Novel frameshift variant (c.409dupG) in SLC25A38 is a common cause of congenital sideroblastic anaemia in the Indian subcontinent

2020 ◽  
pp. jclinpath-2020-206647
Author(s):  
Niveditha Ravindra ◽  
Rekha Athiyarath ◽  
Eswari S ◽  
Sumithra S ◽  
Uday Kulkarni ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Indian Subcontinent ◽  
Nucleotide Polymorphisms ◽  
Rare Disorders ◽  
Phenotype Correlation ◽  
Single Nucleotide ◽  
Pathogenic Variants ◽  
Sideroblastic Anaemia ◽  
Ring Sideroblasts ◽  
Quantify Gene Expression

AimsCongenital sideroblastic anaemias (CSAs) are a group of rare disorders with the presence of ring sideroblasts in the bone marrow. Pathogenic variants are inherited in an autosomal recessive/X-linked fashion. The study was aimed at characterising the spectrum of mutations in SLC25A38 and ALAS2 genes in sideroblastic anaemia patients, exploring the genotype-phenotype correlation and identifying the haplotype associated with any recurrent mutation.Patients and methodsTwenty probable CSA patients were retrospectively analysed for genetic variants in ALAS2 and SLC25A38 genes by direct bidirectional sequencing. Real-time PCR was used to quantify gene expression in a case with promoter region variant in ALAS2. Three single nucleotide polymorphisms were used to establish the haplotype associated with a recurrent variant in the SLC25A38 gene.ResultsSix patients had causative variants in ALAS2 (30%) and 11 had variants in SLC25A38 (55%). The ALAS2 mutated cases presented at a significantly later age than the SLC25A38 cases. A frameshift variant in SLC25A38 (c.409dupG) was identified in six unrelated patients and was a common variant in our population exhibiting ‘founder effect’.ConclusionThis is the largest series of sideroblastic anaemia cases with molecular characterisation from the Indian subcontinent.

scholarly journals Audiological features in Serbian patients with hearing impairment identified with c.35delG in the GJB2 gene

2021 ◽  
pp. 98-98
Author(s):  
Bojana Dobric ◽  
Danijela Radivojevic ◽  
Jovana Jecmenica ◽  
Vassos Neocleous ◽  
Pavlos Fanis ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hearing Impairment ◽  
Autosomal Recessive ◽  
Gjb2 Gene ◽  
Compound Heterozygous ◽  
Heterozygous State ◽  
Phenotype Correlation ◽  
Pathogenic Variants ◽  
Environmental Causes ◽  
35Delg Mutation

Introduction/Objective. Hearing impairment (HI) is the most common sensorineural disorder with an incidence of 1/700-1000 newborns. Variants in the GJB2 gene are the major cause of autosomal recessive nonsyndromic sensorineural hearing loss (ARNSHL). The degree of HI in patients with detected mutations in GJB2 gene ranges from mild to profound. The aim of this study was to determine possible genotype-phenotype association between audiometric characteristics and detected genotypes in ARNSHL patients from Serbia. Methods. Ninety-two patients with ARNSHL underwent genetic analysis with PCR-ARMS and sequencing of the GJB2 gene. Audiological analyses were obtained in all patients using a combination of several methods to estimate the degree of hearing loss. Results. Audiological analysis performed in the 92 probands showed moderate to profound range of hearing loss. All identified pathogenic variants accounted for 42.39% of the mutant alleles (78/184 alleles), with the c.35delG mutation being the most frequent (30.43%). Genotype-phenotype correlation in an isolated group of 37 patients bearing c.35delG in the homozygous, compound heterozygous or heterozygous state. In this group the majority of patients (30/37, 81.08%) exhibited severe to profound hearing deficit. Conclusion. Association between genotype and the degree of hearing impairment in patients analyzed in this study demonstrated that patients with bi-allelic truncating mutations i.e. c.35delG, associate with the more severe hearing loss when compared with those identified with only one affected allele. The various degrees of hearing impairment observed in heterozygous patients could be explained by the presence of an undetected second mutation or other modifier genes or environmental causes.

scholarly journals Discovery of BRCA1/BRCA2 Founder Variants by Haplotype Analysis

2021 ◽  
Author(s):  
Won Kyung Kwon ◽  
Hyeok-Jae Jang ◽  
Jeong Eon Lee ◽  
Yeon Hee Park ◽  
Jai Min Ryu ◽  
...  
Keyword(s):  
Linkage Disequilibrium ◽  
Single Nucleotide Polymorphisms ◽  
Haplotype Analysis ◽  
Medical Center ◽  
Korean Population ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Pathogenic Variants ◽  
Ovarian Cancers ◽  
Brca1 Brca2

Abstract A significant number of hereditary breast or ovarian cancers are caused by germline variants, mostly BRCA1/BRCA2 genes. Because genetic predispositions vary by ethnicity, several studies have reported founder variants of BRCA1/BRCA2 genes. Such founder variants were reported primarily based on their relevant population frequencies. We reviewed the variant data relating to BRCA1 and BRCA2 genes from January, 2012 to March 2019 at Samsung Medical Center, Seoul, Korea. Among the cases with pathogenic variants (PVs) or likely pathogenic variants (LPVs), we defined recurrent variants as those found in more than five unrelated patients. Using single nucleotide polymorphisms, we analyzed patient haplotypes. There were 14 recurrent variants in the BRCA1 gene and seven variants in the BRCA2 gene. Of note, three variants in each gene were primarily detected in Korean populations. Among them, the c.5339T > C BRCA1 variant had a long block sized 74.5 kb. In BRCA2, the c.1399A > T variant had a long block sized 35.5 kb. We suggest that BRCA1 c.5339T > C and BRCA2 c.1399A > T are founder variants of the Korean population. These two recurrent variants were ethnicity-prevalent, primarily found in Korean populations, and the sizes of the linkage disequilibrium blocks are longer than others.

scholarly journals Molecular analyses in Indonesian individuals with intellectual disability and microcephaly

2013 ◽  
Vol 53 (2) ◽  
pp. 83
Author(s):  
Farmaditya EP Mundhofir ◽  
Rahajeng N Tunjungputri ◽  
Willy M Nillesen ◽  
Bregje WM Van Bon ◽  
Martina Ruiterkamp-Versteeg ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Autosomal Recessive ◽  
Brain Size ◽  
Fragile X ◽  
Monozygotic Twin ◽  
Regulatory Subunit ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Pathogenic Mutations ◽  
Subtelomeric Deletion

Background Intellectual disability (ID) often coincides with anabnormal head circumference (HC). Since the HC is a reflectionof brain size, abnormalities in HC may be a sign of a brain anomaly.Although microcephaly is often secondary to ID, hereditary(autosomal recessive) forms of primary microcephaly (MCPH)exist that result in ID.Objective To investigate mutations in MCPH genes in patientswith ID and microcephaly.Methods From a population of 527 Indonesian individuals withID, 48 patients with microcephaly (9.1 %) were selected. Thesepatients were previously found to be normal upon conventionalkaryotyping, fragile X mental retardation 1 (FMRl) gene analysis,subtelomeric deletion, and duplication multiplex ligationdependentprobe amplification (MLPA). Sanger sequencing forabnormal spindle-like microcephaly-associated (ASPM) and WDrepeat domain 62 (WDR62) was performed in all 48 subjects, whilesequencing for microcephalin (MCPHl), cyclin-dependent kinase5 (CDK5) regulatory subunit-associated protein 2 (CD5KRAP2) ,centromere protein} (CENPJ), and SCUfALl interrupting locus(STIL) was conducted in only the subjects with an orbitofrontalcortex (OFC) below -4 SD.Results In all genes investigated, 66 single nucleotide polymorphisms(SNPs) and 15 unclassified variants which were predictedas unlikely to be pathogenic (lN2), were identified. Possiblepathogenic variants (lN3) were identified in ASPM. However,since none of the patients harboured compound heterozygouslikely pathogenic mutations, no molecular MCPH diagnosis couldbe established. Interestingly, one of the patients harboured thesame variants as her unaffected monozygotic twin sister, indicatingthat our cohort included a discordant twin.Conclusions This study is the first to investigate for possible geneticcauses ofMCPH in the Indonesian population. The absenceof causative pathogenic mutations in the MCPH genes tested may originate from several factors. The identification of UV2and UV3 variants as well as the absence of causative pathogenicmutations calls for further investigations.

Clinical and molecular characteristics and time of diagnosis of patients with classical galactosemia in an unscreened population in Turkey

2019 ◽  
Vol 32 (7) ◽  
pp. 675-681
Author(s):  
Pelin Teke Kisa ◽  
Melis Kose ◽  
Ozlem Unal ◽  
Esra Er ◽  
Burcu Ozturk Hismi ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Autosomal Recessive ◽  
Screening Program ◽  
Clinical Manifestations ◽  
Geographical Location ◽  
Molecular Characteristics ◽  
Phenotype Correlation ◽  
Classical Galactosemia ◽  
Pathogenic Variants ◽  
Turkish Patients

Abstract Classical galactosemia is an autosomal recessive inborn error of metabolism caused by biallelic pathogenic variants in the GALT gene. With the benefit of early diagnosis by newborn screening, the acute presentation of galactosemia can be prevented. In this study, we describe the clinical phenotypes, time of diagnosis and GALT genotypes of 76 galactosemia patients from Turkey, where the disease is not yet included in the newborn screening program. The median age at first symptom was 10 days (range 5–20), while the median age at diagnosis was 30 days (range 17–53). Nearly half of the patients (36 patients, 47.4%) were diagnosed later than age 1 month. Fifty-eight individuals were found to have 18 different pathogenic variants in their 116 mutant alleles. In our sample, Q188R variant has the highest frequency with 53%, the other half of the allele frequency of the patients showed 17 different genotypes. Despite presenting with typical clinical manifestations, classical galactosemia patients are diagnosed late in Turkey. Due to the geographical location of our country, different pathogenic GALT variants may be seen in Turkish patients. In the present study, a clear genotype-phenotype correlation could not be established in patients.

scholarly journals Identification of Single-Nucleotide Polymorphisms in the Mitochondrial Genome and Kelch 13 Gene of Plasmodium falciparum in Different Geographical Populations

2021 ◽  
Author(s):  
Tine Kliim Nydahl ◽  
Samuel Yao Ahorhorlu ◽  
Magatte Ndiaye ◽  
Manoj Kumar Das ◽  
Helle Hansson ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Mitochondrial Genome ◽  
Single Nucleotide Polymorphisms ◽  
Indian Subcontinent ◽  
Artemisinin Resistance ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genome Data ◽  
Geographical Populations ◽  
Well Differentiated

The emergence of artemisinin-resistant Plasmodium falciparum parasites in Southeast Asia threatens malaria control and elimination. The interconnectedness of parasite populations may be essential to monitor the spread of resistance. Combining a published barcoding system of geographically restricted single-nucleotide polymorphisms (SNPs), mainly mitochondria of P. falciparum with SNPs in the K13 artemisinin resistance marker, could elucidate the parasite population structure and provide insight regarding the spread of drug resistance. We explored the diversity of mitochondrial SNPs (bp position 611-2825) and identified K13 SNPs from malaria patients in the districts of India (Ranchi), Tanzania (Korogwe), and Senegal (Podor, Richard Toll, Kaolack, and Ndoffane). DNA was amplified using a nested PCR and Sanger-sequenced. Overall, 199 K13 sequences (India: N = 92; Tanzania: N = 48; Senegal: N = 59) and 237 mitochondrial sequences (India: N = 93; Tanzania: N = 48; Senegal: N = 96) were generated. SNPs were identified by comparisons with reference genomes. We detected previously reported geographically restricted mitochondrial SNPs (T2175C and G1367A) as markers for parasites originating from the Indian subcontinent and several geographically unrestricted mitochondrial SNPs. Combining haplotypes with published P. falciparum mitochondrial genome data suggested possible regional differences within India. All three countries had G1692A, but Tanzanian and Senegalese SNPs were well-differentiated. Some mitochondrial SNPs are reported here for the first time. Four nonsynonymous K13 SNPs were detected: K189T (India, Tanzania, Senegal); A175T (Tanzania); and A174V and R255K (Senegal). This study supports the use of mitochondrial SNPs to determine the origin of the parasite and suggests that the P. falciparum populations studied were susceptible to artemisinin during sampling because all K13 SNPs observed were outside the propeller domain for artemisinin resistance.

scholarly journals Informativeness of Single Nucleotide Polymorphisms and Relationships among Onion Populations from Important World Production Regions

2018 ◽  
Vol 143 (1) ◽  
pp. 34-44 ◽  
Author(s):  
Michael J. Havey ◽  
Farhad Ghavami
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Indian Subcontinent ◽  
Genetic Relationships ◽  
Inbred Lines ◽  
Nucleotide Polymorphisms ◽  
Eastern Asia ◽  
Single Nucleotide ◽  
European Origin ◽  
Polymorphic Snps ◽  
America South

Single nucleotide polymorphisms (SNPs) were genotyped using a high-density array and DNAs from individual plants of important onion (Allium cepa L.) populations from major production regions and from the likely progenitor of onion, Allium vavilovii Popov et Vved. Genotypes at 1226 SNPs were used to estimate genetic relationships among these populations and revealed close associations among onions grown in Europe and those in North America, South America, and eastern Asia, supporting paths of introduction from Europe to the Americas and Asia. ‘Nasik Red’ is a population grown on the Indian subcontinent and was divergent from onions of European origin. Frequencies of SNPs among and within populations were used as a measure of informativeness, and 199 commonly polymorphic SNPs were identified distributed across the eight chromosomes of onion. These SNPs will be useful for estimations of relatedness among broader collections of onion populations, mapping of important phenotypes, fingerprinting of inbred lines and hybrids, and quality control of seed lots.

scholarly journals Polymorphisms in MEN1 and DRD2 genes are associated with the occurrence and characteristics of pituitary adenomas

2016 ◽  
Vol 175 (2) ◽  
pp. 145-153 ◽  
Author(s):  
Raitis Peculis ◽  
Inga Balcere ◽  
Vita Rovite ◽  
Kaspars Megnis ◽  
Andra Valtere ◽  
...  
Keyword(s):  
Pituitary Adenomas ◽  
Clinical Symptoms ◽  
Significant Proportion ◽  
Mass Effect ◽  
Nucleotide Polymorphisms ◽  
Phenotype Correlation ◽  
Single Nucleotide ◽  
Hormonal Imbalance ◽  
Genomic Regions

Objective Although pituitary adenomas (PAs) affect a significant proportion of the population, only a fraction have the potential to become clinically relevant during an individual’s lifetime, causing hormonal imbalance or complications due to mass effect. The overwhelming majority of cases are sporadic and without a clear familial history, and the genotype–phenotype correlation in PA patients is poorly understood. Our aim was to investigate the involvement of genes known for their role in familial cases on drug response and tumor suppression in the development and pathology of PAs in a patient group from Latvia. Design The study included 143 cases and 354 controls, we investigated the role of single-nucleotide polymorphisms (SNPs) in seven genes (SSTR2, SSTR5, DRD2, MEN1, AIP, GNAS, and PRKAR1A) associated with pituitary tumor occurrence, phenotype, and clinical symptoms. Methods Genotyping of 96 tag and nonsynonymous SNPs was performed in the genomic regions of interest. Results We discovered a significant association (OR=17.8, CI 0.95=2.18–145.5, P=0.0002) between a rare MEN1 mutation (rs2959656) and clinically active adenoma in our patients. Additionally, rs7131056 at DRD2 was associated with a higher occurrence of extrasellar growth in patients with prolactinoma and somatotropinoma (OR=2.79, CI 0.95=1.58–4.95, P=0.0004). Conclusions rs2959656, a nonsynonymous variant in MEN1, is associated with the development of clinically active PA. Furthermore, rs7131056 in DRD2 contributes to either faster growth of the adenoma or reduced symptomatic presentation, allowing PAs to become larger before detection.

scholarly journals Single Nucleotide Polymorphisms of theGJB2andGJB6Genes Are Associated with Autosomal Recessive Nonsyndromic Hearing Loss

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Ana Paula Grillo ◽  
Flávia Marcorin de Oliveira ◽  
Gabriela Queila de Carvalho ◽  
Ruan Felipe Vieira Medrano ◽  
Sueli Matilde da Silva-Costa ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Single Nucleotide Polymorphisms ◽  
Autosomal Recessive ◽  
Nucleotide Polymorphisms ◽  
Nonsyndromic Hearing Loss ◽  
Single Nucleotide ◽  
Specific Pcr ◽  
Sequence Variations ◽  
Allele Specific ◽  
Allele Specific Pcr

Single nucleotide polymorphisms (SNPs) are important markers in many studies that link DNA sequence variations to phenotypic changes; such studies are expected to advance the understanding of human physiology and elucidate the molecular basis of diseases. TheDFNB1locus, which contains theGJB2andGJB6genes, plays a key role in nonsyndromic hearing loss. Previous studies have identified important mutations in this locus, but the contribution of SNPs in the genes has not yet been much investigated. The aim of this study was to investigate the association of nine polymorphisms located within theDFNB1locus with the occurrence of autosomal recessive nonsyndromic hearing loss (ARNSHL). The SNPs rs3751385 (C/T), rs7994748 (C/T), rs7329857 (C/T), rs7987302 (G/A), rs7322538 (G/A), rs9315400 (C/T), rs877098 (C/T), rs945369 (A/C), and rs7333214 (T/G) were genotyped in 122 deaf patients and 132 healthy controls using allele-specific PCR. There were statistically significant differences between patients and controls, in terms of allelic frequencies in the SNPs rs3751385, rs7994748, rs7329857, rs7987302, rs945369, and rs7333214 (P<0.05). No significant differences between the two groups were observed for rs7322538, rs9315400, and rs877098. Our results suggest that SNPs present in theGJB2andGJB6genes may have an influence on ARNSHL in humans.

scholarly journals Predicting the Most Deleterious Missense Nonsynonymous Single-Nucleotide Polymorphisms of Hennekam Syndrome-Causing CCBE1 Gene, In Silico Analysis

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Khyber Shinwari ◽  
Liu Guojun ◽  
Svetlana S. Deryabina ◽  
Mikhail A. Bolkov ◽  
Irina A. Tuzankina ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
In Silico ◽  
Calcium Binding ◽  
Phosphorylation Site ◽  
In Silico Analysis ◽  
Matrix Remodeling ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Pathogenic Variants ◽  
Hennekam Syndrome

Hennekam lymphangiectasia-lymphedema syndrome has been linked to single-nucleotide polymorphisms in the CCBE1 (collagen and calcium-binding EGF domains 1) gene. Several bioinformatics methods were used to find the most dangerous nsSNPs that could affect CCBE1 structure and function. Using state-of-the-art in silico tools, this study examined the most pathogenic nonsynonymous single-nucleotide polymorphisms (nsSNPs) that disrupt the CCBE1 protein and extracellular matrix remodeling and migration. Our results indicate that seven nsSNPs, rs115982879, rs149792489, rs374941368, rs121908254, rs149531418, rs121908251, and rs372499913, are deleterious in the CCBE1 gene, four (G330E, C102S, C174R, and G107D) of which are the highly deleterious, two of them (G330E and G107D) have never been seen reported in the context of Hennekam syndrome. Twelve missense SNPs, rs199902030, rs267605221, rs37517418, rs80008675, rs116596858, rs116675104, rs121908252, rs147974432, rs147681552, rs192224843, rs139059968, and rs148498685, are found to revert into stop codons. Structural homology-based methods and sequence homology-based tools revealed that 8.8% of the nsSNPs are pathogenic. SIFT, PolyPhen2, M-CAP, CADD, FATHMM-MKL, DANN, PANTHER, Mutation Taster, LRT, and SNAP2 had a significant score for identifying deleterious nsSNPs. The importance of rs374941368 and rs200149541 in the prediction of post-translation changes was highlighted because it impacts a possible phosphorylation site. Gene-gene interactions revealed CCBE1’s association with other genes, showing its role in a number of pathways and coexpressions. The top 16 deleterious nsSNPs found in this research should be investigated further in the future while researching diseases caused CCBE1 gene specifically HS. The FT web server predicted amino acid residues involved in the ligand-binding site of the CCBE1 protein, and two of the substitutions (R167W and T153N) were found to be involved. These highly deleterious nsSNPs can be used as marker pathogenic variants in the mutational diagnosis of the HS syndrome, and this research also offers potential insights that will aid in the development of precision medicines. CCBE1 proteins from Hennekam syndrome patients should be tested in animal models for this purpose.

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