Analysis of autosomal CNV profiles in patients and siblings in autism families

Cosemans N., Brison N., Noens I., Claes P., Vermeesch J., Devriendt K., Peeters H., ''Analysis of autosomal CNV profiles in patients and siblings in autism families'', Abstract book 15th annual BeSHG meeting - Behaviour: Is it genetically determined?, pp. 92, March 6, 2015, Charleroi, Belgium.status: publishe

Analysis of autosomal CNV profiles in patients and siblings in autism families: The contribution of variants of unknown significance

Cosemans N., Brison N., Noens I., Claes P., Vermeesch J., Devriendt K., Peeters H., ''Analysis of autosomal CNV profiles in patients and siblings in autism families: The contribution of variants of unknown significance'', Abstract book 17th international workshop on fragile X and other early-onset cognitive disorders, pp. 24-25, September 27-30, 2015, Illkirch, Strasbourg, France.status: publishe

Analyses of variants of unknown significance in families with non-syndromic autism spectrum disorders and normal intelligence

Peeters H., Cosemans N., Brison N., Noens I., Claes P., Vermeesch J., Devriendt K., ''Analyses of variants of unknown significance in families with non-syndromic autism spectrum disorders and normal intelligence'', Proceedings Genomics disorders meeting: Genomics of Rare Diseases – Beyond the Exome, April 29 - May 1, 2015, Cambridge, UK.status: publishe

Executive functioning and local-global visual processing: Candidate endophenotypes for autism spectrum disorder?

Background: Heterogeneity within autism spectrum disorder (ASD) hampers insight in the etiology and has stimulated the search for endophenotypes. Endophenotypes should meet several criteria, the most important being the association with ASD and the higher occurrence rate in unaffected ASD relatives than in the general population. We evaluated these criteria for executive functioning (EF) and local-global (L-G) visual processing. Methods: By administering an extensive cognitive battery that increases validity of the measures, we examined which of the cognitive anomalies shown by ASD probands also occur in their unaffected relatives (n = 113) compared to typically developing (TD) controls (n = 100). We also provided an overview of studies investigating EF and L-G processing in ASD relatives. Results: For EF, ASD relatives - like ASD probands - showed impairments in response inhibition, cognitive flexibility and generativity (particularly ideational fluency), and EF impairments in daily life. For L-G visual processing, the ASD relatives showed no anomalies on the tasks, but they reported more attention to detail in daily life. Group differences were similar for siblings and for parents of ASD probands, and yielded larger effect sizes in a multiplex subsample. The group effect sizes for the comparison between ASD probands and TD individuals were generally larger than those of the ASD relatives compared to TD individuals. Conclusions: Impaired cognitive flexibility, generativity (specifically ideational fluency) and response inhibition are strong candidate endophenotypes for ASD. Despite resistance to endophenotypic approaches in psychiatry, we argue that endophenotypes are important to bridge the gap between genes and behavior.status: publishe

ZNF462 and KLF12 are disrupted by a de novo translocation in a patient with syndromic intellectual disability and autism spectrum disorder

We describe a patient with a de novo balanced translocation 46,XY,t(9; 13)(q31.2; q22.1) and autism spectrum disorder, intellectual disability, a metopic craniosynostosis, a corpus callosum dysgenesis and dysmorphic facial features, most notably ptosis. Breakpoint mapping was performed by means of targeted locus amplification (TLA) and sequencing, because conventional breakpoint mapping by means of fluorescent in situ hybridization and long-range PCR was hampered by a complex submicroscopic rearrangement. The translocation breakpoints directly affected the genes KLF12 (chromosome 13) and ZNF462 (chromosome 9). The latter gene was disrupted by multiple breakpoints, resulting in the loss of three fragments and a rearrangement of the remaining fragments. Therefore, haploinsufficiency of ZNF462 was assumed. Loss-of-function variants in ZNF462 have recently been published by Weiss et al. (2017) in a series of eight patients from six independent families delineating the ZNF462-associated phenotype. The latter closely matches with the clinical features of the current translocation patient. Besides, no direct evidence for an association of KLF12 to the phenotypic features was found. Therefore, we conclude that the phenotype of the current patient is mainly caused by the disruption of ZNF462. We present clinical data from birth to adulthood and data on the cognitive and behavioral profile of the current patient which may add to a more precise counseling and surveillance of development in young children with ZNF462 mutations. In addition, the current case illustrates that TLA is an efficient method for determining complex chromosomal breakpoints.status: publishe

Genetic profile of isolated congenital diaphragmatic hernia revealed by targeted next-generation sequencing

BACKGROUND: Congenital diaphragmatic hernia (CDH) is characterized by a defective closure of the diaphragm occurring as an isolated defect in 60% of cases. Lung size, liver herniation, and pulmonary circulation are major prognostic indices. Isolated CDH genetics is heterogeneous and poorly understood. Whether genetic lesions are also outcome determinants has never been explored. OBJECTIVES: To identify isolated CDH genetic causes, to fine map the mutational burden, and to search for a correlation between the genotype and the disease severity and outcome. METHODS: Targeted massively parallel sequencing of 143 human and mouse CDH causative and candidate genes in a cohort of 120 fetuses with isolated CDH and detailed outcome measures. RESULTS: Pathogenic and likely pathogenic variants were identified in 10% of the cohort. These variants affect both known CDH causative genes, namely, ZFPM2, GATA4, and NR2F2, and new genes, namely, TBX1, TBX5, GATA5, and PBX1. In addition, mutation burden analysis identified LBR, CTBP2, NSD1, MMP14, MYOD1, and EYA1 as candidate genes with enrichment in rare but predicted deleterious variants. No obvious correlation between the genotype and the phenotype or short-term outcome has been found. CONCLUSION: Targeted resequencing identifies a genetic cause in 10% of isolated CDH and identifies new candidate genes.status: publishe

The clinical relevance of intragenic NRXN1 deletions

BACKGROUND: Intragenic NRXN1 deletions are susceptibility variants for neurodevelopmental disorders; however, their clinical interpretation is often unclear. Therefore, a literature study and an analysis of 43 previously unpublished deletions are provided. METHODS: The literature cohort covered 629 heterozygous NRXN1 deletions: 148 in controls, 341 in probands and 140 in carrier relatives, and was used for clinical hypothesis testing. Exact breakpoint determination was performed for 43 in-house deletions. RESULTS: The prevalence of exonic NRXN1 deletions in controls was ~1/3000 as compared with ~1/800 in patients with neurodevelopmental/neuropsychiatric disorders. The differential distribution of deletions across the gene between controls and probands allowed to distinguish distinct areas within the gene. Exon 6-24 deletions appeared only twice in over 100000 control individuals, had an estimated penetrance for neurodevelopmental disorders of 32.43%, a de novo rate of 50% and segregated mainly with intellectual disability (ID) and schizophrenia. In contrast, exon 1-5 deletions appeared in 20 control individuals, had an estimated penetrance of 12.59%, a de novo rate of 32.5% and were reported with a broad range of neurodevelopmental phenotypes. Exact breakpoint determination revealed six recurrent intron 5 deletions. CONCLUSION: Exon 6-24 deletions have a high penetrance and are mainly associated with ID and schizophrenia. In contrast, the actual contribution of exon 1-5 deletions to a neurodevelopmental/neuropsychiatric disorder in an individual patient and family remains very difficult to assess. To enhance the clinical interpretation, this study provides practical considerations for counselling and an interactive table for comparing a deletion of interest with the available literature data.status: publishe

Facial dysmorphism is influenced by ethnic background of the patient and of the evaluator

The evaluation of facial dysmorphism is a critical step toward reaching a diagnostic. The aim of the present study was to evaluate the ability to interpret facial morphology in African children with intellectual disability (ID). First, 10 experienced clinicians (5 from Africa and 5 from Europe) rated gestalt in 127 African non-Down Syndrome (non-DS) patients using either the score 2 for "clearly dysmorphic", 0 for "clearly non dysmorphic" or 1 for "uncertain". The inter-rater agreement was determined using kappa coefficient. There was only fair agreement between African and European raters (kappa-coefficient = 0.29). Second, we applied the FDNA Face2Gene solution to assess Down Syndrome (DS) faces. Initially, Face2Gene showed a better recognition rate for DS in Caucasian (80 %) compared to African (36.8 %). We trained the Face2Gene with a set of African DS and non-DS photographs. Interestingly, the recognition in African increased to 94.7 %. Thus, training improved the sensitivity of Face2Gene. Our data suggest that human based evaluation is influenced by ethnic background of the evaluator. In addition, computer based evaluation indicates that the ethnic of the patient also influences the evaluation and that training may increase the detection specificity for a particular ethnic.status: publishe