The use of exome and genome sequencing has increased rapidly nowadays. After primary analysis, further analysis can be performed to identify secondary findings that offer medical benefit for patient ...care. Multiple studies have been performed to evaluate secondary findings in different ethnicities. However, relevant data are limited in Chinese. Here, with the use of a cohort consisted of 1116 Hong Kong Chinese exome sequencing data, we evaluated the secondary findings in the 59 genes recommended by the American College of Medical Genetics and Genomics. Fifteen unique pathogenic or likely pathogenic variants in 17 individuals were identified, representing a frequency of 1.52% in our cohort. Although 20 individuals harboured pathogenic or likely pathogenic variants in recessive conditions, none carried bi-allelic mutations in the same gene. Our finding was in accordance with the estimation from the American College of Medical Genetics and Genomics that about 1% individuals harbour secondary findings.
Preemptive pharmacogenetic testing has the potential to improve drug dosing by providing point-of-care patient genotype information. Nonetheless, its implementation in the Chinese population is ...limited by the lack of population-wide data. In this study, secondary analysis of exome sequencing data was conducted to study pharmacogenomics in 1116 Hong Kong Chinese. We aimed to identify the spectrum of actionable pharmacogenetic variants and rare, predicted deleterious variants that are potentially actionable in Hong Kong Chinese, and to estimate the proportion of dispensed drugs that may potentially benefit from genotype-guided prescription. The projected preemptive pharmacogenetic testing prescription impact was evaluated based on the patient prescription data of the public healthcare system in 2019, serving 7.5 million people. Twenty-nine actionable pharmacogenetic variants/ alleles were identified in our cohort. Nearly all (99.6%) subjects carried at least one actionable pharmacogenetic variant, whereas 93.5% of subjects harbored at least one rare deleterious pharmacogenetic variant. Based on the prescription data in 2019, 13.4% of the Hong Kong population was prescribed with drugs with pharmacogenetic clinical practice guideline recommendations. The total expenditure on actionable drugs was 33,520,000 USD, and it was estimated that 8,219,000 USD (24.5%) worth of drugs were prescribed to patients with an implicated actionable phenotype. Secondary use of exome sequencing data for pharmacogenetic analysis is feasible, and preemptive pharmacogenetic testing has the potential to support prescription decisions in the Hong Kong Chinese population.
Summary
Objective
Early onset drug‐resistant epilepsy is a neurologic disorder in which 2 antiepileptic drugs fail to maintain the seizure‐free status of the patient. Heterogeneous clinical ...presentations make the diagnosis challenging. We aim to identify the underlying genetic causes of a pediatric cohort with drug‐resistant epilepsy and evaluate whether the findings can provide information on patient management.
Methods
We include patients with drug‐resistant epilepsy onset before 18 years of age. Singleton clinical chromosomal microarray (CMA) followed by whole exome sequencing (WES) was performed using genomic DNA. In the first‐tier analysis of the exome data, we aimed to identify disease‐causing mutations in 546 genes known to cause, or to be associated with, epilepsy. For negative cases, we proceeded to exome‐wide analysis. Rare coding variants were interrogated for pathogenicity based on the American College of Medical Genetics and Genomics (ACMG) guidelines.
Results
We recruited 50 patients. We identified 6 pathogenic or likely pathogenic mutations, giving a diagnostic yield of 12%. Mutations were found in 6 different genes: SCN8A, SCN1A, MECP2, CDKL5, DEPDC5, and CHD2. The CDKL5 variant was found to be mosaic. One variant of unknown significance (VUS) in KCNT1 was found in a patient with compatible clinical features. Of note, a reported pathogenic SCN5A mutation known to contribute to Brugada syndrome, was also found in the patient with an SCN1A mutation.
Significance
Our study suggests that singleton WES is an effective diagnostic tool for drug‐resistant epilepsy. Genetic diagnosis can help to consolidate the clinical diagnosis, to facilitate phenotypic expansion, and to influence treatment and management options for seizure control in our patients. In our study, a significant portion of the genetic findings are known to be associated with an increased risk of sudden unexpected death in epilepsy (SUDEP). These findings could assist with more appropriate management in patients with epilepsy.
Traditional carrier screening has been utilized for the detection of carriers of genetic disorders. Since a comprehensive assessment of the carrier frequencies of recessive conditions in the Southern ...Chinese population is not yet available, we performed a secondary analysis on the spectrum and carrier status for 315 genes causing autosomal recessive disorders in 1543 Southern Chinese individuals with next-generation sequencing data, 1116 with exome sequencing and 427 with genome sequencing data. Our data revealed that 1 in 2 people (47.8% of the population) was a carrier for one or more recessive conditions, and 1 in 12 individuals (8.30% of the population) was a carrier for treatable inherited conditions. In alignment with current American College of Obstetricians and Gynecologists (ACOG) pan-ethnic carrier recommendations, 1 in 26 individuals were identified as carriers of cystic fibrosis, thalassemia, and spinal muscular atrophy in the Southern Chinese population. When the >1% expanded carrier screening rate recommendation by ACOG was used, 11 diseases were found to meet the criteria in the Southern Chinese population. Approximately 1 in 3 individuals (35.5% of the population) were carriers of these 11 conditions. If the 1 in 200 carrier frequency threshold is used, and additional seven genes would meet the criteria, and 2 in 5 individuals (38.7% of the population) would be detected as a carrier. This study provides a comprehensive catalogue of the carrier spectrum and frequency in the Southern Chinese population and can serve as a reference for careful evaluation of the conditions to be included in expanded carrier screening for Southern Chinese people.
Primary coenzyme Q10 deficiency-7 (COQ10D7) is a rare mitochondrial disease caused by biallelic mutations in
. Here we report the largest cohort of COQ10D7 to date, with 11 southern Chinese patients ...confirmed with biallelic
mutations. Five of them have the classical neonatal-onset encephalo-cardiomyopathy, while the others have infantile onset with more heterogeneous clinical presentations. We also identify a founder mutation
(NM_016035.5): c.370G>A, p.(Gly124Ser) for COQ10D7, suggesting a higher chance of occurrence in the southern Chinese. This study helps improve understanding of the clinical spectrum of this disorder.
Bronchiectasis is the abnormal dilation of the airway which may be caused by various etiologies in children. Beyond the more recognized cause of bacterial and viral infections and primary ...immunodeficiencies, other genetic conditions such as cystic fibrosis and primary ciliary dyskinesia (PCD) can also contribute to the disease. Currently, there is still debate on whether genome sequencing (GS) or exome sequencing reanalysis (rES) would be beneficial if the initial targeted testing results returned negative. This study aims to provide a back-to-back comparison between rES and GS to explore the best integrated approach for the functional and genetics evaluation for patients referred for assessment of bronchiectasis. In phase 1, an initial 60 patients were analyzed by exome sequencing (ES) with one additional individual recruited later as an affected sibling for ES. Functional evaluation of the nasal nitric oxide test, transmission electron microscopy, and high-speed video microscopy were also conducted when possible. In phase 2, GS was performed on 30 selected cases with trio samples available. To provide a back-to-back comparison, two teams of genome analysts were alternatively allocated to GS or rES and were blinded to each other's analysis. The time for bioinformatics, analysis, and diagnostic utility was recorded for evaluation. ES revealed five positive diagnoses (5/60, 8.3%) in phase 1, and four additional diagnoses were made by rES and GS (4/30, 13%) during phase 2. Subsequently, one additional positive diagnosis was identified in a sibling by ES and an overall diagnostic yield of 10/61 (16.4%) was reached. Among those patients with a clinical suspicion of PCD (n = 31/61), the diagnostic yield was 26% (
= 8/31). While GS did not increase the diagnostic yield, we showed that a variant of uncertain significance could only be detected by GS due to improved coverage over ES and hence is a potential benefit for GS in the future. We show that genetic testing is an essential component for the diagnosis of early-onset bronchiectasis and is most effective when used in combination with functional tools such as TEM or HSVM. Our comparison of rES vs. GS suggests that rES and GS are comparable in clinical diagnosis.
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
mutation. In this pilot project, we used short read genome sequencing (GS) to retrospectively re-sequence ten prenatal subjects with
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.
BackgroundExpanded carrier screening (ECS) is a genetic test that investigates the genetic composition of a couple and determines whether their offspring has an elevated risk of inherited disorders. ...Comparisons between commercially available ECS has, however, only shown small overlaps in common genes offered for screening.ObjectivesCompiled with the inadequate information surrounding carrier frequencies in the Chinese population, secondary usage of next generation sequencing could be used in the optimization of ECS panels surrounding clinical utility, public health benefits, and reducing unnecessary socio-psychological stress.MethodsIn this study, a total of 1543 Southern Chinese and 366 Northern Chinese genome and exome sequencing were screened for carrier status over 315 genes. The gene list curated for this study was compiled from three ECS panels offered by frequently used commercial companies and literature reporting high carrier frequencies for treatable inherited disorder in South East Asia population genomics.Results180 unique disease-causing variants were identified and 47.8% (n = 738) of Southern Chinese individuals screened in this study harboured at least 1 disease-causing variant. CNV calling determined 4 unique pathogenic or likely pathogenic copy number variants. A total of 285 unique carrier variants were classified as pathogenic or likely pathogenic. Results have also identified 12 genes with a carrier frequency over 1% including GJB2, HBA1/HBA2, SMN1, SLC22A5, SLC25A13, ATP7B, SLC26A4, GALC, POLG, USH2A, and HBB.ConclusionsThis study shows that secondary analysis of NGS data can illustrate the carrier frequencies in the Southern Chinese population. Through the comparison of different commercially available ECS panels, we identified potential for improvement in the optimization of commercially available ECS panels for the future of precision medicine.
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