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Background: Despite the established knowledge that recurrent copy number variants (CNVs) at the 16p11.2 locus BP4–BP5 confer risk for behavioural and language difficulties, limited research has been conducted on the association between behavioural and social–communicative profiles. The current study aims to further delineate the prevalence, nature and severity of, and the association between, behavioural and social–communicative features of school‐aged children with 16p11.2 deletion syndrome (16p11.2DS) and 16p11.2 duplication (16p11.2Dup). Methods: A total of 68 individuals (n = 47 16p11.2DS and n = 21 16p11.2Dup) aged 6–17 years participated. Standardised intelligence tests were administered, and behavioural and social–communicative skills were assessed by standardised questionnaires. Scores of both groups were compared with population norms and across CNVs. The influence of confounding factors was investigated, and correlation analyses were performed. Results: Compared with the normative sample, children with 16p11.2DS showed high rates of social responsiveness (67%) and communicative problems (69%), while approximately half (52%) of the patients displayed behavioural problems. Children with 16p11.2Dup demonstrated even higher rates of social–communicative problems (80–90%) with statistically significantly more externalising and overall behavioural challenges (89%). In both CNV groups, there was a strong positive correlation between behavioural and social–communicative skills. Conclusions: School‐aged children with 16p11.2 CNVs show high rates of behavioural, social responsiveness and communicative problems compared with the normative sample. These findings point to the high prevalence of autistic traits and diagnoses in these CNV populations. Moreover, there is a high comorbidity between behavioural and social–communicative problems. Patients with difficulties in both domains are vulnerable and need closer clinical follow‐up and care. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Array comparative genomic hybridization (aCGH) has led to an increased detection of causal chromosomal imbalances in individuals with congenital heart defects (CHD). The introduction of aCGH as a diagnostic tool in a clinical cardiogenetic setting entails numerous challenges. Based on our own experience as well as those of others described in the literature, we outline the state of the art and attempt to answer a number of outstanding questions such as the detection frequency of causal imbalances in different patient populations, the added value of higher-resolution arrays, and the existence of predictive factors in syndromic cases. We introduce a step-by-step approach for clinical interpretation of copy number variants (CNV) detected in CHD, which is primarily based on gene content and overlap with known chromosomal syndromes, rather than on CNV inheritance and size. Based on this algorithm, we have reclassified the detected aberrations in aCGH studies for their causality for syndromic and non-syndromic CHD. From this literature overview, supplemented with own investigations in a cohort of 46 sporadic patients with severe non-syndromic CHD, it seems clear that the frequency of causal CNVs in non-syndromic CHD populations is lower than that in syndromic CNV populations (3.6 vs. 19%). Moreover, causal CNVs in non-syndromic CHD mostly involve imbalances with a moderate effect size and reduced penetrance, whereas the majority of causal imbalances in syndromic CHD consistently affects human development and significantly reduces reproductive fitness. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Genome-wide haplotyping strategies, such as karyomapping, haplarithmisis and OnePGT, have paved the way for comprehensive PGT, leveraging PGT-M, PGT-A and PGT-SR in a single workflow. Nevertheless, family-specific challenges can complicate the implementation of current methods. First, to enable haplotype reconstruction, genotyping the prospective parents and direct family members, i.e. offspring of the couple or their parent(s), is required. However, if these references are not available or suitable for phasing, such approaches cannot be used, prompting investigation towards alternative phasing modules. Additionally, the advancement of current technologies leads to the identification of an increasing number of variants of unknown significance. Development of novel analysis approaches can assist further evaluation and interpretation of such variants, based on the familial segregation of the variant, in order to assess if PGT is an appropriate clinical option. Twelve couples i) burdened with a known hereditary genetic disorder participating in the genome-wide haplotyping-based PGT-M program and ii) with at least one parental sibling from the parental side carrying the genetic disorder available, were recruited for the development of the new method. Genotyping data from both prospective parents and parental sibling(s) were used to trace the shared and/or different allele and impute the disease-carrying allele based on identity-by-state (IBS) information. Concurrent haplotyping and copy number typing of embryo biopsies was then performed using an adapted version of siCHILD/haplarithmisis. Six out of 12 (50%) PGT-M couples could be phased using parental sibling(s). This is in line with the theoretical expectations of allele-sharing between sibling-pairs. Genome-wide haplotypes and copy-number profiles generated for each embryo using the new phasing approach were consequently compared to the clinical results, showing 100% concordancy. Clinical implementation of the method has resulted in the analysis of 7 families so far. Additionally, IBS analysis has enabled the inclusion of two special cases in the PGT program. In the first, PGT-M was offered for an X-linked disorder. The female partner had karyotype 47,XXX with presence of both maternal X chromosomes, so that no distinction could be made between the affected and unaffected allele. In the second, IBS analysis revealed the de novo and consequently pathogenic nature of an autosomal dominant variant in the maternal grandmother, allowing PGT. IBS analysis in the context of PGT can be proven to be advantageous on several levels. First, it allows offering genome-wide linkage analysis-based comprehensive PGT to families lacking standard phasing reference(s). A rapid pre-PGT work-up can define whether the couple can benefit from this technology. Importantly, by including more than one extended family member, the chance of obtaining informative results in the interrogated locus increases. Furthermore, by following the familial segregation of the variant of interest using IBS information, more evidence can be obtained regarding its pathogenicity. This is important for making the decision if the specific indication is valid for PGT. [ABSTRACT FROM AUTHOR]