Nele Cosemans

Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases

Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100). Clinical follow-up for NAA15, KMT5B, and ASH1L highlighted new syndromic and nonsyndromic forms of disease.

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 (five from Africa and five 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.

Noise-robust assessment of SNP array based CNV calls through local noise estimation of log R ratios

Abstract Arrays based on single nucleotide polymorphisms (SNPs) have been successful for the large scale discovery of copy number variants (CNVs). However, current CNV calling algorithms still have limitations in detecting CNVs with high specificity and sensitivity, especially in case of small (<100 kb) CNVs. Therefore, this study presents a simple statistical analysis to evaluate CNV calls from SNP arrays in order to improve the noise-robustness of existing CNV calling algorithms. The proposed approach estimates local noise of log R ratios and returns the probability that a certain observation is different from this log R ratio noise level. This probability can be triggered at different thresholds to tailor specificity and/or sensitivity in a flexible way. Moreover, a comparison based on qPCR experiments showed that the proposed noise-robust CNV calls outperformed original ones for multiple threshold values.

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

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.

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.