scholarly journals A single center experience with publicly funded clinical exome sequencing for neurodevelopmental disorders or multiple congenital anomalies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ben Pode-Shakked ◽  
Ortal Barel ◽  
Amihood Singer ◽  
Miriam Regev ◽  
Hana Poran ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Neurodevelopmental Disorders ◽  
Congenital Anomalies ◽  
Brain Magnetic Resonance Imaging ◽  
Autism Spectrum ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Publicly Funded ◽  
Multiple Congenital Anomalies ◽  
Tertiary Center

AbstractExome sequencing (ES) is an important diagnostic tool for individuals with neurodevelopmental disorders (NDD) and/or multiple congenital anomalies (MCA). However, the cost of ES limits the test's accessibility for many patients. We evaluated the yield of publicly funded clinical ES, performed at a tertiary center in Israel, over a 3-year period (2018–2020). Probands presented with (1) moderate-to-profound global developmental delay (GDD)/intellectual disability (ID); or (2) mild GDD/ID with epilepsy or congenital anomaly; and/or (3) MCA. Subjects with normal chromosomal microarray analysis who met inclusion criteria were included, totaling 280 consecutive cases. Trio ES (proband and parents) was the default option. In 252 cases (90.0%), indication of NDD was noted. Most probands were males (62.9%), and their mean age at ES submission was 9.3 years (range 1 month to 51 years). Molecular diagnosis was reached in 109 probands (38.9%), mainly due to de novo variants (91/109, 83.5%). Disease-causing variants were identified in 92 genes, 15 of which were implicated in more than a single case. Male sex, families with multiple-affected members and premature birth were significantly associated with lower ES yield (p < 0.05). Other factors, including MCA and coexistence of epilepsy, autism spectrum disorder, microcephaly or abnormal brain magnetic resonance imaging findings, were not associated with the yield. To conclude, our findings support the utility of clinical ES in a real-world setting, as part of a publicly funded genetic workup for individuals with GDD/ID and/or MCA.

scholarly journals Application of Chromosome Microarray Analysis in the Investigation of Developmental Disabilities and Congenital Anomalies: Single Center Experience and Review of NRXN3 and NEDD4L Deletions

2020 ◽  
Vol 11 (4) ◽  
pp. 197-206
Author(s):  
Alper Han Çebi ◽  
Şule Altıner
Keyword(s):  
Developmental Disabilities ◽  
Microarray Analysis ◽  
Congenital Anomalies ◽  
Copy Number Variations ◽  
Step Test ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Multiple Congenital Anomalies ◽  
Single Center Experience ◽  
Genome Wide

Chromosomal microarray analysis (CMA) is a first step test used for the diagnosis of patients with developmental delay, intellectual disability, autistic spectrum disorder, and multiple congenital anomalies. Its widespread usage has allowed genome-wide identification of copy number variations (CNVs). In our study, we performed a retrospective study on clinical and microarray data of 237 patients with developmental disabilities and/or multiple congenital anomalies and investigated the clinical utility of CMA. Phenotype-associated CNVs were detected in 15.18% of patients. Besides, we detected submicroscopic losses on 14q24.3q31.1 in a patient with speech delay and on 18q21.31q21.32 in twin patients with seizures. Deletions of <i>NRXN3</i> and <i>NEDD4L</i> were responsible for the phenotypes, respectively. This study showed that CMA is a powerful diagnostic tool in this patient group and expands the genotype-phenotype correlations on developmental disabilities.

scholarly journals Clinical Performance of an Ultrahigh Resolution Chromosomal Microarray Optimized for Neurodevelopmental Disorders

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Karen S. Ho ◽  
Hope Twede ◽  
Rena Vanzo ◽  
Erin Harward ◽  
Charles H. Hensel ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Detection Rate ◽  
Clinical Performance ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Ultrahigh Resolution ◽  
Significant Difference

Copy number variants (CNVs) as detected by chromosomal microarray analysis (CMA) significantly contribute to the etiology of neurodevelopmental disorders, such as developmental delay (DD), intellectual disability (ID), and autism spectrum disorder (ASD). This study summarizes the results of 3.5 years of CMA testing by a CLIA-certified clinical testing laboratory 5487 patients with neurodevelopmental conditions were clinically evaluated for rare copy number variants using a 2.8-million probe custom CMA optimized for the detection of CNVs associated with neurodevelopmental disorders. We report an overall detection rate of 29.4% in our neurodevelopmental cohort, which rises to nearly 33% when cases with DD/ID and/or MCA only are considered. The detection rate for the ASD cohort is also significant, at 25%. Additionally, we find that detection rate and pathogenic yield of CMA vary significantly depending on the primary indications for testing, the age of the individuals tested, and the specialty of the ordering doctor. We also report a significant difference between the detection rate on the ultrahigh resolution optimized array in comparison to the array from which it originated. This increase in detection can significantly contribute to the efficient and effective medical management of neurodevelopmental conditions in the clinic.

scholarly journals Levy-Shanske syndrome: mosaic tetrasomy 15q25.3→qter and review of the literature

2019 ◽  
pp. 40-47
Author(s):  
М.Е. Миньженкова ◽  
Ж.Г. Маркова ◽  
Н.А. Демина ◽  
А.А. Тарлычева ◽  
И.В. Канивец ◽  
...  
Keyword(s):  
Congenital Anomalies ◽  
Marker Chromosome ◽  
Distal Portion ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Chromosome 15 ◽  
Review Of The Literature ◽  
Multiple Congenital Anomalies ◽  
Molecular Cytogenetic ◽  
Inverted Duplication

Введение. Тетрасомия дистального района длинного плеча хромосомы 15 является довольно редким событием. В электронной базе данных по сверхчисленным маркерным хромосомам имеются сведения о 24 зарегистрированных случаях с инвертированной дупликацией дистального района длинного плеча хромосомы 15. Частичная тетрасомия 15q может наблюдаться вследствие появления сверхчисленной анальфоидной маркерной хромосомы, состоящей из инвертированной дупликации дистальной части длинного плеча хромосомы 15. Представлен случай мозаичной тетрасомии 15q25.3-qter, у пациента со множественными признаками дизэмбриогенеза. Цель. Молекулярно-цитогенетическая диагностика мозаичного случая инвертированной дупликации 15q25.3→qter у пациента с множественными врожденными аномалиями развития и обзор аналогичных случаев. Методы. Для идентификации малой сверхчисленной маркерной хромосомы и определения уровня мозаицизма использовали комплексную молекулярно-цитогенетическую диагностику, включающую хромосомный микроматричный анализ и FISH-исследование. Результаты. При стандартном цитогенетическом исследовании обнаружена сверхчисленная маркерная хромосома в мозаичном состоянии: 47,ХХ,+mar[8]/46,XX[23]. Для идентификации геномного дисбаланса использовали хромосомный микроматричный анализ, выявивший дупликацию участка длинного плеча хромосомы 15 размером 16,4 млн п.н. FISH-исследование позволило установить, что сверхчисленная маркерная хромосома представлена инвертированной дупликацией района q25.3→qter хромосомы 15 с неоцентромерой, и помогло уточнить уровень мозаицизма, который составил 35%. Заключение. Идентификация структуры и происхождения сверхчисленных маркерных хромосом у пациентов с множественными врожденными аномалиями развития является важной задачей цитогенетической лаборатории. Современные молекулярно-цитогенетические методы диагностики хромосомных аномалий позволяют выявить и охарактеризовать любой случай неоцентромерной формации. Introduction: Tetrasomy for the distal chromosome 15q is rare. Only 24 cases have been described in the literature to date. Tetrasomy for the distal portion of chromosome 15q can be due to a supernumerary analphoid marker chromosome consisting of an inverted duplication of the distal long arm of chromosome 15. We report on a molecular cytogenetic diagnosis of mosaic tetrasomy 15q25.3-qter in a patient with multiple congenital anomalies. Aim: Molecular cytogenetic diagnosis of mosaic case with inverted duplication for the distal portion of 15q25.3→qter in a patient with multiple congenital anomalies and review of the literature. Methods: The case of mosaic supernumerary marker chromosome was characterized by GTG-banding, chromosomal microarray analysis and FISH diagnosis. Results: The chromosome analysis of a child revealed a supernumerary marker chromosome in mosaicism: 47,ХХ,+mar[8]/46,XX[23]. Chromosomal microarray analysis detected a copy gain of 16.4 Mb from the distal long arm of chromosome 15. Further FISH analysis showed an inverted duplication of distal long arm of chromosome 15 with neocentromere. Conclusion: Identification of structure and origin supernumerical marker chromosomes at patients with multiple congenital anomalies is an important problem of cytogenetic diagnostics. Modern molecular -cytogenetic diagnostic methods of chromosomal anomalies allow identifying and characterizing any case of neocentromeres.

scholarly journals Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder

JAMA ◽  
2015 ◽  
Vol 314 (9) ◽  
pp. 895 ◽  
Author(s):  
Kristiina Tammimies ◽  
Christian R. Marshall ◽  
Susan Walker ◽  
Gaganjot Kaur ◽  
Bhooma Thiruvahindrapuram ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Molecular Diagnostic ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Whole Exome

16p13.11 microduplication in 45 new patients: refined clinical significance and genotype–phenotype correlations

2018 ◽  
Vol 57 (5) ◽  
pp. 301-307 ◽  
Author(s):  
Laïla Allach El Khattabi ◽  
Solveig Heide ◽  
Jean-Hubert Caberg ◽  
Joris Andrieux ◽  
Martine Doco Fenzy ◽  
...  
Keyword(s):  
Clinical Significance ◽  
Genetic Counselling ◽  
Essential Role ◽  
Disease Risk ◽  
Significant Risk ◽  
Aortic Disease ◽  
Autism Spectrum ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Cardiac Evaluation

BackgroundThe clinical significance of 16p13.11 duplications remains controversial while frequently detected in patients with developmental delay (DD), intellectual deficiency (ID) or autism spectrum disorder (ASD). Previously reported patients were not or poorly characterised. The absence of consensual recommendations leads to interpretation discrepancy and makes genetic counselling challenging. This study aims to decipher the genotype–phenotype correlations to improve genetic counselling and patients’ medical care.MethodsWe retrospectively analysed data from 16 013 patients referred to 12 genetic centers for DD, ID or ASD, and who had a chromosomal microarray analysis. The referring geneticists of patients for whom a 16p13.11 duplication was detected were asked to complete a questionnaire for detailed clinical and genetic data for the patients and their parents.ResultsClinical features are mainly speech delay and learning disabilities followed by ASD. A significant risk of cardiovascular disease was noted. About 90% of the patients inherited the duplication from a parent. At least one out of four parents carrying the duplication displayed a similar phenotype to the propositus. Genotype–phenotype correlations show no impact of the size of the duplicated segment on the severity of the phenotype. However, NDE1 and miR-484 seem to have an essential role in the neurocognitive phenotype.ConclusionOur study shows that 16p13.11 microduplications are likely pathogenic when detected in the context of DD/ID/ASD and supports an essential role of NDE1 and miR-484 in the neurocognitive phenotype. Moreover, it suggests the need for cardiac evaluation and follow-up and a large study to evaluate the aortic disease risk.

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