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.

scholarly journals MLPA is a practical and complementary alternative to CMA for diagnostic testing in patients with autism spectrum disorders and identifying new candidate CNVs associated with autism

PeerJ ◽  
2019 ◽  
Vol 6 ◽  
pp. e6183 ◽  
Author(s):  
Pavlina Capkova ◽  
Josef Srovnal ◽  
Zuzana Capkova ◽  
Katerina Staffova ◽  
Vera Becvarova ◽  
...  
Keyword(s):  
Clinical Significance ◽  
Diagnostic Testing ◽  
Copy Number Variants ◽  
Ring Chromosome ◽  
Autism Spectrum ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Rare Cnvs ◽  
Pathogenic Variants ◽  
Dependent Probe

Background Autism spectrum disorder (ASD) is a complex heterogeneous developmental disease with a significant genetic background that is frequently caused by rare copy number variants (CNVs). Microarray-based whole-genome approaches for CNV detection are widely accepted. However, the clinical significance of most CNV is poorly understood, so results obtained using such methods are sometimes ambiguous. We therefore evaluated a targeted approach based on multiplex ligation-dependent probe amplification (MLPA) using selected probemixes to detect clinically relevant variants for diagnostic testing of ASD patients. We compare the reliability and efficiency of this test to those of chromosomal microarray analysis (CMA) and other tests available to our laboratory. In addition, we identify new candidate genes for ASD identified in a cohort of ASD-diagnosed patients. Method We describe the use of MLPA, CMA, and karyotyping to detect CNV in 92 ASD patients and evaluate their clinical significance. Result Pathogenic and likely pathogenic mutations were identified by CMA in eight (8.07% of the studied cohort) and 12 (13.04%) ASD patients, respectively, and in eight (8.07%) and four (4.35%) patients, respectively, by MLPA. The detected mutations include the 22q13.3 deletion, which was attributed to ring chromosome 22 formation based on karyotyping. CMA revealed a total of 91 rare CNV in 55 patients: eight pathogenic, 15 designated variants of unknown significance (VOUS)—likely pathogenic, 10 VOUS—uncertain, and 58 VOUS—likely benign or benign. MLPA revealed 18 CNV in 18 individuals: eight pathogenic, four designated as VOUS—likely pathogenic, and six designated as VOUS—likely benign/benign. Rare CNVs were detected in 17 (58.62%) out of 29 females and 38 (60.32%) out of 63 males in the cohort. Two genes, DOCK8 and PARK2, were found to be overlapped by CNV designated pathogenic, VOUS—likely pathogenic, or VOUS—uncertain in multiple patients. Moreover, the studied ASD cohort exhibited significant (p < 0.05) enrichment of duplications encompassing DOCK8. Conclusion Multiplex ligation-dependent probe amplification and CMA yielded concordant results for 12 patients bearing CNV designated pathogenic or VOUS—likely pathogenic. Unambiguous diagnoses were achieved for eight patients (corresponding to 8.7% of the total studied population) by both MLPA and CMA, for one (1.09%) patient by karyotyping, and for one (1.09%) patient by FRAXA testing. MLPA and CMA thus achieved identical reliability with respect to clinically relevant findings. As such, MLPA could be useful as a fast and inexpensive test in patients with syndromic autism. The detection rate of potentially pathogenic variants (VOUS—likely pathogenic) achieved by CMA was higher than that for MLPA (13.04% vs. 4.35%). However, there was no corresponding difference in the rate of unambiguous diagnoses of ASD patients. In addition, the results obtained suggest that DOCK8 may play a role in the etiology of ASD.

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 Peruvian Newborn Male with 3p13 Deletion Syndrome Encompassing the FOXP1 Gene: Review of the Literature

2020 ◽  
Vol 09 (04) ◽  
pp. 270-278
Author(s):  
Hugo H. Abarca-Barriga ◽  
Milana Trubnykova ◽  
Félix Chavesta-Velásquez ◽  
Claudia Barletta-Carrillo ◽  
Marco Ordoñez-Linares ◽  
...  
Keyword(s):  
Copy Number ◽  
Choanal Atresia ◽  
Copy Number Variant ◽  
Autism Spectrum ◽  
Deletion Syndrome ◽  
Chromosomal Microarray ◽  
Facial Dysmorphism ◽  
Chromosomal Microarray Analysis ◽  
Heart Malformation ◽  
Number Variation

AbstractCopy number variation in loss of 3p13 is an infrequently reported entity characterized by hypertelorism, aniridia, microphthalmia, high palate, neurosensorial deafness, camptodactyly, heart malformation, development delay, autism spectrum disorder, seizures, and choanal atresia. The entity is caused probably by haploinsufficiency for FOXP1, UBA3, FAM19A1, and MITF. We report a newborn male with hypotonia, facial dysmorphism, heart malformation, and without clinical diagnosis; nevertheless, the use of appropriate genetic test, such us the chromosomal microarray analysis allowed identification of a copy number variant in loss of 5.5 Mb at chromosome 3 (p13-p14.1), that included 54 genes, encompassing FOXP1 gene. We compare the findings in our Peruvian patient to those of earlier reported patients; furthermore, add new signs for this entity.

scholarly journals 22q11.2 Microduplications: Two Clinical Reports Compared with Similar Cases from the Literature

2020 ◽  
Vol 09 (03) ◽  
pp. 211-220
Author(s):  
Aderonke Oyetunji ◽  
Merlin G. Butler
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
High Resolution ◽  
Autism Spectrum ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Chromosome 22Q11.2 ◽  
Low Copy Repeats ◽  
Velo Cardio Facial Syndrome ◽  
Male Subjects

AbstractWe present two male subjects (6 and 14 years old) with mild dysmorphism, intellectual disability, and/or autism spectrum disorder with chromosome 22q11.2 microduplications of different sizes. We then compared the clinical and genetic findings with similar cases from the literature sharing the same 22q11.2 duplications. These rare duplications in our subjects were identified by high-resolution chromosomal microarray analysis and flanked by low copy repeats in the 22q11.2 region, specifically LCR22A, LCR22B, and LCR22D. The typical 22q11.2 defect generally involves a deletion at breakpoints LCR22A and LCR22D causing DiGeorge or velo-cardio-facial syndrome and not duplications of varying sizes as seen in our male subjects.

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