scholarly journals Evaluating the Clinical Utility of Genome Sequencing for Cytogenetically Balanced Chromosomal Abnormalities in Prenatal Diagnosis

2021 ◽  
Vol 11 ◽  
Author(s):  
Mullin Ho Chung Yu ◽  
Jeffrey Fong Ting Chau ◽  
Sandy Leung Kuen Au ◽  
Hei Man Lo ◽  
Kit San Yeung ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
Clinical Utility ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Genetic Material ◽  
Genetic Diagnosis ◽  
Pilot Project ◽  
Additional Information ◽  
Increased Risk ◽  
Gain Loss

Balanced chromosomal abnormalities (BCAs) are changes in the localization or orientation of a chromosomal segment without visible gain or loss of genetic material. BCAs occur at a frequency of 1 in 500 newborns and are associated with an increased risk of multiple congenital anomalies and/or neurodevelopmental disorders, especially if it is a de novo mutation. In this pilot project, we used short read genome sequencing (GS) to retrospectively re-sequence ten prenatal subjects with de novo BCAs and compared the performance of GS with the original karyotyping. GS characterized all BCAs found by conventional karyotyping with the added benefit of precise sub-band delineation. By identifying BCA breakpoints at the nucleotide level using GS, we found disruption of OMIM genes in three cases and identified cryptic gain/loss at the breakpoints in two cases. Of these five cases, four cases reached a definitive genetic diagnosis while the other one case had a BCA interpreted as unknown clinical significance. The additional information gained from GS can change the interpretation of the BCAs and has the potential to improve the genetic counseling and perinatal management by providing a more specific genetic diagnosis. This demonstrates the added clinical utility of using GS for the diagnosis of BCAs.

scholarly journals First Report of a de novo 10q23.31q23.33 Microdeletion: Obesity, Intellectual Disability and Microcephaly

2021 ◽  
pp. 1-5
Author(s):  
Ayberk Turkyilmaz ◽  
Erdal Kurnaz ◽  
Atilla Cayir
Keyword(s):  
Intellectual Disability ◽  
Array Cgh ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Autism Spectrum ◽  
Comparative Genomic ◽  
Facial Dysmorphism ◽  
Genetic And Environmental Factors

Intellectual disability (ID) is characterized by limited or insufficient development of mental abilities, including intellectual functioning impairments, such as learning and understanding cause-effect relationships. Some cases have ID as the only finding and are called isolated cases. Conversely, cases accompanied by facial dysmorphism, microcephaly, autism spectrum disorder, epilepsy, obesity, and congenital anomalies are called syndromic developmental delay (DD)/ID. Isolated and syndromic DD/ID cases show extreme genetic heterogeneity. Genetic etiology can be detected in approximately 40% of the cases, whereas chromosomal abnormalities are observed in 25%. Obesity is a multifactorial disease in which both genetic and environmental factors play important roles. The role of heredity in obesity has been reported to be between 40 and 70%. Array-based comparative genomic hybridization (array-CGH) can detect CNVs in the whole genome at a higher resolution than conventional cytogenetic methods. Array-CGH is currently recommended as the first-tier genetic test for ID cases worldwide. In the present study, we aimed to evaluate clinical, radiological, and genetic analyses of a 12-year and 4-month-old girl with microcephaly, ID, and obesity. In the array-CGH analysis, a 3.1-Mb deletion, arr[GRGh37] 10q23.31g23.33 (92745793_95937944)×1 was detected, and this alteration was evaluated to be pathogenic. We consider that haploinsufficiency of the candidate genes (<i>GPR120</i>, <i>KIF11</i>, <i>EXOC6</i>, <i>CYP26A1</i>, <i>CYP26C1</i>, and <i>LGI1</i>) in the deletion region may explain microcephaly, ID, obesity, seizures, and ophthalmological findings in our patient. The investigation of 10q23.31q23.33 microdeletion in cases with syndromic obesity may contribute to molecular genetic diagnosis.

scholarly journals The mutation spectrum in familial versus sporadic congenital cataract based on next-generation sequencing

2020 ◽  
Author(s):  
Fan Fan ◽  
Yi Luo ◽  
Jihong Wu ◽  
Chao Gao ◽  
Xin Liu ◽  
...  
Keyword(s):  
Congenital Cataract ◽  
De Novo ◽  
Genetic Diagnosis ◽  
Mutation Spectrum ◽  
Next Generation ◽  
De Novo Mutations ◽  
Additional Information ◽  
Significant Difference ◽  
Targeted Ngs ◽  
Sporadic Cases

Abstract Purpose Congenital cataract (CC) is a significant cause of lifelong visual loss. Its genetic diagnosis is challenging due to marked genetic heterogeneity. The purpose of this article is to report the genetic findings in sporadic and familial CC patients.Methods Patients (n=54) who were clinically diagnosed with CC and their parents were recruited. Blood samples were collected in our hospital. Mutations were detected by high-throughput, next-generation DNA sequencing (NGS) targeting 792 genes frequently involved in common inherited eye diseases.Results We identified variants in 11/38 cases (28.95%) of sporadic CC and 14/16 cases (87.5%) of familial CC, indicating a significant difference (P=0.000). Of the 14 variants identified in sporadic cases, 9 were previously reported mutations, and 5 were novel mutations, including 2 de novo mutations (CRYBB2 c.487C>T, FYCO1c.215A>T). The most frequent variants in our cohort were in crystallins and cytoskeletal genes (7/30, 23.33%), followed by X-linked syndromic proteins (13.33%) and transcriptional factors (10.00%). Additional information on the possibility of complications with inherited ocular or systemic diseases other than CC was provided in 20/30 (66.67%) variants.Conclusions These results contribute to expanding the mutation spectrum and frequency. Targeted NGS in CC provided significant diagnostic information and enabled more accurate genetic counseling. This study reports the different distributions of mutation genes in familial and sporadic CC cases.

It's time to include the assessment of the aberrant right subclavian artery as screening test on ultrasound examination at 18–21 weeks of gestation

2018 ◽  
Author(s):  
M.V. Medvedev, A.Yu. Blinov, N.A. Altynnik et all
Keyword(s):  
Risk Factors ◽  
Subclavian Artery ◽  
Gestational Age ◽  
Trisomy 21 ◽  
Chromosomal Abnormalities ◽  
Ultrasound Examination ◽  
Genetic Diagnosis ◽  
Invasive Procedure ◽  
Aberrant Right Subclavian Artery ◽  
Increased Risk

Aberrant right subclavian artery (ARSA) is the most common embryologic abnormality of the aortic arch. 3973 fetuses were examined by ultrasound at 12–34 weeks of gestation and 34 fetuses with ARSA (mean gestational age: 20.2 weeks) was identified in our centre. ARSA was assessed in the axial plane on the level of three vessels and trachea view. ARSA was an isolated finding in 19 (55.9%) fetuses and non-isolated in 15 (44.1 %) fetuses. 6 (17.6 %) of these of 34 were aneuploidies: Trisomy 21 was diagnosed in 5 fetuses, Trisomy 18 in 1 fetus. 22q11 microdeletion was detected in 1 fetus. No cases with chromosomal abnormalities were detected in all 19 fetuses with isolated ARSA. Isolated ARSA does not seem to be associated with a significantly increased risk of aneuploidy. When ARSA is identified a detailed anatomy scan should be recommended. An invasive procedure with genetic diagnosis should be discussed when additional ultrasound abnormalities or risk factors for aneuploidy are found. Prenatal ultrasound diagnosis of ARSA based on previously published cases are discussed.

scholarly journals Combining exome/genome sequencing with data repository analysis reveals novel gene–disease associations for a wide range of genetic disorders

2021 ◽  
Author(s):  
Aida M. Bertoli-Avella ◽  
Krishna K. Kandaswamy ◽  
Suliman Khan ◽  
Natalia Ordonez-Herrera ◽  
Kornelia Tripolszki ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
De Novo ◽  
Genetic Diagnosis ◽  
Data Repository ◽  
Data Repositories ◽  
Human Phenotype ◽  
Novel Gene ◽  
Published Evidence ◽  
Wide Range ◽  
Disease Associations

Abstract Purpose Within this study, we aimed to discover novel gene–disease associations in patients with no genetic diagnosis after exome/genome sequencing (ES/GS). Methods We followed two approaches: (1) a patient-centered approach, which after routine diagnostic analysis systematically interrogates variants in genes not yet associated to human diseases; and (2) a gene variant centered approach. For the latter, we focused on de novo variants in patients that presented with neurodevelopmental delay (NDD) and/or intellectual disability (ID), which are the most common reasons for genetic testing referrals. Gene–disease association was assessed using our data repository that combines ES/GS data and Human Phenotype Ontology terms from over 33,000 patients. Results We propose six novel gene–disease associations based on 38 patients with variants in the BLOC1S1, IPO8, MMP15, PLK1, RAP1GDS1, and ZNF699 genes. Furthermore, our results support causality of 31 additional candidate genes that had little published evidence and no registered OMIM phenotype (56 patients). The phenotypes included syndromic/nonsyndromic NDD/ID, oral–facial–digital syndrome, cardiomyopathies, malformation syndrome, short stature, skeletal dysplasia, and ciliary dyskinesia. Conclusion Our results demonstrate the value of data repositories which combine clinical and genetic data for discovering and confirming gene–disease associations. Genetic laboratories should be encouraged to pursue such analyses for the benefit of undiagnosed patients and their families.

Comparison of Thrombelastography with Common Coagulation Tests

1981 ◽  
Vol 46 (04) ◽  
pp. 752-756 ◽  
Author(s):  
L Zuckerman ◽  
E Cohen ◽  
J P Vagher ◽  
E Woodward ◽  
J A Caprini
Keyword(s):  
Laboratory Tests ◽  
Clinical Utility ◽  
Blood Clotting ◽  
Strong Relationship ◽  
Relative Strength ◽  
Additional Information ◽  
Patients With Cancer ◽  
Two Samples ◽  
Coagulation Tests ◽  
Common Laboratory

SummaryThrombelastography, although proven as a useful research tool has not been evaluated for its clinical utility against common coagulation laboratory tests. In this study we compare the thrombelastographic measurements with six common tests (the hematocrit, platelet count, fibrinogen, prothrombin time, activated thromboplastin time and fibrin split products). For such comparisons, two samples of subjects were selected, 141 normal volunteers and 121 patients with cancer. The data was subjected to various statistical techniques such as correlation, ANOVA, canonical and discriminant analysis to measure the extent of the correlations between the two sets of variables and their relative strength to detect blood clotting abnormalities. The results indicate that, although there is a strong relationship between the thrombelastographic variables and these common laboratory tests, the thrombelastographic variables contain additional information on the hemostatic process.

scholarly journals Effective variant filtering and expected candidate variant yield in studies of rare human disease

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Brent S. Pedersen ◽  
Joe M. Brown ◽  
Harriet Dashnow ◽  
Amelia D. Wallace ◽  
Matt Velinder ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Rare Disease ◽  
Genome Sequencing ◽  
Autosomal Dominant ◽  
De Novo ◽  
Autosomal Dominant Inheritance ◽  
Compound Heterozygous ◽  
Whole Genome ◽  
Dominant Inheritance ◽  
Family Based

AbstractIn studies of families with rare disease, it is common to screen for de novo mutations, as well as recessive or dominant variants that explain the phenotype. However, the filtering strategies and software used to prioritize high-confidence variants vary from study to study. In an effort to establish recommendations for rare disease research, we explore effective guidelines for variant (SNP and INDEL) filtering and report the expected number of candidates for de novo dominant, recessive, and autosomal dominant modes of inheritance. We derived these guidelines using two large family-based cohorts that underwent whole-genome sequencing, as well as two family cohorts with whole-exome sequencing. The filters are applied to common attributes, including genotype-quality, sequencing depth, allele balance, and population allele frequency. The resulting guidelines yield ~10 candidate SNP and INDEL variants per exome, and 18 per genome for recessive and de novo dominant modes of inheritance, with substantially more candidates for autosomal dominant inheritance. For family-based, whole-genome sequencing studies, this number includes an average of three de novo, ten compound heterozygous, one autosomal recessive, four X-linked variants, and roughly 100 candidate variants following autosomal dominant inheritance. The slivar software we developed to establish and rapidly apply these filters to VCF files is available at https://github.com/brentp/slivar under an MIT license, and includes documentation and recommendations for best practices for rare disease analysis.

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