De novo missense mutation Y174S in exon 1 of the adrenoleukodystrophy (ALD) gene

AbstractMitochondrial dynamics such as fission and fusion play a vital role in normal brain development and neuronal activity. DNM1L encodes a dynamin-related protein 1 (Drp1), which is a GTPase essential for proper mitochondrial fission. The clinical phenotype of DNM1L mutations depends on the degree of mitochondrial fission deficiency, ranging from severe encephalopathy and death shortly after birth to initially normal development and then sudden onset of refractory status epilepticus with very poor neurologic outcome. We describe a case of a previously healthy 3-year-old boy with a mild delay in speech development until the acute onset of a refractory status epilepticus with subsequent epileptic encephalopathy and very poor neurologic outcome. The de novo missense mutation in DNM1L (c.1207C > T, p.R403C), which we identified in this case, seems to determine a unique clinical course, strikingly similar to four previously described patients in literature with the identical de novo heterozygous missense mutation in DNM1L.

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Extending the phenotype of Xia-Gibbs syndrome in a two-year-old patient with craniosynostosis with a novel de novo AHDC1 missense mutation

European Journal of Medical Genetics ◽

10.1016/j.ejmg.2019.03.001 ◽

2020 ◽

Vol 63 (1) ◽

pp. 103637 ◽

Cited By ~ 4

Author(s):

Evren Gumus

Keyword(s):

Missense Mutation ◽

De Novo

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A de novo missense mutation in the gene encoding the SOX10 transcription factor in a Spanish sporadic case of Waardenburg syndrome type IV

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.32181 ◽

2008 ◽

Vol 146A (8) ◽

pp. 1032-1037 ◽

Cited By ~ 17

Author(s):

Matías Morín ◽

Antonio Viñuela ◽

Teresa Rivera ◽

Manuela Villamar ◽

Miguel A. Moreno-Pelayo ◽

...

Keyword(s):

Transcription Factor ◽

Missense Mutation ◽

De Novo ◽

Sporadic Case ◽

Syndrome Type ◽

Waardenburg Syndrome ◽

Gene Encoding ◽

Type Iv

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Novel compound heterozygous EPG5 mutations consisted with a missense mutation and a microduplication in the exon 1 region identified in a Japanese patient with Vici syndrome

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.40500 ◽

2018 ◽

Vol 176 (12) ◽

pp. 2803-2807 ◽

Cited By ~ 2

Author(s):

Shino Shimada ◽

Kyoko Hirasawa ◽

Akiko Takeshita ◽

Hidetsugu Nakatsukasa ◽

Keiko Yamamoto-Shimojima ◽

...

Keyword(s):

Missense Mutation ◽

Japanese Patient ◽

Compound Heterozygous ◽

Exon 1

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A de novo missense mutation inSLC12A5found in a compound heterozygote patient with epilepsy of infancy with migrating focal seizures

Clinical Genetics ◽

10.1111/cge.13049 ◽

2017 ◽

Vol 92 (6) ◽

pp. 654-658 ◽

Cited By ~ 16

Author(s):

T. Saito ◽

A. Ishii ◽

K. Sugai ◽

M. Sasaki ◽

S. Hirose

Keyword(s):

Missense Mutation ◽

De Novo ◽

Compound Heterozygote ◽

Focal Seizures

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Identification of a Novel de Novo Variant in the SYT2 Gene Causing a Rare Type of Distal Hereditary Motor Neuropathy

Genes ◽

10.3390/genes11111238 ◽

2020 ◽

Vol 11 (11) ◽

pp. 1238

Author(s):

Olga Mironovich ◽

Elena Dadali ◽

Sergey Malmberg ◽

Tatyana Markova ◽

Oxana Ryzhkova ◽

...

Keyword(s):

Missense Mutation ◽

Clinical Presentation ◽

De Novo ◽

Clinical Manifestations ◽

Motor Neuropathy ◽

Rare Type ◽

Hereditary Motor ◽

Electrophysiological Testing ◽

Hereditary Motor Neuropathy ◽

De Novo Variant

Objective: To report the first de novo missense mutation in the SYT2 gene causing distal hereditary motor neuropathy. Methods: Genetic testing was carried out, including clinical exome sequencing for the proband and Sanger sequencing for the proband and his parents. We described the clinical and electrophysiological features found in the patient. Results: We reported a proband with a new de novo missense mutation, c.917C>T (p.Ser306Leu), in the C2B domain of SYT2. The clinical presentation was similar to that of phenotypes described in previous studies. A notable feature in our study was normal electrophysiological testing results of the patient. Conclusions: In this study we reinforced the association between SYT2 mutations and distal hereditary motor neuropathy. We also described the clinical presentation of the patient carrying this pathogenic variant and provided unusual results of electrophysiological testing. The results showed that a diagnosis of SYT2-associated neuropathy should be based on the similarity of clinical manifestations, rather than the results of electrophysiological testing.

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GEN-03 GENOTYPE-PHENOTYPE CORRELATION IN 111 FAMILIES OF VON HIPPEL-LINDAU DISEASE IN JAPAN

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz039.034 ◽

2019 ◽

Vol 1 (Supplement_2) ◽

pp. ii8-ii8

Author(s):

Hiroshi Kanno ◽

Tetsuya Yoshizumi ◽

Masamichi Shinonaga ◽

Masahiro Yao

Keyword(s):

Amino Acids ◽

Missense Mutation ◽

Splice Site ◽

Phenotype Correlation ◽

Exon 2 ◽

Endolymphatic Sac Tumor ◽

Von Hippel Lindau ◽

Genotype Phenotype Correlation ◽

Exon 1 ◽

Vhl Disease

Abstract BACKGROUND AND AIM von Hippel-Lindau (VHL) disease is a hereditary disease which manifest central nervous system (CNS) hemangioblastoma, retinal angioma, renal cell carcinoma (RCC), pheochromocytoma, endolymphatic sac tumor, and pancreas cyst. The VHL gene is located at 3p25.3 and is corresponding to 213 amino acids. Genotype-phenotype correlation analyses of VHL disease have been recently reported from several foreign countries, but the genotype-phenotype correlation has not been characterized since above 10 years ago. Therefore, this study aimed to evaluate the VHL mutation spectrum and genotype-phenotype correlations in Japanese VHL patients. METHODS Blood samples of 111 unrelated families of VHL disease were collected and DNAs were extracted. Direct sequencing and real-time PCR analysis were performed. Consequently, the clinical manifestations and family histories of the subjects were evaluated. RESULTS We identified VHL mutations as follows: missense 47; deletion 17; insertion 5; nonsense 8; splice-site 9; larger deletion 25. At hot-spot codon 167, 4 minsense mutations were identified, with Arg167Trp, 4 cases; Arg167Gln2, 2 cases. At codon 155, splice-site mutations were identified at 6 cases. Mutation sites were distributed in exon 1, 45; exon 2, 21; exon 3, 36. Large deletions were distributed in exon 1 & 2, 1; exon 2& 3, 1; all exons, 11. Genotype-phenotype correlation analysis revealed that age-specific risk and number of CNS hemangioblastoma were significantly higher in subjects carrying missense mutation within HIF-α binding site or non-missense mutation (P < 0.05). In addition, penetrance of RCC was significantly higher in subjects carrying non-missense mutation (P < 0.05). CONCLUSIONS The results of this study were similar to the previous foreign studies. This study provides insight into the genotype-phenotype correlation in that amino acids substitutions in the HIF- α binding and non-sense mutations may predispose VHL patients to age-related risk and number of CNS hemangioblastoma.

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A de novo missense mutation of the CYLD gene with multiple familial trichoepithelioma

Clinical and Experimental Dermatology ◽

10.1111/ced.14515 ◽

2020 ◽

Author(s):

W.‐X. Jia ◽

W.‐R. Li ◽

Y.‐D. Wu ◽

Y.‐Y. Zhang ◽

P. Cheng ◽

...

Keyword(s):

Missense Mutation ◽

De Novo ◽

Cyld Gene

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Epilepsy with a de novo missense mutation in the sodium channel a1 subunit: A case report

Acta Paediatrica ◽

10.1080/08035250600778628 ◽

2006 ◽

Vol 95 (12) ◽

pp. 1703-1706 ◽

Cited By ~ 2

Author(s):

Evangelia Stefanaki ◽

Vasiliki Aggelakou ◽

M. Orfanou ◽

E. Kokori ◽

S. Boutoufianakis

Keyword(s):

Case Report ◽

Sodium Channel ◽

Missense Mutation ◽

De Novo ◽

Subunit A

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Novel Mechanism of β0 Thalassemia: Missense Mutation of the Last Nucleotide of β Globin Exon 1 (G->C) Leads to Undetectable Transcript and Mutant Peptide.

Blood ◽

10.1182/blood.v108.11.1598.1598 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1598-1598

Author(s):

Neeraj Agarwal ◽

Mariluz P. Mojica-Henshaw ◽

Ferdane Kutlar ◽

Amos Gaikwad ◽

Ching N. Ou ◽

...

Keyword(s):

African American ◽

Missense Mutation ◽

Sickle Cell ◽

Globin Gene ◽

Enzyme Analysis ◽

African American Patient ◽

Globin Mrna ◽

Mutant Peptide ◽

Exon 1

Abstract Hemoglobin Monroe (Hb Monroe) results from a point mutation (G->C) in the last nucleotide of β globin exon 1, which is also the penultimate nucleotide of codon 30 of the β globin mRNA (AGG->ACG/Arg->Thr). Hb Monroe was described seventeen years ago simultaneously by two groups: in an African American female with β thalassemia intermedia, wherein the thalassemia was thought to result from highly unstable peptide (Hemoglobin.1989;13:67); and in a North African female with compound β thalassemia (Proc Natl Acad Sci U S A.1989;86:1041) wherein the Hb Monroe mutation was thought to result in abnormal pre-mRNA splicing as detected in an in vitro cell-free transcription assay. We evaluated a 31-year old previously asymptomatic woman of Asian Indian (Bengali) descent, who presented with flu like symptoms and found to have low hemoglobin level (9.5 gm/dL), microcytosis (MCV 68 fL), moderately elevated liver enzymes and serum ferritin concentration of 3000 ng/ml. A liver biopsy revealed increased liver iron and significant fibrosis. Hemoglobin analysis, which was interpreted as compound heterozygosity for HbE/β0 thalassemia, revealed HbF: 51%, HbE: 43.2%, HbA2: 5.8%. β globin gene sequencing showed Hb Monroe and E mutations. The asymptomatic brother of the proband had borderline anemia (Hb 12 gm %), microcytosis (MCV 70 fl), HbF: 8.5 %, HbA: 87.2%, HbA2: 5.0% and was heterozygous for Hb Monroe mutation by Bme 15801 restriction enzyme analysis of genomic DNA. We set out to determine the molecular basis of the thalassemia phenotype associated with Hb Monroe mutation and whether this mutation in our subjects is present on African haplotype or had arisen independently. Since we could not detect the mutant peptide either in fresh hemolysate or reticulocyte enriched preparations; we expanded the peripheral blood erythroid progenitor cells in vitro of both proband and her brother. Hemoglobin analysis by both HPLC and mass spectrophotometry did not detect Hb Monroe peptide in the expanded cells. β globin cDNA from the reticulocytes and expanded erythroid progenitors was amplified using three different primer sets and no splice variants were detectable. Sequencing of the amplified cDNA revealed only normal β globin mRNA transcript. Other β globin gene mutations cis to Hb Monroe are being ruled out; to date, we have not found any promoter region or stop codon mutations, deletions or splicing mutations from promoter - 90 region to 3′ UTR including poly-A region. Haplotype analysis revealed a different haplotype from the two African American patients, indicating an independent origin of Hb Monroe mutation in our cases. Interestingly, both of our cases have elevated HbF, as did the two originally reported Hb Monroe patients (16.5 and 85%) and a currently unreported African American patient with sickle cell - β0 thalassemia due to Hb Monroe (11.4%). Hb F was also high in a group of nine patients reported with sickle cell - β0 thalassemia due to Hb Monroe (3.1%– 8.9%; Hemoglobin.1998; 22:153). We conclude that this missense mutation, IVS1-1 (G->C/Arg 30 Thr) results in undetectable transcript and mutant Hb peptide leading to β0 thalassemia. The molecular mechanism of the undetectable mutant transcript is being investigated.

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