Deep phenotyping and association with diagnostic yield of prenatal exome sequencing for fetal brain abnormalities

Abstract Background: Neurological diseases are phenotypically and genotypically heterogeneous. Clinical exome sequencing (CES) has been shown to provide a high diagnostic yield for these disorders in the European population but remains to be demonstrated for the Indian population. Methods: A cohort of 19 idiopathic patients with neurological phenotypes, primarily intellectual disability and developmental delay, were recruited. CES covering 4620 genes was performed on all patients. Candidate variants were validated by Sanger sequencing. Results: CES in 19 patients provided identified 21 variants across 16 genes which have been associated with different neurological disorders. Fifteen variants were reported previously and 6 variants were novel to our study. Eleven patients were diagnosed with autosomal dominant de novo variants, 7 with autosomal recessive and 1 with X-linked recessive variants. CES provided definitive diagnosis to 10 patients, hence the diagnostic yield was 53%. Conclusion: Our study suggests that the diagnostic yield of CES in the Indian population is comparable to that reported in the European population. CES together with deep phenotyping could be a cost-effective way of diagnosing rare neurological disorders in the Indian population.

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One test for all: whole exome sequencing significantly improves the diagnostic yield in growth retarded patients referred for molecular testing for Silver–Russell syndrome

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01683-x ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Robert Meyer ◽

Matthias Begemann ◽

Christian Thomas Hübner ◽

Daniela Dey ◽

Alma Kuechler ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Diagnostic Yield ◽

Uniparental Disomy ◽

Molecular Testing ◽

Main Body ◽

Comprehensive Overview ◽

Maternal Uniparental Disomy ◽

Whole Exome ◽

Silver Russell Syndrome

Abstract Background Silver-Russell syndrome (SRS) is an imprinting disorder which is characterised by severe primordial growth retardation, relative macrocephaly and a typical facial gestalt. The clinical heterogeneity of SRS is reflected by a broad spectrum of molecular changes with hypomethylation in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat) as the most frequent findings. Monogenetic causes are rare, but a clinical overlap with numerous other disorders has been reported. However, a comprehensive overview on the contribution of mutations in differential diagnostic genes to phenotypes reminiscent to SRS is missing due to the lack of appropriate tests. With the implementation of next generation sequencing (NGS) tools this limitation can now be circumvented. Main body We analysed 75 patients referred for molecular testing for SRS by a NGS-based multigene panel, whole exome sequencing (WES), and trio-based WES. In 21/75 patients a disease-causing variant could be identified among them variants in known SRS genes (IGF2, PLAG1, HMGA2). Several patients carried variants in genes which have not yet been considered as differential diagnoses of SRS. Conclusions WES approaches significantly increase the diagnostic yield in patients referred for SRS testing. Several of the identified monogenetic disorders have a major impact on clinical management and genetic counseling.

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Exome sequencing in paediatric patients with movement disorders

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01688-6 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Anna Ka-Yee Kwong ◽

Mandy Ho-Yin Tsang ◽

Jasmine Lee-Fong Fung ◽

Christopher Chun-Yu Mak ◽

Kate Lok-San Chan ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Movement Disorders ◽

Rare Variants ◽

Diagnostic Yield ◽

Neurological Diseases ◽

Genetic Diagnosis ◽

Potential Treatment ◽

Paediatric Patients ◽

Whole Exome

Abstract Background Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis. Results We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation. Conclusions A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management. The study highlights the potential of implementing precision medicine in the patients.

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OP25.01: How accurate is the offline analysis of 3D volume datasets in the diagnosis of fetal brain abnormalities?

Ultrasound in Obstetrics and Gynecology ◽

10.1002/uog.8156 ◽

2010 ◽

Vol 36 (S1) ◽

pp. 124-124

Author(s):

M. Salman ◽

H. Mousa ◽

P. Twining ◽

D. K. James ◽

M. Momtaz ◽

...

Keyword(s):

Fetal Brain ◽

Brain Abnormalities ◽

Offline Analysis ◽

3D Volume

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OP13.09: Pulsed-wave Doppler of the middle cerebral artery in fetal brain abnormalities

Ultrasound in Obstetrics and Gynecology ◽

10.1002/uog.4539 ◽

2007 ◽

Vol 30 (4) ◽

pp. 499-500

Author(s):

L. R. Pistorius ◽

R. Gooskens ◽

P. H. Stoutenbeek

Keyword(s):

Middle Cerebral Artery ◽

Cerebral Artery ◽

Fetal Brain ◽

Brain Abnormalities ◽

Pulsed Wave Doppler

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Whole genome sequencing provides better diagnostic yield and future value than whole exome sequencing

The Medical Journal of Australia ◽

10.5694/mja17.01176 ◽

2018 ◽

Vol 209 (5) ◽

pp. 197-199 ◽

Cited By ~ 10

Author(s):

John S Mattick ◽

Marcel Dinger ◽

Nicole Schonrock ◽

Mark Cowley

Keyword(s):

Whole Genome Sequencing ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genome Sequencing ◽

Diagnostic Yield ◽

Whole Genome ◽

Whole Exome ◽

Future Value

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Next-Generation Sequencing Gene Panels and “Solo” Clinical Exome Sequencing Applied in Structurally Abnormal Fetuses

Fetal Diagnosis and Therapy ◽

10.1159/000519701 ◽

2021 ◽

pp. 1-11

Author(s):

Montse Pauta ◽

Berta Campos ◽

Maria Segura-Puimedon ◽

Gemma Arca ◽

Alfons Nadal ◽

...

Keyword(s):

Next Generation Sequencing ◽

Exome Sequencing ◽

Diagnostic Yield ◽

Monogenic Disease ◽

Chromosomal Microarray Analysis ◽

Next Generation ◽

Clinical Exome Sequencing ◽

Gene Panels ◽

Generation Sequencing ◽

Structural Anomalies

Objective: The aim of the study was to assess the diagnostic yield of 2 different next-generation sequencing (NGS) approaches: gene panel and “solo” clinical exome sequencing (solo-CES), in fetuses with structural anomalies and normal chromosomal microarray analysis (CMA), in the absence of a known familial mutation. Methodology: Gene panels encompassing from 2 to 140 genes, were applied mainly in persistent nuchal fold/fetal hydrops and in large hyperechogenic kidneys. Solo-CES, which entails sequencing the fetus alone and only interpreting the Online Mendelian Inheritance in Man genes, was performed in multisystem or recurrent structural anomalies. Results: During the study period (2015–2020), 153 NGS studies were performed in 148 structurally abnormal fetuses with a normal CMA. The overall diagnostic yield accounted for 35% (53/153) of samples and 36% (53/148) of the fetuses. Diagnostic yield with the gene panels was 31% (15/49), similar to 37% (38/104) in solo-CES. Conclusions: A monogenic disease was established as the underlying cause in 35% of selected fetal structural anomalies by gene panels and solo-CES.

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The potential diagnostic yield of whole exome sequencing in pregnancies complicated by fetal ultrasound anomalies

Acta Obstetricia Et Gynecologica Scandinavica ◽

10.1111/aogs.14053 ◽

2020 ◽

Author(s):

Karin E. M. Diderich ◽

Kathleen Romijn ◽

Marieke Joosten ◽

Lutgarde C. P. Govaerts ◽

Marike Polak ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Diagnostic Yield ◽

Fetal Ultrasound ◽

Whole Exome

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Re-analysis of whole-exome sequencing data uncovers novel diagnostic variants and improves molecular diagnostic yields for sudden death and idiopathic diseases

Genome Medicine ◽

10.1186/s13073-019-0702-2 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 3

Author(s):

Elias L. Salfati ◽

Emily G. Spencer ◽

Sarah E. Topol ◽

Evan D. Muse ◽

Manuel Rueda ◽

...

Keyword(s):

Sudden Death ◽

Rare Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Diagnostic Yield ◽

Molecular Diagnostic ◽

Sudden Unexplained Death ◽

Unexplained Death ◽

Pathogenic Variants ◽

Whole Exome

Abstract Background Whole-exome sequencing (WES) has become an efficient diagnostic test for patients with likely monogenic conditions such as rare idiopathic diseases or sudden unexplained death. Yet, many cases remain undiagnosed. Here, we report the added diagnostic yield achieved for 101 WES cases re-analyzed 1 to 7 years after initial analysis. Methods Of the 101 WES cases, 51 were rare idiopathic disease cases and 50 were postmortem “molecular autopsy” cases of early sudden unexplained death. Variants considered for reporting were prioritized and classified into three groups: (1) diagnostic variants, pathogenic and likely pathogenic variants in genes known to cause the phenotype of interest; (2) possibly diagnostic variants, possibly pathogenic variants in genes known to cause the phenotype of interest or pathogenic variants in genes possibly causing the phenotype of interest; and (3) variants of uncertain diagnostic significance, potentially deleterious variants in genes possibly causing the phenotype of interest. Results Initial analysis revealed diagnostic variants in 13 rare disease cases (25.4%) and 5 sudden death cases (10%). Re-analysis resulted in the identification of additional diagnostic variants in 3 rare disease cases (5.9%) and 1 sudden unexplained death case (2%), which increased our molecular diagnostic yield to 31.4% and 12%, respectively. Conclusions The basis of new findings ranged from improvement in variant classification tools, updated genetic databases, and updated clinical phenotypes. Our findings highlight the potential for re-analysis to reveal diagnostic variants in cases that remain undiagnosed after initial WES.

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