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Molecular syndromology
S. Karger
Molecular syndromology

S. Karger

1661-8769

Molecular syndromology/Journal Molecular syndromologyESCISCI
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    Deep White Matter Cysts in a Patient with Aicardi-Goutières Syndrome and SAMHD1 Variants

    Martin,Poot
    3页
      原文链接:
    • NSTL
    • Karger

    Comprehensive Genetic Analysis of RASopathy in the Era of Next-Generation Sequencing and Definition of a Novel Likely Pathogenic KRAS Variation

    Selma,DemirHümeyra,Ya?ar K?stekAsl?han,Sanr?Ruken,Y?ld?r?m...
    11页
    查看更多>>摘要：Introduction: Germline pathogenic variations of the genes encoding the components of the Ras-MAPK pathway are found to be responsible for RASopathies, a clinically and genetically heterogeneous group of diseases. In this study, we aimed to present the results of patients genetically investigated for RASopathy-related mutations in our Genetic Diagnosis Center. Methods: The results of 51 unrelated probands with RASopathy and 4 affected relatives (31 male, 24 female; mean age: 9.327 ± 8.214) were included in this study. Mutation screening was performed on DNA samples from peripheral blood of the patients either by Sanger sequencing of PTPN11 hotspot regions (10/51 probands), or by a targeted amplicon next-generation sequencing panel (41/51 probands) covering the exonic regions of BRAF, CBL, HRAS, KRAS, LZTR1, MAP2K1, MAP2K2, NF1, NRAS, PTPN11, RAF1, RASA2, RIT1, SHOC2, SOS1, SOS2, SPRED1, and KAT6B genes. Results: Pathogenic/likely pathogenic variations found in 22 out of 51 probands (43.13%) and their 4 affected family members were located in PTPN11, BRAF, KRAS, NF1, RAF1, SOS1, and SHOC2 genes. The c.148A>C (p.Thr50Pro) variation in the KRAS gene was a novel variant detected in a sibling in our patient cohort. We found supportive evidence for the pathogenicity of the NF1 gene c.5606G>T (p.Gly1869Val) variation which we defined in an affected boy who inherited the mutation from his affected father. Conclusion: Although PTPN11 is the most frequently mutated gene in our patient cohort, as in most previous reports, different mutation distribution among the other genes studied motivates the use of a next-generation sequencing gene panel including the possible responsible genes.
      原文链接:
    • NSTL
    • Karger

    Evaluation of the Effect of FOXO3 rs13217795 Genotype and Minor Allele (C) on Clinical Chemistry and Genetic Risk of Diabetes Among the Elderly Individuals from Northern India

    Sartaj,HussainSuraj Singh,YadavMonisha,BanerjeeKauser,Usman...
    9页
    查看更多>>摘要：The forkhead box O family (FOXO) is expressed ubiquitously in a spatio-temporal manner and plays a key role in cellular metabolism, senescence, and aging. Genetic mutations in FOXO lead to metabolic diseases and cancer,and affect the longevity of individuals. Our study investigated how the genetic risk of type 2 diabetes mellitus (T2DM) altered due to an intronic variant rs13217795 of the longevity-associated FOXO3 gene in the geriatric population of North India. Genotypic characteristics of rs13217795 were determined among 347 age sex-matched (177 diabetic cases, 170 healthy controls) elderly individuals by TaqMan SNP assays after clinical assessment. Clinical chemistry and circulating cytokines level were assessed by biochemical and immunoassays. Genotype frequencies were not significantly (p = 0.526) different between cases and controls. The minor allele (C) frequency in diabetic cases and controls was 0.47 and 0.49, respectively (OR = 0.94, 95% CI = 0.69–1.26, p > 0.05). The minor allele was associated with lower fasting plasma glucose (FPG), fasting insulin, HOMA-IR, CRP, TNF-α, and IL-6 (p < 0.05). The homozygous minor allele carriers showed significantly lower levels of FPG, HOMA-IR, and TNF-α in T2DM patients. The minor allele (C) of intronic polymorphism in FOXO3 (rs13217795: T/C) confers the protective role characterized by its association with a decrease in glycemic and insulin resistance and proinflammatory markers.
      原文链接:
    • NSTL

    The Methylation Status in the Chromosome 11p15.5 Region and Metabolic Disorders in Children with Syndromic and Nonsyndromic Intrauterine Growth Restriction

    Emre,?zerFiliz,GeyikZeynep,Alp ünkarOya,Ercan...
    9页
    查看更多>>摘要：Loss of methylation (LoM) of the imprinting control region 1 (ICR1) in the chromosome 11p15.5 domain is detected in patients with Silver-Russell syndrome (SRS), characterized by asymmetric pre- and postnatal growth restriction, and typical craniofacial features. The patients with intrauterine growth restriction (IUGR) possess a high risk for adult metabolic problems. This study is aimed to investigate the methylation levels of the chromosome 11p15.5 region and metabolic problems in children with syndromic and nonsyndromic IUGR. Methylation analysis was performed for chromosome 11p15.5 in 49 patients (33 with suspected SRS and 16 nonsyndromic IUGR) with Netchine-Harbison clinical scoring (NHCS); uniparental disomy for chromosomes 6, 7, 14, and 20 was evaluated for those who were negative. LoM of ICR1 was detected in 14 of 33 suspected SRS patients with 3 or more criteria of NHCS, 5 had borderline LoM. Maternal uniparental disomy of the chromosomes 7 and 14 was found in 2 patients. The overall detection rate of SRS was 45.5%. While clinical findings were similar in patients with LoM and borderline LoM of ICR1, typical craniofacial findings were significantly less in the patients with normal methylation. Methylation patterns were not found to be impaired in the nonsyndromic IUGR group. Metabolic complications were evaluated in a total of 63 patients including 33 SRS-suspicious, 16 nonsyndromic IUGR, and 14 patients with 3M or SHORT syndrome. Increased rates of hypercalciuria, insulin resistance, and dyslipidemia were detected in patients with both syndromic and nonsyndromic IUGR. We would like to emphasize that detecting typical facial findings is effective in the diagnosis of SRS and paying attention to metabolic problems in the follow-up of patients with IUGR is recommended.
      原文链接:
    • NSTL
    • Karger

    Association SOD2 and PON1 Gene Polymorphisms with Polycystic Ovary Syndrome in Saudi Women

    Afrah F.,AlkhurijiSuliman Y.,AlOmarZainb A.,BabayManal F.,El-khadragy...
    6页
    查看更多>>摘要：Polycystic ovary syndrome (PCOS) is a considered one of the most common female disorders associated with reproductive, metabolic, and psychological problems. The etiology of PCOS is still not yet disclosed; however, evidence for a genetic basis has been reported. In this study, we investigate the associations between superoxide dismutase 2 (SOD2) (rs4880) and paraoxonase 1 (PON1) (rs705379) polymorphisms in PCOS in Saudi women. The study included 99 females with PCOS and 98 healthy women as a control. Single nucleotide polymorphisms (SNPs) of promoter regions were determined using TaqMan genotyping assays. Regarding the polymorphism at SOD2 (rs4880), the CC, CT, and TT genotypes were present at rates of 32, 61, and 7% in PCOS patients, and 47, 43, and 10% in controls, respectively. The frequency of the CT genotype in PCOS patients (0.61) was significantly higher than in controls (0.43) (OR = 2.05, CI: 1.16–3.61; p = 0.015). The wild homozygous genotype (CC) with the phenotype alanine appears to confer protection against the disease compared to molecules sharing at least one valine (genotypes, CT + TT). Regarding the polymorphism at PON1 (rs705379), the rates of CC, CT, and TT genotypes were 34, 50, and 16% in PCOS patients and 33, 63, and 2% in controls, respectively. The rate of the TT genotype in PCOS patients was significantly higher than that in controls (p = 0.0058). SOD2 and PON1 polymorphisms may be genetic factors that affect the occurrence of PCOS in Saudi females.
      原文链接:
    • NSTL
    • Karger

    Genetic Characterization of Hereditary Cancer Syndromes Based on Targeted Next-Generation Sequencing

    Pelin,ErcoskunCigdem,Yuce KahramanGuller,OzkanAbdulgani,Tatar...
    9页
    查看更多>>摘要：A hereditary cancer syndrome is a genetic predisposition to cancer caused by a germline mutation in cancer-related genes. Identifying the disease-causing variant is important for both the patient and relatives at risk in cancer families because this could be a guide in treatment and secondary cancer prevention. In this study, hereditary cancer panel harboring cancer-related genes was performed on MiSeq Illumina NGS system from peripheral blood samples. Sequencing files were fed into a cloud-based data analysis pipeline. Reportable variants were classified according to the American College of Medical Genetics and Genomics guidelines. Three hundred five individuals were included in the study. Different pathogenic/likely pathogenic variants were detected in 75 individuals. The majority of these variants were in the MUTYH, BRCA2, and CHEK2 genes. Nine novel pathogenic/likely pathogenic variants were identified in BRCA1, BRCA2, GALNT12, ATM, MLH1, MSH2, APC, and KIT genes. We obtained interesting and novel variants which could be related to hereditary cancer, and this study confirmed that NGS is an indispensable method for the risk assessment in cancer families.
      原文链接:
    • NSTL
    • Karger

    Aicardi-Goutières Syndrome due to a SAMHD1 Mutation Presenting with Deep White Matter Cysts

    Barbara,OleksyHanna,MierzewskaJolanta,TryfonMaria,Wypch?o...
    7页
    查看更多>>摘要：We report on the first Polish patient diagnosed with the Aicardi-Goutières syndrome 5 (AGS5). AGS is caused by mutations in one of 9 genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, IFIH, LSM11, RNU7-1) which stimulate the type I interferon response. The diagnosis was confirmed by identifying a compound heterozygous mutation p.(Phe165Ser)/p.(Gln235*) in the SAMHD1 gene using whole-exome sequencing. The cystic lesions in the temporal lobes are an uncommon finding in the presented patient carrying a SAMHD1 mutation. Reporting new cases expands the range of phenotypes and plays the crucial role in understanding the AGS pathogenesis and creates new therapy approaches.
      原文链接:
    • NSTL
    • Karger

    A Case of Combined Oxidative Phosphorylation Deficiency 35 Associated with a Novel Missense Variant of the TRIT1 Gene

    Mira?,Y?ld?r?m?mer,Bekta?Ebru,Tun?ezNur?ah,Yeniay Süt...
    7页
    查看更多>>摘要：Combined oxidative phosphorylation deficiency 35 (COXPD35) is a rare autosomal recessive disorder associated with homozygous or compound heterozygous mutations in the tRNA isopentenyltransferase (TRIT1) gene in chromosome 1p34.2. To date, only 10 types of allelic variants in the TRIT1 gene have been previously reported in 9 patients with COXPD35. Herein, we describe a case with a novel homozygous missense variant in TRIT1. A 6-year, 6-month-old boy presented with global developmental delay, microcephaly, intractable seizures, and failure to thrive. The other main clinical manifestations were intellectual disability, spastic tetraparesis, truncal hypotonia, malnutrition, polyuria and polydipsia, ketotic hypoglycemia, dysmorphic facial features, strabismus, bicuspid aortic valve, and nephrolithiasis. The detailed biochemical, radiological, and metabolic evaluations were unremarkable. Chromosomal analysis confirmed a normal male 46,XY karyotype and the array comparative genomic hybridization analysis revealed no abnormalities. We identified a novel homozygous missense variant of c.246G>C (p.Met82Ile) in the TRIT1 gene, and the variant was confirmed by Sanger sequencing. The present case is the first report describing strabismus, ketotic hypoglycemia, nephrolithiasis, and bicuspid aortic valve in TRIT1-related COXPD35. This study expands the genotype-phenotype spectrum of TRIT1-related COXPD35.
      原文链接:
    • NSTL
    • Karger

    An Atypical Presentation of Mevalonate Kinase Deficiency in Response to Colchicine Treatment

    Merve,Ko? YekedüzNeslihan,Do?uluümmühan,?ncülEngin,K?se...
    6页
    查看更多>>摘要：Mevalonate kinase deficiency (MKD) is a periodic fever syndrome. Nonsteroidal anti-inflammatory drugs, corticosteroids, and anakinra are the most common treatments. However, colchicine is considered insufficient in disease control. In this case report, we present an 8-month-old infant with an atypical presentation of MKD. She had recurrent fever episodes, diarrhea, and lethargy. Elevated mevalonic acid was not detected in the urine. However, the genetic investigation showed a novel pathogenic heterozygous c.925G>C (p.Gly309Arg) variant and a heterozygous c.1129G>A (p.Val377Ile) mutation in the MVK gene. The patient was treated with colchicine for 8 months. During treatment, no further fever episode had been observed. It should be kept in mind that mevalonic acid excretion may not be present in the urine with mild MKD. Colchicine may be a reasonable option in mild MKD patients for a longer duration of treatment due to favorable adverse event profiles.
      原文链接:
    • NSTL
    • Karger

    Xq21.1q21.31 Duplication in Two Male Siblings

    Charlotte Ann,Sherlaw-SturrockSarah,GrahamAnita,MorganLisa,Reali...
    7页
    查看更多>>摘要：Despite the increased use of array comparative genomic hybridisation, duplications of Xq remain rarely reported in the literature. Xq21.1q21.31 duplication has previously been reported only once in a boy with features of Prader Willi syndrome (PWS). We report 2 malesiblings with maternally inherited duplication of Xq21.1q21.31 who demonstrate a variable phenotype. The proband has Prader Willi-like features such as global developmental delay, autism, obesity, short hands, and small genitalia with a history of food seeking behaviour, while his younger brother has isolated speech delay with some autistic features under evaluation. Both siblings have features such as bitemporal narrowing and small hands. It is therefore likely that the phenotype of duplications in this region is broader than PWS phenocopy, and further cases would be required to elucidate this.
      原文链接:
    • NSTL
    • Karger