetectable levels of functional and quantitative fibrinogen, was conducted. Sequence analysis of the fibrinogen genes showed a homozygous G-to-A mutation at the fifth nucleotide (nt 2395) of the third intervening sequence (IVS) of the γ-chain gene. Her first-degree relatives, who had approximately half the normal fibrinogen values and showed concordance between functional and immunologic levels, were heterozygtes. The G-to-A change predicts the disappearance of a donor splice site. After transfection with a construct, containing either the wild-type or the mutated sequence, cells with the mutant construct showed an aberrant messenger RNA (mRNA), consistent with skipping of exon 3, but not the expected mRNA. Sequencing of the abnormal mRNA showed the complete absence of exon 3. Skipping of exon 3 predicts the deletion of amino acid sequence from residue 16 to residue 75 and shifting of reading frame at amino acid 76 with a premature stop codon within exon 4 at position 77. Thus, the truncated γ-chain gene product would not interact with other chains to form the mature fibrinogen molecule. The current findings show that mutations within highly conserved IVS regions of fibrinogen genes could affect the efficiency of normal splicing, giving rise to congenital afibrinogenemia.

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Differential diagnosis of pseudotrisomy 13 syndrome

Case Reports in Perinatal Medicine ◽

10.1515/crpm-2012-0039 ◽

2012 ◽

Vol 1 (1-2) ◽

Author(s):

Danízar Vásquez Carlón ◽

Margarita Alvarez de la Rosa Rodríguez ◽

Ana I. Padilla Pérez ◽

Ingrid Martínez Wallin ◽

Juan M. Troyano Luque

Keyword(s):

Differential Diagnosis ◽

Prenatal Diagnosis ◽

Poor Prognosis ◽

Autosomal Recessive ◽

Literature Search ◽

Normal Karyotype ◽

Autosomal Recessive Disorder ◽

Limited Information ◽

The Poor ◽

Similar Phenotype

AbstractPseudotrisomy 13 syndrome is determined by the combination of three findings: holoprosencephaly, postaxial polydactyly, and a normal karyotype. We report two cases of a prenatal diagnosis of pseudotrisomy 13 syndrome and one case of a suspected hydrolethalus syndrome, another disorder with a similar phenotype and karyotype. Thorough literature search yields limited information, and the genetic cause of this syndrome remains unclear; however, it is thought to be monogenic and inherited as an autosomal recessive disorder. Given the poor prognosis and the easily recognizable malformations associated with this disease, it is important to perform an early diagnosis.

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A Rare Cause of Refractory Severe Polyhydramnios: Antenatal Bartter Syndrome

Medicina ◽

10.3390/medicina57030272 ◽

2021 ◽

Vol 57 (3) ◽

pp. 272

Author(s):

Gina Nam ◽

Angela Cho ◽

Mi-hye Park

Keyword(s):

Pregnant Woman ◽

Prenatal Diagnosis ◽

Preterm Labor ◽

Autosomal Recessive ◽

Genetic Diagnosis ◽

Autosomal Recessive Disorder ◽

Bartter Syndrome ◽

Case Presentation ◽

Good Clinical Condition

Background: Antenatal Bartter syndrome is an autosomal recessive disorder causing severe polyuria that leads to severe polyhydramnios and preterm labor. Prenatal diagnosis of antenatal Bartter syndrome is difficult because the genetic diagnosis can only be confirmed following a clinical diagnosis in infants. Reports of prenatal diagnosis and treatment of antenatal Bartter syndrome are limited. Case Presentation: We present the case of a 33-year-old pregnant woman with refractory polyhydramnios at 31 weeks of gestation. There were no structural anomalies or placental problems on ultrasonography; therefore, antenatal Bartter syndrome was suspected. With repeated amniocentesis and indomethacin therapy, the pregnancy continued to 36 weeks of gestation. The clinical features of the infant and subsequent genetic testing confirmed the diagnosis of antenatal Bartter syndrome. The baby was in good clinical condition at the 3-month follow-up visit. Conclusions: For pregnant women with early onset and refractory severe polyhydramnios without morphological anomalies, antenatal Bartter syndrome should be highly suspected.

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A G-to-A mutation in IVS-3 of the human gamma fibrinogen gene causing afibrinogenemia due to abnormal RNA splicing

Blood ◽

10.1182/blood.v96.7.2501.h8002501_2501_2505 ◽

2000 ◽

Vol 96 (7) ◽

pp. 2501-2505

Author(s):

Maurizio Margaglione ◽

Rosa Santacroce ◽

Donatella Colaizzo ◽

Davide Seripa ◽

Gennaro Vecchione ◽

...

Keyword(s):

Amino Acid ◽

Rna Splicing ◽

Messenger Rna ◽

Stop Codon ◽

Premature Stop Codon ◽

Autosomal Recessive Disorder ◽

Chain Gene ◽

Hemorrhagic Diathesis ◽

Reading Frame ◽

Congenital Afibrinogenemia

Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by a hemorrhagic diathesis of variable severity. Although more than 100 families with this disorder have been described, genetic defects have been characterized in few cases. An investigation of a young propositus, offspring of a consanguineous marriage, with undetectable levels of functional and quantitative fibrinogen, was conducted. Sequence analysis of the fibrinogen genes showed a homozygous G-to-A mutation at the fifth nucleotide (nt 2395) of the third intervening sequence (IVS) of the γ-chain gene. Her first-degree relatives, who had approximately half the normal fibrinogen values and showed concordance between functional and immunologic levels, were heterozygtes. The G-to-A change predicts the disappearance of a donor splice site. After transfection with a construct, containing either the wild-type or the mutated sequence, cells with the mutant construct showed an aberrant messenger RNA (mRNA), consistent with skipping of exon 3, but not the expected mRNA. Sequencing of the abnormal mRNA showed the complete absence of exon 3. Skipping of exon 3 predicts the deletion of amino acid sequence from residue 16 to residue 75 and shifting of reading frame at amino acid 76 with a premature stop codon within exon 4 at position 77. Thus, the truncated γ-chain gene product would not interact with other chains to form the mature fibrinogen molecule. The current findings show that mutations within highly conserved IVS regions of fibrinogen genes could affect the efficiency of normal splicing, giving rise to congenital afibrinogenemia.

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Report of a Novel Homozygous Nonsense DDR2 Mutation in an Indian Adult Male with Spondylo-meta-epiphyseal Dysplasia, Short Limb-Abnormal Calcification Type

Journal of Pediatric Genetics ◽

10.1055/s-0039-1683382 ◽

2019 ◽

Vol 08 (03) ◽

pp. 153-156

Author(s):

Neerja Gupta ◽

Alec Reginald Errol Correa ◽

Manisha Jana ◽

Madhulika Kabra

Keyword(s):

Short Stature ◽

Adult Male ◽

Nonsense Mutation ◽

Autosomal Recessive ◽

Autosomal Recessive Disorder ◽

Short Limb ◽

Radiological Features ◽

Epiphyseal Dysplasia ◽

Adult Male Patient ◽

Homozygous Nonsense Mutation

AbstractSpondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type is a rare autosomal recessive disorder causing severe disproportionate short stature along with typical radiological features. We report an adult male patient with typical features and a novel homozygous nonsense mutation c.2422C > T (p.Gln808Ter) in DDR2. This is the first report of the disease from India.

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