scholarly journals Clinical characteristics and prenatal diagnosis in 22 families in Henan Province of China with X-linked agammaglobulinemia (XLA) related with Bruton’s tyrosine kinase (BTK) gene mutations.

2020 ◽  
Author(s):  
shanshan gao ◽  
Shuang Hu ◽  
Huikun Duan ◽  
Li Wang ◽  
Xiangdong Kong
Keyword(s):  
Prenatal Diagnosis ◽  
Clinical Symptoms ◽  
Genetic Diagnosis ◽  
Splice Site Mutation ◽  
Large Deletion ◽  
Missense Mutations ◽  
Male Fetus ◽  
Site Mutation ◽  
Female Fetus ◽  
Exon 2

Abstract Background: X-linked agammaglobulinaemia (XLA) is a rare immunodeficiency disease, and the main clinical symptoms is recurrent severe infections. BTK is the main disease-causing gene, and the genetic mode is X chromosome recessive inheritance. But the current mutations do not fully explain this disorder. Methods: We detected the percentage of CD19+ B cells and serum immunoglobulin (IgG, IgA, and IgM) levels by Flow cytometer and rate scatter immunoturbidimetry, and investigated the mutation profile of BTK gene through Sanger sequencing and Real- Time PCR in 22 XLA patients. Results: We described the clinical symptoms and investigated the genetic mutations in 22 XLA patients, and then identified six novel mutations of BTK gene, which included 2 missense mutations (c.23G>T and c.112T>C), 2 frameshift mutations (c.522_523insC and c.1060delA), 1 large deletion (deletion of exon 2 to 5), and 1 splice-site mutation (c.1631+2T>C). Prenatal diagnosis were performed in six families (F10, F11, F15, F18, F20 and F21). F10 was a male fetus without c.922_923delGA mutation; F15 was a male fetus without c.1631+1G>T splicing mutation; F20 was a female fetus without c.1931T>C mutation; and F21 was a male fetus without large deletion mutation. All four fetuses were less likely to become XLA patients in the future. Family 11 and Family 18 were male fetuses with c.1060delA and c.1684C>T mutations, respectively. The pregnant women in F18 chose to terminate the pregnancy, and the F11 chose to continue the pregnancy. Conclusion: It is noticeable that we confirmed the diagnosis of 22 XLA patients from 22 unrelated families and found six new pathogenic mutations. Prenatal diagnosis was performed in six families. Early genetic diagnosis and routine lifelong immunoglobulin replacement therapy can prevent and treat the infections of the XLA children and save their lives.

scholarly journals Clinical characteristics and prenatal diagnosis for 22 families in Henan Province of China with X-linked agammaglobulinemia (XLA) related to Bruton’s tyrosine kinase (BTK) gene mutations.

2020 ◽  
Author(s):  
shanshan gao ◽  
Shuang Hu ◽  
Huikun Duan ◽  
Li Wang ◽  
Xiangdong Kong
Keyword(s):  
Pregnant Woman ◽  
Prenatal Diagnosis ◽  
Clinical Symptoms ◽  
Genetic Diagnosis ◽  
Large Deletion ◽  
Missense Mutations ◽  
Male Fetus ◽  
Causative Gene ◽  
Female Fetus ◽  
Exon 2

Abstract Background: X-linked agammaglobulinaemia (XLA) is a rare immunodeficiency disease for which recurrent severe infection is the major clinical symptom. BTK is the main causative gene, with X chromosome recessive inheritance. However, the mutations reported to date do not fully explain the disorder.Methods: We detected the percentage of CD19+ B cells and serum immunoglobulin (IgG, IgA, and IgM) levels by flow cytometry and rate scatter immunoturbidimetry, and investigated the BTK mutation profile in 22 XLA patients using Sanger sequencing and real-time PCR .Results: We evaluated the clinical symptoms of 22 XLA patients and investigated genetic mutations present, identifying six novel mutations in the BTK gene: 2 missense mutations (c.23G>T and c.112T>C), 2 frameshift mutations (c.522_523insC and c.1060delA), 1 large deletion (deletion of exon 2 to 5), and 1 splice-site mutation (c.1631+2T>C). Prenatal diagnoses were performed in six families (F10, F11, F15, F18, F20 and F21), with the following results: the male fetus in Family 10 (F10) did not carry the c.922_923delGA mutation; the male fetus in Family 15 (F15) did not carry the c.1631+1G>T splicing mutation; the female fetus in Family 20 (F20) did not carry the c.1931T>C mutation; the male fetus in Family 21 (F21) did not carry the large deletion mutation. Hence, these four fetuses are not likely to develop XLA. Male fetuses with c.1060delA and c.1684C>T mutations were identified in Family 11 and Family 18, respectively. The pregnant woman in F18 chose to terminate the pregnancy, whereas the pregnant woman in F11 chose to continue the pregnancy.Conclusion: We confirmed the diagnosis of 22 XLA patients from 22 unrelated families and detected six new pathogenic mutations. Prenatal diagnosis was performed in six families. Early genetic diagnosis and routine lifelong immunoglobulin replacement therapy can prevent and treat infections in XLA children, saving their lives.

scholarly journals The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene

Blood ◽  
1995 ◽  
Vol 86 (10) ◽  
pp. 3797-3804 ◽  
Author(s):  
Q Zhu ◽  
M Zhang ◽  
RM Blaese ◽  
JM Derry ◽  
A Junker ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Point Mutations ◽  
Gene Mutations ◽  
Exon Skipping ◽  
Splice Site Mutation ◽  
Missense Mutations ◽  
Site Mutation ◽  
Exon 2 ◽  
Wiskott Aldrich Syndrome ◽  
Was Gene

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by thrombocytopenia, small platelets, eczema, recurrent infections, and immunodeficiency. Besides the classic WAS phenotype, there is a group of patients with congenital X-linked thrombocytopenia (XLT) who have small platelets but only transient eczema, if any, and minimal immune deficiency. Because the gene responsible for WAS has been sequenced, it was possible to correlate the WAS phenotypes with WAS gene mutations. Using a fingerprinting screening technique, we determined the approximate location of the mutation in 13 unrelated WAS patients with mild to severe clinical symptoms. Direct sequence analysis of cDNA and genomic DNA obtained from patient-derived cell lines showed 12 unique mutations distributed throughout the WAS gene, including insertions, deletions, and point mutations resulting in amino acid substitutions, termination, exon skipping, or splicing defects. Of 4 unrelated patients with the XLT phenotype, 3 had missense mutations affecting exon 2 and 1 had a splice-site mutation affecting exon 9. Patients with classic WAS had more complex mutations, resulting in termination codons, frameshift, and early termination. These findings provide direct evidence that XLT and WAS are caused by mutations of the same gene and suggest that severe clinical phenotypes are associated with complex mutations.

IGF2 Mutations

2019 ◽  
Vol 105 (1) ◽  
pp. 116-125 ◽  
Author(s):  
Yohei Masunaga ◽  
Takanobu Inoue ◽  
Kaori Yamoto ◽  
Yasuko Fujisawa ◽  
Yasuhiro Sato ◽  
...  
Keyword(s):  
High Frequency ◽  
Low Frequency ◽  
Splice Site Mutation ◽  
Missense Mutations ◽  
Site Mutation ◽  
Exon 2 ◽  
Mild Degree ◽  
Reduced Body ◽  
Limb Malformations ◽  
Silver Russell Syndrome

Abstract Objective IGF2 is a paternally expressed growth-promoting gene. Here, we report five cases with IGF2 mutations and review IGF2 mutation-positive patients described in the literature. We also compare clinical features between patients with IGF2 mutations and those with H19/IGF2:IG-DMR epimutations. Results We recruited five cases with IGF2 mutations: case 1 with a splice site mutation (c.–6–1G>C) leading to skipping of exon 2 and cases 2–5 with different missense mutations (p.(Cys70Tyr), p.(Cys71Arg), p.(Cys33Ser), and p.(Cys45Ser)) affecting cysteine residues involved in the S-S bindings. All the mutations resided on the paternally inherited allele, and the mutation of case 5 was present in a mosaic condition. Clinical assessment revealed Silver–Russell syndrome (SRS) phenotype with Netchine–Harbison scores of ≥5/6 in all the apparently nonmosaic 14 patients with IGF2 mutations (cases 1–4 described in this study and 10 patients reported in the literature). Furthermore, compared with H19/IGF2:IG-DMR epimutations, IGF2 mutations were associated with low frequency of hemihypoplasia, high frequency of feeding difficulty and/or reduced body mass index, and mild degree of relative macrocephaly, together with occasional development of severe limb malformations, high frequency of cardiovascular anomalies and developmental delay, and low serum IGF-II values. Conclusions This study indicates that IGF2 mutations constitute a rare but important cause of SRS. Furthermore, while both IGF2 mutations and H19/IGF2:IG-DMR epimutations lead to SRS, a certain degree of phenotypic difference is observed between the two groups, probably due to the different IGF2 expression pattern in target tissues.

scholarly journals Identification of Missense Mutation Pro77Arg As A Founder Mutation in Morquio-A Syndrome in Indian Gujarati Patel Ethnicity

2020 ◽  
Author(s):  
Jayesh J Sheth ◽  
Riddhi Bhavsar ◽  
Aadhira Nair ◽  
Chandni Patel ◽  
Premal Naik ◽  
...  
Keyword(s):  
Splice Site ◽  
Haplotype Analysis ◽  
Founder Mutation ◽  
Splice Site Mutation ◽  
Missense Mutations ◽  
Site Mutation ◽  
Exon 2 ◽  
Morquio A ◽  
Healthy Control ◽  
Morquio A Syndrome

Abstract Background: Morquio A syndrome (MPS IVA) is a mucopolysaccharide group storage disorder caused due to the deficient activity of the lysosomal enzyme N-acetylgalactoseamine-6-sulfatase encoded by GALNS. The present study represents the mutation spectrum of GALNS in 25 Gujarati Patel patients of India clinically and biochemically confirmed with Morquio-A disorder.Methods: Urinary GAG quantitation and leucocyte enzyme assay was carried out in all 25 patients. This was followed by molecular characterization by amplification and sequencing of the exons and adjacent intronic regions of GALNS gene. Haplotype analysis was performed in patients showing p.P77R variant, using microsatellite markers D16S3121, D16S3026 and D16S3023 and SNPs.Results: We identified 11 mutations that include eight missense mutations: (p.L36R, p.D39G, p.P77R, p.C79R, pP125L, p.P151L, p.G255A and p.L350P), one splice site mutation: (c.121-7C>G), one small insertion: (c.1241_1242insA, p.I416HfsTer2) and one small deletion: (c.839_41delACA). Of these, three missense mutations (p.D39G, p.G255A and p.L350P), one splice site and the two indels mentioned above are novel. In the present study, we found maximum number of mutant alleles in exon 2, and of note, the variant p.P77R was seen in fourteen patients. Conclusion: p.P77R variant was predominantly found in Gujarati Patel community and the results of haplotype analysis indicated it to be the founder mutation in this community. Further, a study of 200 unrelated healthy control participants from Gujarat has identified this mutation in the heterozygous status in two individuals. Overall, our study suggests that p.P77R is likely to be a founder mutation for Morquio-A syndrome in Gujarati Patel ethnicity.

scholarly journals Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset

2021 ◽  
Vol 22 (7) ◽  
pp. 3786
Author(s):  
Andreas Brodehl ◽  
Alexey Meshkov ◽  
Roman Myasnikov ◽  
Anna Kiseleva ◽  
Olga Kulikova ◽  
...  
Keyword(s):  
Medical History ◽  
Splice Site Mutation ◽  
Pathogenic Mutation ◽  
Large Deletion ◽  
Loss Of Function ◽  
Arrhythmogenic Cardiomyopathy ◽  
Site Mutation ◽  
Snp Arrays ◽  
Number Of Patients ◽  
History Of

About 50% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2–c.378+1G>T) in the first patient and a nonsense mutation (DSG2–p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases.

scholarly journals Vitamin D 1α-Hydroxylase Gene Mutations in Patients with 1α-Hydroxylase Deficiency

2007 ◽  
Vol 92 (8) ◽  
pp. 3177-3182 ◽  
Author(s):  
Chan Jong Kim ◽  
Larry E. Kaplan ◽  
Farzana Perwad ◽  
Ningwu Huang ◽  
Amita Sharma ◽  
...  
Keyword(s):  
Vitamin D ◽  
Direct Sequencing ◽  
Gene Mutations ◽  
Splice Site Mutation ◽  
Autosomal Recessive Disorder ◽  
The United States ◽  
Site Mutation ◽  
Hydroxylase Deficiency ◽  
Exon 2 ◽  
Hydroxylase Gene

Abstract Context: Vitamin D 1α-hydroxylase deficiency, also known as vitamin D-dependent rickets type 1, is an autosomal recessive disorder characterized by the early onset of rickets with hypocalcemia and is caused by mutations of the 25-hydroxyvitamin D 1α-hydroxylase (1α-hydroxylase, CYP27B1) gene. The human gene encoding the 1α-hydroxylase is 5 kb in length, located on chromosome 12, and comprises nine exons and eight introns. We previously isolated the human 1α-hydroxylase cDNA and gene and identified 19 different mutations in 25 patients with 1α-hydroxylase deficiency. Objectives, Patients, and Methods: We analyzed the 1α-hydroxylase gene of 10 patients, five from Korea, two from the United States, and one each from Argentina, Denmark, and Morocco, all from nonconsanguineous families. Each had clinical and radiographic features of rickets, hypocalcemia, and low serum concentrations of 1,25-dihydroxyvitamin D3. Results: Direct sequencing identified the responsible 1α-hydroxylase gene mutations in 19 of 20 alleles. Four novel and four known mutations were identified. The new mutations included a nonsense mutation in exon 6, substitution of adenine for guanine (2561G→A) creating a stop signal at codon 328; deletion of adenine in exon 9 (3922delA) causing a frameshift; substitution of thymine for cytosine in exon 2 (1031C→T) causing the amino acid change P112L; and a splice site mutation, substitution of adenine for guanine in the first nucleotide of intron 7 (IVS7+1 G→A) causing a frameshift. Conclusions: Mutations in the 1α-hydroxylase gene previously were identified in 44 patients, to which we add 10 more. The studies show a strong correlation between 1α-hydroxylase mutations and the clinical findings of 1α-hydroxylase deficiency.

scholarly journals The mutational spectrum of Hunter syndrome reveals correlation between biochemical and clinical profiles in Tunisian patients

2020 ◽  
Author(s):  
latifa chkioua ◽  
Oussama Grissa ◽  
Nadia Leban ◽  
Moez Gribaa ◽  
Hela Boudabous ◽  
...  
Keyword(s):  
Nonsense Mutation ◽  
Dermatan Sulfate ◽  
Splice Site Mutation ◽  
Hunter Syndrome ◽  
Molecular Testing ◽  
Missense Mutations ◽  
Lysosomal Storage ◽  
High Concentration ◽  
Site Mutation ◽  
Mps Ii

Abstract Background: Mucopolysaccharidosis type II (MPS II) or Hunter syndrome is an X-linked recessive lysosomal storage disorder resulting from deficient activity of iduronate 2-sulfatase (IDS) and the progressive lysosomal accumulation of sulfated glycosaminoglycans (GAGs). Methods: A diagnosis of MPS II or Hunter syndrome was performed based on the following approach after a clinical and paraclinical suspicion. Two biochemical and molecular tests were carried out separately and according to the availability of the biological material. Results: All patients in this cohort presented the most common MPS II clinical features. Electrophoresis of GAGs on a cellulose acetate plate in the presence of a high concentration of heparane sulfate showed an abnormal dermatan sulfate band in the patients compared with that in a control case. Furthermore, leukocyte IDS activity ranged from 0.00 to 0.75 nmol/h/mg of leukocyte protein in patients.Five previously reported mutations were identified in this study patients: one splice site mutation, c.240+1G>A; two missense mutations, p.R88P and p.G94D; a large deletion of exon 1 to exon 7; and one nonsense mutation, p.Q396*. In addition, two novel alterations were identified in the MPS II patients: one frame shift mutation, p.D450Nfs*95 and one nonsense mutation, p.Q204*. Additionally, five known IDS polymorphisms were identified in the patients: c.419-16 delT, c.641C>T (p.T214M), c.438 C>T (p.T146T), c.709-87G>A, and c.1006+38T>C.Conclusions: The high level of urine GAGs and the deficiency of iduronate 2-sulfatase activity was associated with the phenotype expression of Hunter syndrome. Molecular testing was useful for the patients’ phenotypic classification and the detection of carriers.

Detection of Ten New Mutations by Screening the Gene Encoding Factor IX of Danish Hemophilia B Patients

1995 ◽  
Vol 73 (05) ◽  
pp. 774-778 ◽  
Author(s):  
Marianne Schwartz ◽  
Jørgen Ingerslev ◽  
Elma Scheibel ◽  
Lise Rud Nielsen
Keyword(s):  
Point Mutations ◽  
Splice Site Mutation ◽  
Factor Ix ◽  
Hemophilia B ◽  
Missense Mutations ◽  
Coding Region ◽  
Site Mutation ◽  
Gene Encoding ◽  
Base Pair Deletion ◽  
Wide Range

SummaryHemophilia B is caused by a wide range of mutations. In order to characterize the mutations among patients in Denmark, we have systematically screened the entire coding region, the promoter region and exon flanking sequences of the gene encoding factor IX using single strand conformation and heteroduplex analyses. Patients from 32 different families were examined, and point mutations (23 different) were found in all of them. Ten of the mutations have not been reported by others; they include a splice site mutation, a single base pair deletion, and missense mutations. Notably, the study contains a female patient and a previously described Leyden mutation. In ten families with sporadic cases of hemophilia B, all 10 mothers were found to be carriers. The origin of two of these mutations was established.

scholarly journals Genetic analysis of 62 Chinese families with Duchenne muscular dystrophy and strategies of prenatal diagnosis in a single center

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Jingjing Zhang ◽  
Dingyuan Ma ◽  
Gang Liu ◽  
Yuguo Wang ◽  
An Liu ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
De Novo ◽  
Clinical Symptoms ◽  
Perinatal Care ◽  
Genetic Diagnosis ◽  
Point Mutations ◽  
Inherited Disease ◽  
Positive Results

Abstract Background Duchenne muscular dystrophy (DMD) is a severe X-linked recessive neuromuscular disorder. Patients with DMD usually have severe and fatal symptoms, including progressive irreversible muscle weakness and atrophy complicated with gastrocnemius muscle pseudohypertrophy. DMD is caused by mutations in the dystrophin-encoding DMD gene, including large rearrangements and point mutations. This retrospective study was aimed at supplying information on our 4-year clinical experience of DMD genetic and prenatal diagnosis at the Department of Prenatal Diagnosis in Women’s Hospital of Nanjing Medical University. Methods Multiplex ligation-dependent probe amplification (MLPA) was used to detect the exon deletions or duplications. And Ion AmpliSeq™ panel for inherited disease was used as the next-generation sequencing (NGS) method to identify the point mutations in exons of DMD gene, but the introns were not sequenced. Results In this study, the large deletions and duplications of DMD gene were detected in 32 (51.6%) of the 62 families, while point mutations were detected in 20 families (32.3%). The remaining 10 families with a negative genetic diagnosis need to be reevaluated for clinical symptoms or be detected by other molecular methods. Notably, six novel mutations were identified, including c.412A > T(p.Lys138*), c.2962delT(p.Ser988Leufs*16), c.6850dupA (p.Ser2284Lysfs*7), c.5139dupA (p.Glu 1714Argfs*5), c.6201_6203delGCCins CCCA(p.Val2069Cysfs*14) and c.10705A > T (p.Lys3569*). In 52 families with positive results, 45 mothers (86.5%) showed positive results during carrier testing and de novo mutations arose in 7 probands. The prenatal diagnosis was offered to 34 fetuses whether the pregnant mother was a carrier or not. As a result, eight male fetuses were affected, three female fetuses were carriers, and the remaining fetuses had no pathogenic mutation. Conclusions This study reported that MLPA and NGS could be used for screening the DMD gene mutations. Furthermore, the stepwise procedure of prenatal diagnosis of DMD gene was shown in our study, which is important for assessing the mutation type of fetuses and providing perinatal care in DMD high-risk families.

A Novel Splice Site Variant in FOXN1 in A Patient with Abnormal Newborn Screening for Severe Combined Immunodeficiency and Congenital Lymphopenia

2021 ◽  
Author(s):  
Ori Scott ◽  
Jenny Garkaby ◽  
Jessica Willett-Pachul ◽  
Yehonatan Pasternak
Keyword(s):  
Splice Site ◽  
Severe Combined Immunodeficiency ◽  
Splice Site Mutation ◽  
Missense Mutations ◽  
Combined Immunodeficiency ◽  
Site Mutation ◽  
Cd8 Cells ◽  
Cell Counts ◽  
Epithelial Development ◽  
Whole Exome

Background: The Forkhead box protein N1 (FOXN1) is a key regulator of thymic epithelial development, and its complete deficiency leads to a nude-severe combined immunodeficiency (SCID) phenotype. More recently, heterozygous mutations in FOXN1 have been linked with a syndrome of congenital lymphopenia and a wide clinical spectrum, with most cases being caused by missense mutations. Aim: To broaden the genotypic and phenotypic spectrum of heterozygous FOXN1 deficiency. Methods: Case report of a patient with FOXN1 haploinsufficiency due to a novel splice-site mutation. Results: Our patient was identified at 3 weeks of life given an abnormal newborn screen (NBS) for SCID, and was found to have congenital lymphopenia preferentially affecting CD8+ T-cells. Her cellular and humoral function were both excellent, and she has remained entirely asymptomatic and thriving for the first 3 years of her life. The patient was found on whole exome sequencing to carry a heterozygous splice-site mutation in the FOXN1 gene, affecting the Forkhead domain. The mutation was also identified in her asymptomatic mother. Conclusion: Heterozygous FOXN1 mutations are an increasingly-recognized cause of congenital lymphopenia. Our experience suggests most patients remain clinically well, with main manifestation including T-lymphopenia, mostly affecting CD8+ cells. Identification of the same variant in an asymptomatic parent suggests age-dependent improvement in T-cell counts and an overall benign course, while provides impetus for diligent conservative management with regular follow-up.

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