A novel germline GATA2 frameshift mutation with a premature stop codon in a family with congenital sensory hearing loss and myelodysplastic syndrome

Nonsyndromic hereditary hearing loss is a common sensory defect in humans that is clinically and genetically highly heterogeneous. So far, 122 genes have been associated with this disorder and 50 of them have been linked to autosomal dominant (DFNA) forms like DFNA68, a rare subtype of hearing impairment caused by disruption of a stereociliary scaffolding protein (HOMER2) that is essential for normal hearing in humans and mice. In this study, we report a novel HOMER2 variant (c.832_836delCCTCA) identified in a Spanish family by using a custom NGS targeted gene panel (OTO-NGS-v2). This frameshift mutation produces a premature stop codon that may lead in the absence of NMD to a shorter variant (p.Pro278Alafs*10) that truncates HOMER2 at the CDC42 binding domain (CBD) of the coiled-coil structure, a region that is essential for protein multimerization and HOMER2-CDC42 interaction. c.832_836delCCTCA mutation is placed close to the previously identified c.840_840dup mutation found in a Chinese family that truncates the protein (p.Met281Hisfs*9) at the CBD. Functional assessment of the Chinese mutant revealed decreased protein stability, reduced ability to multimerize, and altered distribution pattern in transfected cells when compared with wild-type HOMER2. Interestingly, the Spanish and Chinese frameshift mutations might exert a similar effect at the protein level, leading to truncated mutants with the same Ct aberrant protein tail, thus suggesting that they can share a common mechanism of pathogenesis. Indeed, age-matched patients in both families display quite similar hearing loss phenotypes consisting of early-onset, moderate-to-profound progressive hearing loss. In summary, we have identified the third variant in HOMER2, which is the first one identified in the Spanish population, thus contributing to expanding the mutational spectrum of this gene in other populations, and also to clarifying the genotype–phenotype correlations of DFNA68 hearing loss.

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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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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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Identification of Main Genetic Causes Responsible for Non-Syndromic Hearing Loss in a Peruvian Population

Genes ◽

10.3390/genes10080581 ◽

2019 ◽

Vol 10 (8) ◽

pp. 581 ◽

Cited By ~ 1

Author(s):

Figueroa-Ildefonso ◽

Bademci ◽

Rajabli ◽

Cornejo-Olivas ◽

Villanueva ◽

...

Keyword(s):

Hearing Loss ◽

Genetic Factors ◽

Stop Codon ◽

Premature Stop Codon ◽

Gjb2 Gene ◽

Pathogenic Variants ◽

Novel Variants ◽

Syndromic Hearing Loss ◽

Different Populations ◽

Global Population

: Hearing loss (HL) is a common sensory disorder affecting over 5% of the global population. The etiology underlying HL includes congenital and acquired causes; genetic factors are the main cause in over 50% of congenital cases. Pathogenic variants in the GJB2 gene are a major cause of congenital non-syndromic hearing loss (NSHL), while their distribution is highly heterogeneous in different populations. To the best of our knowledge, there is no data regarding the genetic etiologies of HL in Peru. In this study, we screened 133 Peruvian families with NSHL living in Lima. We sequenced both exons of the GJB2 gene for all probands. Seven probands with familial NSHL that remained negative for GJB2 variants underwent whole genome sequencing (WGS). We identified biallelic pathogenic variants in GJB2 in 43 probands; seven were heterozygous for only one allele. The c.427C>T variant was the most common pathogenic variant followed by the c.35delG variant. WGS revealed three novel variants in MYO15A in two probands, one of them was predicted to affect splicing and the others produce a premature stop codon. The Peruvian population showed a complex profile for genetic variants in the GJB2 gene, this particular profile might be a consequence of the admixture history in Peru.

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A novel homozygous frameshift mutation in the FUCA1 gene causes both severe and mild fucosidosis

Journal of Clinical Pathology ◽

10.1136/jclinpath-2018-205074 ◽

2018 ◽

Vol 71 (9) ◽

pp. 821-824 ◽

Cited By ~ 1

Author(s):

Nasrollah Saleh-Gohari ◽

Kolsoum Saeidi ◽

Roya Zeighaminejad

Keyword(s):

Next Generation Sequencing ◽

Frameshift Mutation ◽

Stop Codon ◽

Premature Stop Codon ◽

Gene Mutations ◽

Next Generation ◽

Lysosomal Storage ◽

Illumina Hiseq ◽

Almost All ◽

Generation Sequencing

AimsFucosidosis is a rare autosomal recessive lysosomal storage disorder caused by α-L-fucosidase deficiency as a result of FUCA1 gene mutations. Here, we studied clinical features and the molecular basis of fucosidosis in a family from Iran, including two probands and nine family members.MethodsDNA sample of two probands were screened for gene defects using a next generation sequencing technique. The sequencing processes were performed on an Illumina Hiseq 4000 platform. Sequence reads were analysed using BWA-GATK.ResultsNext generation sequencing revealed a frameshift mutation caused by 2 bp deletion (c.837_838 delTG; p.Cys279) in the FUCA1 gene. The identified mutation was tested in all participants. Homozygous patients had almost all the complications associated with fucosidosis, while heterozygous carriers were unaffected.ConclusionsThe variant c.837_838 delTG; p.Cys279 has not been reported previously and is predicted to be pathogenic due to a premature stop codon.

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A Frameshift Mutation in MC1R and a High Frequency of Somatic Reversions Cause Black Spotting in Pigs

Genetics ◽

10.1093/genetics/158.2.779 ◽

2001 ◽

Vol 158 (2) ◽

pp. 779-785 ◽

Cited By ~ 2

Author(s):

J M H Kijas ◽

M Moller ◽

G Plastow ◽

L Andersson

Keyword(s):

Frameshift Mutation ◽

Coat Color ◽

Stop Codon ◽

Phenotypic Expression ◽

Premature Stop Codon ◽

Black Spot ◽

White Background ◽

Coding Region ◽

Black Spots ◽

Color Sequence

Abstract Black spotting on a red or white background in pigs is determined by the EP allele at the MC1R/Extension locus. A previous comparison of partial MC1R sequences revealed that EP shares a missense mutation (D121N) with the ED2 allele for dominant black color. Sequence analysis of the entire coding region now reveals a second mutation in the form of a 2-bp insertion at codon 23 (nt67insCC). This mutation expands a tract of six C nucleotides to eight and introduces a premature stop codon at position 56. This frameshift mutation is expected to cause a recessive red color, which was in fact observed in some breeds with the EP allele present (Tamworth and Hereford). RT-PCR analyses were conducted using skin samples taken from both spotted and background areas of spotted pigs. The background red area had transcript only from the mutant nt67insCC MC1R allele, whereas the black spot also contained a transcript without the 2-bp insertion. This indicates that black spots are due to somatic reversion events that restore the frame and MC1R function. The phenotypic expression of the EP allele is highly variable and the associated coat color ranges from red, red with black spots, white with black spots, to almost completely solid black. In several breeds of pigs the phenotypic manifestation of this allele has been modified by selection for or against black spots.

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Mutation detection and prenatal diagnosis of XLHED pedigree

PeerJ ◽

10.7717/peerj.3691 ◽

2017 ◽

Vol 5 ◽

pp. e3691 ◽

Cited By ~ 4

Author(s):

Yao Lin ◽

Wei Yin ◽

Zhuan Bian

Keyword(s):

Prenatal Diagnosis ◽

Structural Changes ◽

Frameshift Mutation ◽

Stop Codon ◽

Direct Sequencing ◽

Premature Stop Codon ◽

Deciduous Teeth ◽

Chinese Family ◽

Female Carrier ◽

Causative Gene

Background The phenotypic characters of X -linked Hypohidrotic Ectodermal Dysplasia (XLHED) are the dysplasia of epithelial- and mesenchymal-derived organs. Ectodysplasin (EDA) is the causative gene of XLHED. Methods The current study reported a large Chinese XLHED pedigree. The genomic DNA of adult and fetus was extracted from peripheral blood and shed chorion cell respectively. The nucleotide variation in EDA gene was screened through direct sequencing the coding sequence. The methylation state of EDA gene’s promoter was evaluated by pyrosequencing. Results This Chinese XLHED family had two male patients and three carriers. All of them were with a novel EDA frameshift mutation. The mutation, c.172-173insGG, which leads to an immediate premature stop codon in exon one caused severe structural changes of EDA. Prenatal diagnosis suggested that the fetus was a female carrier. The follow-up observation of this child indicated that she had mild hypodontia of deciduous teeth at age six. The methylation level of EDA gene’s promoter was not related to carriers’ phenotype changes in this family. Discussion We reported a new frameshift mutation of EDA gene in a Chinese family. Prenatal diagnosis can help to predict the disease status of the fetus.

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A Novel PORCN Frameshift Mutation Leading to Focal Dermal Hypoplasia: A Case Report

Cytogenetic and Genome Research ◽

10.1159/000487580 ◽

2018 ◽

Vol 154 (3) ◽

pp. 119-121

Author(s):

Ceren D. Durmaz ◽

John McGrath ◽

Lu Liu ◽

Halil G. Karabulut

Keyword(s):

Case Report ◽

Frameshift Mutation ◽

Stop Codon ◽

Novel Mutation ◽

Premature Stop Codon ◽

Clinical Findings ◽

Gorlin Syndrome ◽

Focal Dermal Hypoplasia ◽

Skeletal Defects ◽

The Right

Focal dermal hypoplasia (FDH), also known as Goltz-Gorlin syndrome, is a rare, multisystemic, X-linked dominant genodermatosis characterized by defective development of mesodermal and ectodermal tissues. Major clinical features of the disorder are skin manifestations, skeletal defects, and developmental eye abnormalities. FDH is caused by heterozygous mutations in the PORCN gene located at Xp11.23, and 90% of individuals with FDH are females. Here, we report a female patient with cutaneous changes, multiple eye anomalies, short stature, and ectrodactyly of the right foot. These clinical findings were compatible with the diagnosis of FDH, and a novel mutation, NM_022825.3:c.488delG was found in the PORCN gene causing a premature stop codon.

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Molecular characterization of pathogenic OTOA gene conversions in hearing loss patients

10.22541/au.160034228.86260436/v2 ◽

2021 ◽

Author(s):

Sacha Laurent ◽

Corinne Gehrig ◽

Thierry Nouspikel ◽

Sami S Amr ◽

Andrea Oza ◽

...

Keyword(s):

Hearing Loss ◽

Stop Codon ◽

Premature Stop Codon ◽

Allelic Loss ◽

Loss Of Function ◽

Chain Reactions ◽

Polymerase Chain Reactions ◽

Long Read ◽

Gene Conversions

Bi-allelic loss-of-function variants of OTOA are a well-known cause of moderate-to-severe hearing loss. Whereas non-allelic homologous recombination-mediated deletions of the gene are well known, gene conversions to pseudogene OTOAP1 have been reported in the literature but never fully described nor their pathogenicity assessed. Here, we report two unrelated patients with moderate hearing-loss, who were compound heterozygotes for a converted allele and a deletion of OTOA. The conversions were initially detected through sequencing depths anomalies at the OTOA locus after exome sequencing, then confirmed with long range polymerase chain reactions. Both conversions lead to loss-of-function by introducing a premature stop codon in exon 22 (p.Glu787*). Using genomic alignments and long read nanopore sequencing, we found that the two probands carry stretches of converted DNA of widely different lengths (at least 9 kbp and around 900 bp, respectively).

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