Three Novel Mutations and a De Novo Deletion Mutation of the DAX-1 Gene in Patients with X-Linked Adrenal Hypoplasia Congenita

The DAX-1 [DSS (dosage sensitive sex)-AHC critical region on the X, gene 1] gene is responsible for X-linked adrenal hypoplasia congenita (AHC). However, DAX-1 protein structure-function relationships are not well understood. Identification of missense mutations may help to reveal these relationships. We analyzed the DAX-1 gene from seven patients in six kindreds with X-linked AHC and identified one frameshift mutation, two missense mutations, and three deletion mutations. Case 1 had a 388delAG frameshift mutation, inducing a premature stop codon at position 70. Case 2 had a missense mutation, Lys382Asn, which encodes an asparagine (Asn) for lysine (Lys) at position 382. Sibling cases of 3-1 and 3-2 had a missense mutation of Trp291Cys, which encodes a substitution of cysteine (Cys) for tryptophan (Try) at position 291. The tryptophan (Trp) at position 291 and lysine (Lys) at position 382 in human DAX-1 protein are highly conserved among other related orphan nuclear receptor superfamily members. Cases 4, 5, and 6 showed deletion mutation. In case 6, a de novo deletion mutation was revealed by both southern hybridization and polymerase chain reaction (PCR) of a GGAA tetranucleotide tandem repeat. These findings suggest that: 1) Trp at position 291 and Lys at position 382, located in the C-terminal presumptive ligand binding domain, are important to the functional role of the DAX-1 protein in adrenal embryogenesis and/or in hypothalamic-pituitary activity; and 2) molecular analysis of the DAX-1 gene may help genetic counseling, even in cases with deletion mutation, because a detection of de novo deletion may exclude another affected or carrier child.

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A novel de novo frameshift mutation in NR0B1 and low prenatal estriol in adrenal hypoplasia congenita

Annals of the New York Academy of Sciences ◽

10.1111/nyas.13962 ◽

2018 ◽

Vol 1433 (1) ◽

pp. 7-11 ◽

Cited By ~ 1

Author(s):

Ahmed Khattab ◽

Carol Nelson-Williams ◽

Vivienne Cabreza ◽

Anne Macdonald ◽

Erin Loring ◽

...

Keyword(s):

Frameshift Mutation ◽

De Novo ◽

Adrenal Hypoplasia Congenita ◽

Adrenal Hypoplasia

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X-linked adrenal hypoplasia congenita: Novel missense mutation of DAX-1 gene

Medicina Clínica (English Edition) ◽

10.1016/j.medcle.2018.04.013 ◽

2019 ◽

Vol 152 (6) ◽

pp. 242-243

Author(s):

Ángela Domínguez García ◽

Alfredo Santana Rodríguez ◽

María Fátima Cabrera Guedes

Keyword(s):

Missense Mutation ◽

Adrenal Hypoplasia Congenita ◽

Adrenal Hypoplasia

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A Novel Frameshift Mutation of SCNN1G Causing Liddle Syndrome with Normokalemia

American Journal of Hypertension ◽

10.1093/ajh/hpz053 ◽

2019 ◽

Vol 32 (8) ◽

pp. 752-758

Author(s):

Peng Fan ◽

Yu-Mo Zhao ◽

Di Zhang ◽

Ying Liao ◽

Kun-Qi Yang ◽

...

Keyword(s):

Genetic Testing ◽

Frameshift Mutation ◽

Stop Codon ◽

Single Gene ◽

Family Members ◽

Premature Stop Codon ◽

Chinese Family ◽

Autosomal Dominant Disorder ◽

Liddle Syndrome ◽

Genetic Sequencing

Abstract BACKGROUND Liddle syndrome (LS) is an autosomal dominant disorder caused by single-gene mutations of the epithelial sodium channel (ENaC). It is characterized by early-onset hypertension, spontaneous hypokalemia and low plasma renin and aldosterone concentrations. In this study, we reported an LS pedigree with normokalemia resulting from a novel SCNN1G frameshift mutation. METHODS Peripheral blood samples were collected from the proband and eight family members for DNA extraction. Next-generation sequencing and Sanger sequencing were performed to identify the SCNN1G mutation. Clinical examinations were used to comprehensively evaluate the phenotypes of two patients. RESULTS Genetic analysis identified a novel SCNN1G frameshift mutation, p.Arg586Valfs*598, in the proband with LS. This heterozygous frameshift mutation generated a premature stop codon and deleted the vital PY motif of ENaC. The same mutation was present in his elder brother with LS, and his mother without any LS symptoms. Biochemical examination showed normokalemia in the three mutation carriers. The mutation identified was not found in any other family members, 100 hypertensives, or 100 healthy controls. CONCLUSIONS Our study identified a novel SCNN1G frameshift mutation in a Chinese family with LS, expanding the genetic spectrum of SCNN1G. Genetic testing helped us identify LS with a pathogenic mutation when the genotypes and phenotype were not completely consistent because of the hypokalemia. This case emphasizes that once a proband is diagnosed with LS by genetic testing, family genetic sequencing is necessary for early diagnosis and intervention for other family members, to protect against severe cardiovascular complications.

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Mutations of TET2 and JAK2 but Not CBL Are Detectable in a High Portion of Patients with Refractory Anemia with Ring Sideroblasts and Thrombocytosis (RARS-T).

Blood ◽

10.1182/blood.v114.22.1766.1766 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1766-1766

Author(s):

Johanna Flach ◽

Sonja Schindela ◽

Frank Dicker ◽

Susanne Schnittger ◽

Alexander Kohlmann ◽

...

Keyword(s):

Microarray Analysis ◽

Stop Codon ◽

Myeloproliferative Neoplasms ◽

Premature Stop Codon ◽

Jak2v617f Mutation ◽

Refractory Anemia ◽

Missense Mutations ◽

Myeloid Malignancies ◽

Ring Sideroblasts ◽

Equity Ownership

Abstract Abstract 1766 Poster Board I-792 Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) forms a provisional entity within the category of MDS/MPN-U in the 2008 WHO classification. Although the identification of the JAK2V617F mutation was an important first step in distinguishing this entity from other hematological diseases, further genetic characterization is necessary. We performed comprehensive cytogenetic and molecular genetic investigations including targeted analysis of JAK2V617F, TET2, MPLW515 and CBL, markers known to be altered in MPN, as well as genome-wide single nucleotide polymorphism microarray analysis (SNP-A) in 23 RARS-T patients who fulfilled WHO 2008 diagnostic criteria. The JAK2V617F mutation was detectable in 15 out of 19 analyzed patients (78.9%), four of which were homozygous. However, our patients neither carried a MPLW515 mutation nor mutations in exons 8 or 9 of CBL genes. These genes were recently described to be mainly mutated in myeloproliferative neoplasms. In addition, conventional cytogenetic analysis did not reveal any recurrent cytogenetic abnormalities in RARS-T patients. We also performed SNP microarray analysis in a subset of 10 RARS-T patients. Although we did neither observe recurrent chromosomal gains or losses nor recurring regions of UPD, one patient showed a deletion spanning a 1.3 Mb region on the long arm of chromosome 4 (start: 105,497,200 bp from pter; end: 106,825,780 bp from pter). The deleted region contained TET2, a gene recently found to be altered in many subtypes of myeloid malignancies. To further clarify the 4q24 deletion detected by SNP-A analysis we performed fluorescence in situ hybridization (FISH). 20 out of 100 analyzed interphase nuclei and three metaphases showed only one signal for the probe spanning the TET2 gene in this patient. Interphase FISH with the TET2 probe was performed in nine additional cases not analyzed by SNP arrays due to a lack of material, but no additional case showing a deletion was detected. In addition to FISH, we performed TET2 sequencing in 19/23 RARS-T patients. TET2 mutations were detected in 5/19 patients (26%), of which 3/5 also presented the JAK2V617F mutation, whereas the remaining 2/5 did neither show JAK2V617F nor MPL nor CBL mutations. The five patients showed 6 individually different TET2 mutations. Three were nonsense and two missense mutations. One patient displayed a frameshift mutation leading to a premature stop codon. In summary, RARS-T patients demonstrated a high frequency of both JAK2 and TET2 mutations. Together with the less common MPL mutations described by others RARS-T presents a variety of mutations that overlap with the spectrum of mutations seen in MPN and other myeloid malignancies. Thus, a combination of molecular markers including JAK2 and TET2 should be investigated to more precisely describe RARS-T as an independent disease entity. Disclosures Flach: MLL Munich Leukemia Laboratory: Employment. Schindela:MLL Munich Leukemia Laboratory: Employment. Dicker:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Weiss:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.

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Hereditary Multiple Exostoses: Clinical, Molecular and Radiologic Survey in 9 Families

Prague Medical Report ◽

10.14712/23362936.2017.8 ◽

2017 ◽

Vol 118 (2-3) ◽

pp. 87-94

Author(s):

Karel Medek ◽

Jiří Zeman ◽

Tomáš Honzík ◽

Hana Hansíková ◽

Štěpánka Švecová ◽

...

Keyword(s):

Malignant Transformation ◽

De Novo ◽

Stop Codon ◽

Premature Stop Codon ◽

Gene Mutations ◽

Nonsense Mutations ◽

Hereditary Multiple Exostoses ◽

Multiple Exostoses ◽

The Mean

Hereditary multiple exostoses (HME) represents a heterogeneous group of diseases often associated with progressive skeletal deformities. Most frequently, mutations inEXT1andEXT2genes with autosomal dominant inheritance are responsible for HME. In our group of 9 families with HME we evaluated the clinical course of the disease and analysed molecular background using Sanger sequencing and MLPA inEXT1andEXT2genes. The mean age in our group of patients, when the first exostosis was recognised was 4.5 years (range 2–10 years) and the number of exostoses per one patient documented on X-ray ranged from 2 to 54. Most of the exostoses developed before the growth was completed and they were dominantly localised in the distal femurs, proximal tibia, proximal humerus and distal radius. In all patients, at least one to 8 surgeries were necessary due to complaints and local complications, but neither patient developed malignant transformation. In half of the patients, the disease resulted in short stature. DNA analyses were positive in 7 families. In five probands, differentEXT1gene mutations resulting in premature stop-codon (p.Gly124Argfs*65, p.Leu191*, p.Trp364Lysfs*11, p.Val371Glyfs*10, p.Leu490Profs*31) were found. In two probands, nonsense mutations were found inEXT2gene (p.Val187Profs*115, p.Cys319fs*46). Five mutations have been novel and two mutations have occurredde novoin probands. Although the risk for malignant transformation is usually low, especially in patients with low number of exostoses, early diagnostics and longitudinal follow up of patients is of a big importance, because early surgery can prevent progression of secondary bone deformities.

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YWHAG Mutations Cause Childhood Myoclonic Epilepsy and Febrile Seizures: Molecular Sub-regional Effect and Mechanism

Frontiers in Genetics ◽

10.3389/fgene.2021.632466 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xing-Guang Ye ◽

Zhi-Gang Liu ◽

Jie Wang ◽

Jie-Min Dai ◽

Pei-Xiu Qiao ◽

...

Keyword(s):

Missense Mutation ◽

De Novo ◽

Febrile Seizures ◽

Epileptic Encephalopathy ◽

Myoclonic Epilepsy ◽

Missense Mutations ◽

Regional Effect ◽

Diverse Range ◽

Mild Phenotype ◽

Truncating Mutation

YWHAG, which encodes an adapter protein 14-3-3γ, is highly expressed in the brain and regulates a diverse range of cell signaling pathways. Previously, eight YWHAG mutations have been identified in patients with epileptic encephalopathy (EE). In this study, using trios-based whole exome sequencing, we identified two novel YWHAG mutations in two unrelated families with childhood myoclonic epilepsy and/or febrile seizures (FS). The identified mutations included a heterozygous truncating mutation (c.124C>T/p.Arg42Ter) and a de novo missense mutation (c.373A>G/p.Lys125Glu). The two probands experienced daily myoclonic seizures that were recorded with ictal generalized polyspike-slow waves, but became seizure-free with simple valproate treatment. The other affected individuals presented FS. The truncating mutation was identified in the family with six individuals of mild phenotype, suggesting that YWHAG mutations of haploinsufficiency are relatively less pathogenic. Analysis on all missense mutations showed that nine mutations were located within 14-3-3γ binding groove and another mutation was located at residues critical for dimerization, indicating a molecular sub-regional effect. Mutation Arg132Cys, which was identified recurrently in five patients with EE, would have the strongest influence on binding affinity. 14-3-3γ dimers supports target proteins activity. Thus, a heterozygous missense mutation would lead to majority dimers being mutants; whereas a heterozygous truncating mutation would lead to only decreasing the number of wild-type dimer, being one of the explanations for phenotypical variation. This study suggests that YWHAG is potentially a candidate pathogenic gene of childhood myoclonic epilepsy and FS. The spectrum of epilepsy caused by YWHAG mutations potentially range from mild myoclonic epilepsy and FS to severe EE.

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Truncating Mutation in FOXC2 Gene in Familial Hemorrhoids and Varicose Veins

International Journal of Biology and Biomedical Engineering ◽

10.46300/91011.2020.14.5 ◽

2020 ◽

Vol 14 ◽

Keyword(s):

Frameshift Mutation ◽

Stop Codon ◽

Varicose Veins ◽

Premature Stop Codon ◽

Genetic Mutations ◽

Physiological Factors ◽

Vascular Integrity ◽

Truncating Mutation ◽

Two Samples

Hemorrhoids and varicose veins are conditions resulting from loss of vascular integrity and, despite being worldwide health concerns, their pathogenesis has not been clearly defined. Many risk factors have been linked to the development of these complications including diet, defecating habits, alcohol consumption and other physiological factors. There are limited studies involving the possible role of genetic mutations in the development of hemorrhoids and varicose veins. FoxC2 is an important transcription factor that plays many roles in a variety of embryonic developmental processes, including angiogenesis. In the current study, we aimed to investigate the role of the FOXC2 gene variations in the development of familial hemorrhoids and varicose veins in the Jordanian population. Thirty-two samples were collected from eight families manifested hemorrhoids and/or varicose veins conditions. DNA sequencing was performed to screen variation in the FOXC2 gene. Two individuals with severe and early onset of hemorrhoids and varicose veins from the same family showed a frameshift mutation (881'inT) in the coding exon of the FOXC2 gene resulting in a premature stop codon at position +1386 (294 residues truncated peptide). In conclusion, our results support a possible role of genetic predisposition in the development of hemorrhoids and varicose veins with a frequency of 6% in the selected population

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Erratum: clinical and molecular characteristics of patients with 46,xy dsd due to nr5a1 gene mutations (Probl Endokrinol (Mosk). 2020 Sep 16;66(3):62-69. Russian. doi: 10.14341/probl12445)

Problems of Endocrinology ◽

10.14341/probl12848 ◽

2021 ◽

Vol 67 (6) ◽

pp. 124-126

Author(s):

N. Yu. Kalinchenko ◽

A. A. Kolodkina ◽

N. Yu. Raygorodskaya ◽

A. N. Tiulpakov

Keyword(s):

Stop Codon ◽

Premature Stop Codon ◽

Gene Mutations ◽

Synonymous Substitution ◽

Molecular Characteristics ◽

Missense Mutations ◽

Reading Frame ◽

Splicing Site

n the article some corrections were needed. Abstract: “Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 15 were not previously described”. has been corrected to read “Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 22 were not previously described”. Results: “Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 15 were not previously described”, has been corrected to read “Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 22 were not previously described”. Among the newly identified variants in the NR1A1 gene, two lead to the premature stop codon -p. Y197X and p. Y25X, two lead to a shift in the reading frame-p. N385fs and p. L245fs, which does not allow us to doubt their pathogenicityAmong the previously undescribed variant changes, 5 missense mutations (p. C283Y, p. C283B, p.H24Q, p.M126K, p.E81K) and 1 synonymous substitution affecting the splicing site (E330E) were evaluated as pathogenic, and 5 others as probably pathogenic.Has been corrected to read: Among the newly identified variants in the NR1A1 gene, two lead to the premature stop codon -p. Y197X and p. Y25X, two lead to a shift in the reading frame — p.N385SfsX10 and p.L245AfsX53, which does not allow us to doubt their pathogenicity Among the previously undescribed variants, 5 missense mutations (p.C283Y, p.С283F, p.H24Q, p.M126K, p.A82T) and 1 synonymous substitution affecting the splicing site (E330E) were predicted as pathogenic, and 5 others as probably pathogenic by calculating pathogenicity. The authors apologize for these errors.

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X-linked adrenal hypoplasia congenita with a novel DAX1 missense mutation

Endocrine Abstracts ◽

10.1530/endoabs.37.ep45 ◽

2015 ◽

Author(s):

Fen-Yu Tseng ◽

Yu-Ting Tseng ◽

Shyang-Ron Shih ◽

Pei-Lung Chen

Keyword(s):

Missense Mutation ◽

Adrenal Hypoplasia Congenita ◽

Adrenal Hypoplasia

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A de novo synonymous variant in EFTUD2 disrupts normal splicing and causes mandibulofacial dysostosis with microcephaly: case report

BMC Medical Genetics ◽

10.1186/s12881-020-01121-y ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Arthur Jacob ◽

Jennifer Pasquier ◽

Raphael Carapito ◽

Frédéric Auradé ◽

Anne Molitor ◽

...

Keyword(s):

Splice Site ◽

De Novo ◽

Stop Codon ◽

Premature Stop Codon ◽

Genetic Alterations ◽

Donor Splice Site ◽

Donor Splice ◽

First Case ◽

Synonymous Variant ◽

Mandibulofacial Dysostosis

Abstract Background Mandibulofacial dysostosis with microcephaly (MFDM) is a rare autosomal dominant genetic disease characterized by intellectual and growth retardations, as well as major microcephaly, induced by missense and splice site variants or microdeletions in the EFTUD2 gene. Case presentation Here, we investigate the case of a young girl with symptoms of MFDM and a normal karyotype. Whole-exome sequencing of the family was performed to identify genetic alterations responsible for this phenotype. We identified a de novo synonymous variant in the EFTUD2 gene. We demonstrated that this synonymous variant disrupts the donor splice-site in intron 9 resulting in the skipping of exon 9 and a frameshift that leads to a premature stop codon. Conclusions We present the first case of MFDM caused by a synonymous variant disrupting the donor splice site, leading to exon skipping.

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