Prenatal Diagnosis of Birth Defects by Exome Sequencing

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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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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