PATHOGENIC VARIANTS WITHIN ACMG SECONDARY FINDINGS GENES IN 24,591 HEALTHY INDIVIDUALS USING CLINICAL EXOME SEQUENCING FOR CARRIER SCREENING

AbstractPurposeAccurate profiling of population-specific recessive diseases is essential for the design of cost-effective carrier screening programs. However, minority populations and ethnic groups, including Vietnamese, are still under-represented in existing genetic studies. Here we reported the first comprehensive study of recessive diseases in the Vietnamese population.MethodsClinical exome sequencing (CES) data of 4,503 disease-associated genes obtained from a cohort of 985 Vietnamese individuals was analyzed to identify pathogenic variants, associated diseases and their carrier frequencies in the population.ResultsEighty-five recessive diseases were identified in the Vietnamese population, among which seventeen diseases had carrier frequencies of at least 1% (1 in 100 individuals). Three diseases were especially prevalent in the Vietnamese population with carrier frequencies of 2-12 times higher than in other East Asia or the world populations, including Beta-thalassemia (1 in 25), citrin deficiency (1 in 33) and phenylketonuria (1 in 40). Seven novel pathogenic and three likely pathogenic variants associated with nine recessive diseases were also discovered.ConclusionsThe comprehensive profile of recessive diseases identified in this study shall enable the design of cost-effective carrier screening programs specific to the Vietnamese population. The newly discovered pathogenic variants may also exist in other populations at extremely low frequencies, thus representing a valuable resource for future research. Our study has demonstrated the advantage of population-specific genetic studies to advance the knowledge and practice of medical genetics.

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Clinical Exome Sequencing Reveals MKRN3 Pathogenic Variants in Familial and Nonfamilial Idiopathic Central Precocious Puberty

Hormone Research in Paediatrics ◽

10.1159/000453262 ◽

2016 ◽

Vol 87 (2) ◽

pp. 88-94 ◽

Cited By ~ 11

Author(s):

Nelmar Valentina Ortiz-Cabrera ◽

Rosa Riveiro-Álvarez ◽

Miguel Ángel López-Martínez ◽

Pilar Pérez-Segura ◽

Isabel Aragón-Gómez ◽

...

Keyword(s):

Exome Sequencing ◽

Precocious Puberty ◽

Central Precocious Puberty ◽

Pathogenic Variants ◽

Idiopathic Central Precocious Puberty ◽

Clinical Exome Sequencing

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Prioritizing variants of uncertain significance for reclassification using a rule-based algorithm in inherited retinal dystrophies

npj Genomic Medicine ◽

10.1038/s41525-021-00182-z ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Ionut-Florin Iancu ◽

Almudena Avila-Fernandez ◽

Ana Arteche ◽

Maria Jose Trujillo-Tiebas ◽

Rosa Riveiro-Alvarez ◽

...

Keyword(s):

Exome Sequencing ◽

Rare Diseases ◽

Molecular Diagnostic ◽

Rule Based ◽

Variants Of Uncertain Significance ◽

Inherited Retinal Dystrophies ◽

Pathogenic Variants ◽

Retinal Dystrophies ◽

Clinical Exome Sequencing ◽

Uncertain Significance

AbstractInherited retinal dystrophies (IRD) are a highly heterogeneous group of rare diseases with a molecular diagnostic rate of >50%. Reclassification of variants of uncertain significance (VUS) poses a challenge for IRD diagnosis. We collected 668 IRD cases analyzed by our geneticists using two different clinical exome-sequencing tests. We identified 114 unsolved cases pending reclassification of 125 VUS and studied their genomic, functional, and laboratory-specific features, comparing them to pathogenic and likely pathogenic variants from the same cohort (N = 390). While the clinical exome used did not show differences in diagnostic rate, the more IRD-experienced geneticist reported more VUS (p = 4.07e-04). Significantly fewer VUS were reported in recessive cases (p = 2.14e-04) compared to other inheritance patterns, and of all the genes analyzed, ABCA4 and IMPG2 had the lowest and highest VUS frequencies, respectively (p = 3.89e-04, p = 6.93e-03). Moreover, few frameshift and stop-gain variants were found to be informed VUS (p = 6.73e-08 and p = 2.93e-06). Last, we applied five pathogenicity predictors and found there is a significant proof of deleteriousness when all score for pathogenicity in missense variants. Altogether, these results provided input for a set of rules that correctly reclassified ~70% of VUS as pathogenic in validation datasets. Disease- and setting-specific features influence VUS reporting. Comparison with pathogenic and likely pathogenic variants can prioritize VUS more likely to be reclassified as causal.

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Secondary findings in 622 Turkish clinical exome sequencing data

Journal of Human Genetics ◽

10.1038/s10038-021-00936-8 ◽

2021 ◽

Author(s):

Esra Arslan Ateş ◽

Ayberk Türkyilmaz ◽

Özlem Yıldırım ◽

Ceren Alavanda ◽

Hamza Polat ◽

...

Keyword(s):

Exome Sequencing ◽

Sequencing Data ◽

Secondary Findings ◽

Exome Sequencing Data ◽

Clinical Exome Sequencing

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Clinical exome sequencing data reveal high diagnostic yields for congenital diaphragmatic hernia plus (CDH+) and new phenotypic expansions involving CDH

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-107317 ◽

2021 ◽

pp. jmedgenet-2020-107317

Author(s):

Tiana M Scott ◽

Ian M Campbell ◽

Andres Hernandez-Garcia ◽

Seema R Lalani ◽

Pengfei Liu ◽

...

Keyword(s):

Congenital Diaphragmatic Hernia ◽

Exome Sequencing ◽

Diaphragmatic Hernia ◽

De Novo ◽

Diagnostic Yield ◽

Fanconi Anaemia ◽

Compound Heterozygous ◽

Pathogenic Variants ◽

Clinical Exome Sequencing ◽

Made In

BackgroundCongenital diaphragmatic hernia (CDH) is a life-threatening birth defect that often co-occurs with non-hernia-related anomalies (CDH+). While copy number variant (CNV) analysis is often employed as a diagnostic test for CDH+, clinical exome sequencing (ES) has not been universally adopted.MethodsWe analysed a clinical database of ~12 000 test results to determine the diagnostic yields of ES in CDH+ and to identify new phenotypic expansions.ResultsAmong the 76 cases with an indication of CDH+, a molecular diagnosis was made in 28 cases for a diagnostic yield of 37% (28/76). A provisional diagnosis was made in seven other cases (9%; 7/76). Four individuals had a diagnosis of Kabuki syndrome caused by frameshift variants in KMT2D. Putatively deleterious variants in ALG12 and EP300 were each found in two individuals, supporting their role in CDH development. We also identified individuals with de novo pathogenic variants in FOXP1 and SMARCA4, and compound heterozygous pathogenic variants in BRCA2. The role of these genes in CDH development is supported by the expression of their mouse homologs in the developing diaphragm, their high CDH-specific pathogenicity scores generated using a previously validated algorithm for genome-scale knowledge synthesis and previously published case reports.ConclusionWe conclude that ES should be ordered in cases of CDH+ when a specific diagnosis is not suspected and CNV analyses are negative. Our results also provide evidence in favour of phenotypic expansions involving CDH for genes associated with ALG12-congenital disorder of glycosylation, Rubinstein-Taybi syndrome, Fanconi anaemia, Coffin-Siris syndrome and FOXP1-related disorders.

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Molecular diagnosis of non-syndromic hearing loss patients using a stepwise approach

Scientific Reports ◽

10.1038/s41598-021-83493-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jing Wang ◽

Jiale Xiang ◽

Lisha Chen ◽

Hongyu Luo ◽

Xiuhua Xu ◽

...

Keyword(s):

Hearing Loss ◽

Multiplex Pcr ◽

Exome Sequencing ◽

Molecular Diagnosis ◽

Nonsyndromic Hearing Loss ◽

Secondary Findings ◽

Pathogenic Variants ◽

Molecular Etiology ◽

Syndromic Hearing Loss ◽

Generation Sequencing

AbstractHearing loss is one of the most common birth disorders in humans, with an estimated prevalence of 1–3 in every 1000 newborns. This study investigates the molecular etiology of a hearing loss cohort using a stepwise strategy to effectively diagnose patients and address the challenges posed by the genetic heterogeneity and variable mutation spectrum of hearing loss. In order to target known pathogenic variants, multiplex PCR plus next-generation sequencing was applied in the first step; patients which did not receive a diagnosis from this were further referred for exome sequencing. A total of 92 unrelated patients with nonsyndromic hearing loss were enrolled in the study. In total, 64% (59/92) of the patients were molecularly diagnosed, 44 of them in the first step by multiplex PCR plus sequencing. Exome sequencing resulted in eleven diagnoses (23%, 11/48) and four probable diagnoses (8%, 4/48) among the 48 patients who were not diagnosed in the first step. The rate of secondary findings from exome sequencing in our cohort was 3% (2/58). This research presents a molecular diagnosis spectrum of 92 non-syndromic hearing loss patients and demonstrates the benefits of using a stepwise diagnostic approach in the genetic testing of nonsyndromic hearing loss.

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Molecular diagnosis of non-syndromic hearing loss patients using a stepwise approach

10.1101/2020.09.20.20197145 ◽

2020 ◽

Author(s):

Jing Wang ◽

Jiale Xiang ◽

Lisha Chen ◽

Hongyu Luo ◽

Jingjing Xu ◽

...

Keyword(s):

Hearing Loss ◽

Multiplex Pcr ◽

Exome Sequencing ◽

Molecular Diagnosis ◽

Genetic Test ◽

Secondary Findings ◽

Pathogenic Variants ◽

Molecular Etiology ◽

Syndromic Hearing Loss ◽

Generation Sequencing

Background Hearing loss is one of the most common birth disorders in humans with an estimated prevalence of 1-3 in every 1000 newborns. This study has investigated the molecular etiology of a deaf cohort using a stepwise strategy to effectively diagnose patients and the challenges faced to verify genetic heterogenicity and the variable mutation spectrums of hearing loss. Methods In order to target known pathogenic variants, multiplex PCR plus next-generation sequencing was applied in the first tier, while undiagnosed cases were further referred to exome sequencing. A total of 92 unrelated patients with nonsyndromic hearing loss were enrolled. Results In total, 64% (59/92) of patients were molecularly diagnosed, 44 of which were identified in the first tier by multiplex PCR plus sequencing. Of 48 undiagnosed patients from the first tier, exome sequencing identified eleven diagnoses (23%, 11/48) and four probably diagnoses (8%, 4/48). The rate of secondary findings of exome sequencing in our cohort is 3.4%. Conclusion The research presented a molecular diagnosis spectrum of 92 non-syndromic hearing loss patients and demonstrated the benefits of using the stepwise diagnostic approach in the genetic test of the non-syndromic hearing loss patient cohort.

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Identification and Classification of Rare Variants in NPC1 and NPC2 in Quebec

Scientific Reports ◽

10.1038/s41598-021-89630-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lahoud Touma ◽

Marjorie Labrecque ◽

Martine Tetreault ◽

Antoine Duquette

Keyword(s):

Exome Sequencing ◽

Rare Variants ◽

Variant Calling ◽

Allelic Frequency ◽

Healthy Individuals ◽

Pathogenic Variants ◽

Niemann Pick Disease ◽

Novel Variants ◽

Uncertain Significance ◽

Niemann Pick

AbstractNiemann–Pick disease type C (NPC) is a treatable autosomal recessive neurodegenerative condition which leads to a variety of progressive manifestations. Despite most cases being diagnosed at a young age, disease prevalence may be underestimated, especially in adults, and interpretation of NPC1 and NPC2 variants can be difficult. This study aims to identify potential pathogenic variants in a large cohort of healthy individuals and classify their risk of pathogenicity to assist with future interpretation of variants. The CARTaGENE (CaG) cohort was used to identify possible variants of NPC1 and NPC2. Nine-hundred and eleven RNA samples and 198 exome sequencing were screened for genetic variants through a bio-informatic pipeline performing alignment and variant calling. The identified variants were analyzed using annotations for allelic frequency, pathogenicity and conservation scores. The ACMG guidelines were used to classify the variants. These were then compared to existing databases and previous studies of NPC prevalence, including the Tübingen NPC database. Thirty-two distinct variants were identified after running the samples in the RNA-sequencing pipeline, two of which were classified as pathogenic and 21 of which were not published previously. Furthermore, 46 variants were both identified in our population and with the Tübingen database, the majority of which were of uncertain significance. Ten additional variants were found in our exome-sequencing sample. This study of a sample from a population living in Quebec demonstrates a variety of rare variants, some of which were already described in the literature as well as some novel variants. Classifying these variants is arduous given the scarcity of available literature, even so in a population of healthy individuals. Yet using this data, we were able to identify two pathogenic variants within our population and several new variants not previously identified.

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An audit and insights from clinical exome sequencing in psychiatry: genotype-phenotype correlation

10.31219/osf.io/5fu6t ◽

2020 ◽

Author(s):

Jayant Mahadevan ◽

Reeteka Sud ◽

Ravi Kumar Nadella ◽

Vani P ◽

Anand G Subramaniam ◽

...

Keyword(s):

Exome Sequencing ◽

Psychiatric Symptoms ◽

Pathogenic Variant ◽

Clinical Exome Sequencing ◽

Mapt Gene ◽

Nf1 Gene ◽

Novel Variant ◽

History Of ◽

Atypical Presentations ◽

Minor Physical Anomalies

BACKGROUND:Psychiatric syndromes have polymorphic symptomatology, and are known to be heritable. Psychiatric symptoms (and even syndromes) often occur as part of the clinical presentation in rare Mendelian syndromes. Clinical exome sequencing reports may help with refining diagnosis and influence treatment decisions, in addition to providing a window into the biology of brain and behaviour. We describe a clinical audit of 12 individuals who sought treatment at our hospital, and for whom targeted sequencing was ordered. Three cases are discussed in detail to demonstrate correlations between genotype and phenotype in the clinic.METHODS:Targeted Next-Generation Sequencing (NGS) was done using Clinical Exome Panel (TruSight One, Illumina) covering coding exons and flanking intronic sequences of 4811 genes associated with known inherited diseases. Variants detected were classified according to the American College for Medical Genetics (ACMG) recommendation for standards of interpretation and reporting of sequence variations.RESULTS:Ten out of twelve cases had at least one pathogenic variant. In one of these cases, we detected a known pathogenic variant in MAPT gene in a suspected FTD case, which helped us to confirm the diagnosis. In another case, we detected a novel variant predicted to be deleterious in NF1 gene. Identification of this mutation suggested a change in treatment for the patient, that was of benefit. The same patient also harboured a novel variant in the TRIO gene. This gene may be involved in biological processes that underlie the patient’s psychiatric illness.CONCLUSIONS:The cases discussed here exemplify different scenarios under which targeted exome sequencing can find meaningful application in the clinic: confirming diagnosis (MAPT variant), or modifying treatment (NF1). We suggest that clinical exome sequencing can be a helpful addition to a clinician’s toolkit when there are expediting factors to consider— such as early-onset, strong family history of mental illness, complex/atypical presentations and minor physical anomalies or neurocutaneous markers.

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