Use of medical exome sequencing for identification of underlying genetic defects in NICU : experience in a cohort of 2,303 neonates in China

Prenatal screening and diagnosis are increasingly becoming a part of medical practice. Prenatal screening can reduce the incidence of birth defects which cause morbidity and mortality in newborns. With emerging technologies, now it is possible to diagnose the genetic basis of birth defects more accurately in the prenatal period for early management. Different approaches are available for detecting genetic defects at different levels like karyotyping, chromosomal microarrays and Sanger sequencing. However, many cases still remain undiagnosed. Next generation sequencing has revolutionized the field of genetics that can detect genetic defects at the level of a single base pair. It includes both whole exome sequencing (WES) and whole genome sequencing (WGS). WES has particularly accelerated the discovery of disease-causing variants in many monogenic anomalies postnatally. Research is being conducted on the use of whole exome sequencing in the prenatal diagnostics of genetic anomalies detected by ultrasound. It is a more efficient way of getting an insight into the molecular basis of birth defects compared with conventional genetic approaches. However, technical and ethical issues need to be addressed before introducing this technique into routine prenatal clinical practice. Fetal cell sampling is done by invasive medical procedures like amniocentesis or chorionic villus sampling. However, noninvasive strategy of collecting fetal DNA from maternal plasma is an exciting and emerging domain. It is evident that in the coming years, we shall be able to use these techniques in the routine clinical setting and to improve the diagnosis and management of birth disorders during prenatal period.

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Phenotypic Heterogeneity and Genotypic Spectrum of Primary Immunodeficiencies with Whole Exome Sequencing in a Thai Patient Cohort

10.22541/au.162826615.59279018/v1 ◽

2021 ◽

Author(s):

Maliwan Tengsujaritkul ◽

Narissara Suratannon ◽

Chupong Ittiwut ◽

Rungnapa Ittiwut ◽

Pantipa Chatchatee ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Clinical Decision Making ◽

Diagnostic Yield ◽

Disease Onset ◽

Clinical Manifestations ◽

Genetic Defects ◽

Diagnostic Strategy ◽

Patient Cohort ◽

Whole Exome

Background: Primary immunodeficiency diseases (PIDs) comprise more than 400 rare diseases with potential life-threatening conditions. Clinical manifestations and genetic defects are heterogeneous and diverse among populations. Here, we aimed to characterize the clinical, immunological and genetic features of Thai pediatric patients with PIDs. The use of whole exome sequencing (WES) in diagnosis and clinical decision making was also assessed. Methods: 36 unrelated patients with clinical and laboratory findings consistent with PIDs were recruited from January 2010 to December 2020. WES was performed to identify the underlying genetic defects. Results: The median age of disease onset was 4 months (range; 1 month to 13 years) and 24 were male (66.7%). Recurrent sinopulmonary tract infection was the most common clinical presentation followed by septicemia, and severe pneumonia. Using WES, we successfully identified the underlying genetic defects in 18 patients (50%). Of the 20 variants identified, six have not been previously described (30%). According to the International Union of Immunological Societies (IUIS), 38.9% of these detected cases (7/18) were found to harbor variants associated with genes in combined immunodeficiencies with associated or syndromic features (Class II). Conclusion: The diagnostic yield of WES in this patient cohort was 50%. Six novel genetic variants in PID genes were identified. The clinical usefulness of WES in PIDs was demonstrated, emphasizing it as an effective diagnostic strategy in these genetically heterogeneous disorders.

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Insights from the genetic characterization of central precocious puberty associated with multiple anomalies

Human Reproduction ◽

10.1093/humrep/deaa306 ◽

2020 ◽

Author(s):

Ana Pinheiro Machado Canton ◽

Ana Cristina Victorino Krepischi ◽

Luciana Ribeiro Montenegro ◽

Silvia Costa ◽

Carla Rosenberg ◽

...

Keyword(s):

Exome Sequencing ◽

Precocious Puberty ◽

De Novo ◽

Central Precocious Puberty ◽

Genetic Defects ◽

Chromosomal Microarray Analysis ◽

National Council ◽

Methylation Analysis ◽

Candidate Regions ◽

Selection Of

Abstract STUDY QUESTION Is there an (epi)genetic basis in patients with central precocious puberty (CPP) associated with multiple anomalies that unmasks underlying mechanisms or reveals novel genetic findings related to human pubertal control? SUMMARY ANSWER In a group of 36 patients with CPP associated with multiple phenotypes, pathogenic or likely pathogenic (epi)genetic defects were identified in 12 (33%) patients, providing insights into the genetics of human pubertal control. WHAT IS KNOWN ALREADY A few studies have described patients with CPP associated with multiple anomalies, but without making inferences on causalities of CPP. Genetic-molecular studies of syndromic cases may reveal disease genes or mechanisms, as the presentation of such patients likely indicates a genetic disorder. STUDY DESIGN, SIZE, DURATION This translational study was based on a genetic-molecular analysis, including genome-wide high throughput methodologies, for searching structural or sequence variants implicated in CPP and DNA methylation analysis of candidate regions. PARTICIPANTS/MATERIALS, SETTING, METHODS A cohort of 197 patients (188 girls) with CPP without structural brain lesions was submitted to a detailed clinical evaluation, allowing the selection of 36 unrelated patients (32 girls) with CPP associated with multiple anomalies. Pathogenic allelic variants of genes known to cause monogenic CPP (KISS1R, KISS1, MKRN3 and DLK1) had been excluded in the entire cohort (197 patients). All selected patients with CPP associated with multiple anomalies (n = 36) underwent methylation analysis of candidate regions and chromosomal microarray analysis. A subset (n = 9) underwent whole-exome sequencing, due to presenting familial CPP and/or severe congenital malformations and neurocognitive abnormalities. MAIN RESULTS AND THE ROLE OF CHANCE Among the 36 selected patients with CPP, the more prevalent associated anomalies were metabolic, growth and neurocognitive conditions. In 12 (33%) of them, rare genetic abnormalities were identified: six patients presented genetic defects in loci known to be involved with CPP (14q32.2 and 7q11.23), whereas the other six presented defects in candidate genes or regions. In detail, three patients presented hypomethylation of DLK1/MEG3:IG-DMR (14q32.2 disruption or Temple syndrome), resulting from epimutation (n = 1) or maternal uniparental disomy of chromosome 14 (n = 2). Seven patients presented pathogenic copy number variants: three with de novo 7q11.23 deletions (Williams–Beuren syndrome), three with inherited Xp22.33 deletions, and one with de novo 1p31.3 duplication. Exome sequencing revealed potential pathogenic variants in two patients: a sporadic female case with frameshift variants in TNRC6B and AREL1 and a familial male case with a missense substitution in UGT2B4 and a frameshift deletion in MKKS. LIMITATIONS, REASONS FOR CAUTION The selection of patients was based on a retrospective clinical characterization, lacking a longitudinal inclusion of consecutive patients. In addition, future studies are needed, showing the long-term (mainly reproductive) outcomes in the included patients, as most of them are not in adult life yet. WIDER IMPLICATIONS OF THE FINDINGS The results highlighted the relevance of an integrative clinical-genetic approach in the elucidation of mechanisms and factors involved in pubertal control. Chromosome 14q32.2 disruption indicated the loss of imprinting of DLK1 as a probable mechanism of CPP. Two other chromosomal regions (7q11.23 and Xp22.33) represented new candidate loci potentially involved in this disorder of pubertal timing. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by grant number 2018/03198-0 (to A.P.M.C.) and grant number 2013/08028-1 (to A.C.V.K) from the São Paulo Research Foundation (FAPESP), and grant number 403525/2016-0 (to A.C.L.) and grant number 302849/2015-7 (to A.C.L.) and grant number 141625/2016-3 (to A.C.V.K) from the National Council for Scientific and Technological Development (CNPq). The authors have nothing to disclose. TRIAL REGISTRATION NUMBER N/A.

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Common Variable Immunodeficiency with Genetic Defects Identified by Whole Exome Sequencing

BioMed Research International ◽

10.1155/2018/3724630 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Ran Li ◽

Yali Zheng ◽

Yuqian Li ◽

Rongbao Zhang ◽

Fang Wang ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Common Variable Immunodeficiency ◽

Respiratory Infections ◽

Genetic Diagnosis ◽

Genetic Defects ◽

Compound Heterozygous ◽

Recurrent Respiratory Infections ◽

Whole Exome ◽

Common Variable

Common variable immunodeficiency (CVID) belongs to the primary immunodeficiency disorders (PIDs), presenting a profound heterogeneity in phenotype and genotype, with monogenic or complex causes. Recurrent respiratory infections are the most common clinical manifestations. CVID patients can also develop various autoimmune and lymphoproliferative complications. Genetic testing such as whole exome sequencing (WES) can be utilized to investigate likely genetic defects, helping for better clinical management. We described the clinical phenotypes of three sporadic cases of CVID, who developed recurrent respiratory infections with different autoimmune and lymphoproliferative complications. WES was applied to screen disease-causing or disease-associated mutations. Two patients were identified to have monogenic disorders, with compound heterozygous mutations in LRBA for one patient and a frameshift insertion in NFKB1 for another. The third patient was identified to be a complex form of CVID. Two novel mutations were identified, respectively, in LRBA and NFKB1. A combination of clinical and genetic diagnosis can be more extensively utilized in the clinical practice due to the complexity and heterogeneity of CVID.

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22q11.2 deletion carriers and schizophrenia-associated novel variants

The British Journal of Psychiatry ◽

10.1192/bjp.bp.113.138420 ◽

2014 ◽

Vol 204 (5) ◽

pp. 398-399 ◽

Cited By ~ 8

Author(s):

S. Balan ◽

Y. Iwayama ◽

T. Toyota ◽

M. Toyoshima ◽

M. Maekawa ◽

...

Keyword(s):

Exome Sequencing ◽

Genetic Variants ◽

Genetic Architecture ◽

The Other ◽

Genetic Defects ◽

Neuronal Function ◽

Complete Understanding ◽

22Q11.2 Deletion ◽

Whole Exome ◽

Novel Variants

SummaryThe penetrance of schizophrenia risk in carriers of the 22q11.2 deletion is high but incomplete, suggesting the possibility of additional genetic defects. We performed whole exome sequencing on two individuals with 22q11.2 deletion, one with schizophrenia and the other who was psychosisfree. The results revealed novel genetic variants related to neuronal function exclusively in the person with schizophrenia (frameshift: KAT8, APOH and SNX31; nonsense: EFCAB11 and CLVS2). This study paves the way towards a more complete understanding of variant dose and genetic architecture in schizophrenia.

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