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Background: Learning disabilities are one of the most consistently reported features in Velo-Cardio-Facial Syndrome (VCFS). Earlier reports on IQ in children with VCFS were, however, limited by small sample sizes and ascertainment biases. The aim of the present study was therefore to replicate these earlier findings and to investigate intellectual abilities in a large sample of children with VCFS. In addition, we aimed to identify factors that may contribute to within-syndrome variability in cognitive performance, such as the mode of inheritance of the deletion, sex, the presence of a heart defect and psychiatric morbidity. Method: IQ data of 103 children with VCFS (56 males, 47 females) were collected. Psychiatric diagnosis was additionally recorded. Results: Children with VCFS had a mean full-scale IQ (FSIQ) of 73.48 (range: 50-109). There were no effects of sex, presence of a heart defect and psychiatric condition on intellectual profile. Inheritance of the deletion affected cognitive performance in VCFS, with children with familial deletions having significant lower FSIQ than children with a "de novo" deletion. Conclusions: Learning disabilities are very common in children with VCFS, although marked within syndrome variability is noted. One factor contributing to this variability seems to be the mode of inheritance of the deletion.

The 22q11.2 deletion syndrome (22q11.2DS) is one of the most frequent microdeletion syndromes and presents with a highly variable phenotype. In most affected individuals, specific but subtle facial features can be seen. In this observational study, we aim to investigate the craniofacial and dental features of 20 children with a confirmed diagnosis of 22q11.2DS by analyzing 3-dimensional (3D) facial surface scans, 2-dimensional (2D) clinical photographs, panoramic and cephalometric radiographs, and dental casts. The 3D facial scans were compared to scans of a healthy control group and analyzed using a spatially dense geometric morphometric approach. Cephalometric radiographs were digitally traced, and measurements were compared to existing standards. Occlusal and dental features were studied on dental casts and panoramic radiographs. Interestingly, a general trend of facial hypoplasia in the lower part of the face could be evidenced with the 3D facial analysis in children with 22q11.2DS compared to controls. Cephalometric analysis confirmed a dorsal position of the mandible to the maxilla in 2D and showed an enlarged cranial base angle. Measurements for occlusion did not differ significantly from standards. Despite individual variability, we observed a retruded lower part of the face as a common feature, and we also found a significantly higher prevalence of tooth agenesis in our cohort of 20 children with 22q11.2DS (20%). Furthermore, 3D facial surface scanning proved to be an important noninvasive, diagnostic tool to investigate external features and the underlying skeletal pattern. [ABSTRACT FROM AUTHOR]

Background: The Netherlands and Belgium have been among the first countries to offer non-invasive prenatal testing (NIPT) as a first-tier screening test. Despite similarities, differences exist in counseling modalities and test uptake. This study explored decision-making and perspectives of pregnant women who opted for NIPT in both countries., Methods: A questionnaire study was performed among pregnant women in the Netherlands (NL) (n = 587) and Belgium (BE) (n = 444) opting for NIPT, including measures on informed choice, personal and societal perspectives on trisomy 21, 18 and 13 and pregnancy termination., Results: Differences between Dutch and Belgian women were shown in the level of informed choice (NL: 83% vs. BE: 59%, p < 0.001), intention to terminate the pregnancy in case of confirmed trisomy 21 (NL: 51% vs. BE: 62%, p = 0.003) and trisomy 13/18 (NL: 80% vs. BE: 73%, p = 0.020). More Belgian women considered trisomy 21 a severe condition (NL: 64% vs. BE: 81%, p < 0.001). Belgian women more frequently indicated that they believed parents are judged for having a child with trisomy 21 (BE: 42% vs. NL: 16%, p < 0.001) and were less positive about quality of care and support for children with trisomy 21 (BE: 23% vs. NL: 62%, p < 0.001)., Conclusion: Differences in women's decision-making regarding NIPT and the conditions screened for may be influenced by counseling aspects and country-specific societal and cultural contexts., (© 2023 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Cancer is diagnosed in one in 1000 to 1500 pregnancies. Most frequently encountered malignancies during pregnancy are breast cancer, hematological cancer, cervical cancer and malignant melanoma. Maternal cancer is associated with an increased risk of IUGR and preterm labor, especially in patients with systemic disease or those receiving chemotherapy during pregnancy, requiring a high-risk obstetrical follow-up. Fetal aneuploidy screening by non-invasive prenatal testing (NIPT) can lead to the incidental identification of copy number alterations derived from non-fetal cell-free DNA (cfDNA), as seen in certain cases of maternal malignancy. The identification of tumor-derived cfDNA requires further clinical, biochemical, radiographic and histological investigations to confirm the diagnosis. In such cases, reliable risk estimation for fetal trisomy 21, 18 and 13 is impossible. Therefore, invasive testing should be offered when ultrasonographic screening reveals an increased risk for chromosomal anomalies, or when a more accurate test is desired. When the fetal karyotype is normal, long term implications for the fetus refer to the consequences of the maternal disease and treatment during pregnancy. This manuscript addresses parental questions when NIPT suggests a maternal malignancy. Based on current evidence and our own experience, a clinical management scheme in a multidisciplinary setting is proposed., (© 2021 John Wiley & Sons Ltd.)

Objective: Belgian genetic centers established a database containing data on all chromosomal microarrays performed in a prenatal context. A study was initiated to evaluate postnatal development in children diagnosed prenatally with a non-benign copy number variant (CNV)., Methods: All children diagnosed with a prenatally detected non-benign CNV in a Belgian genetic center between May 2013 and February 2015 were included in the patient population. The control population consisted of children who had undergone an invasive procedure during pregnancy, with no or only benign CNVs. Child development was evaluated at 36 months using three (3) questionnaires: Ages and Stages Questionnaire Third edition, Ages and Stages Questionnaire Social-Emotional Second Edition and a general questionnaire., Results: A significant difference in communication and personal-social development was detected between children with a reported susceptibility CNV and both children with an unreported susceptibility CNV and the control population. The outcome of children with a particular CNV is discussed in a case-by-case manner., Conclusion: Our postnatal follow-up project of children with a prenatally detected non-benign CNV is the first nationwide project of its kind. A higher number of cases for each CNV category is however needed to confirm our findings., (© 2020 John Wiley & Sons, Ltd.)

Non-syndromic cleft lip with or without cleft palate (nsCL/P) ranks among the most common human congenital malformations, and has a multifactorial background in which both exogenous and genetic risk factors act in concert. The present report describes a genome-wide association study (GWAS) involving a total of 285 nsCL/P patients and 1212 controls from the Netherlands and Belgium. Twenty of the 40 previously reported nsC/LP susceptibility loci were replicated, which underlined the validity of this sample. SNV-based analysis of the data identified an as yet unreported suggestive locus at chromosome 16p12.1 ( p -value of the lead SNV: 4.17 × 10 -7 ). This association was replicated in two of three patient/control replication series (Central European and Yemeni). Gene analysis of the GWAS data prioritized SH3PXD2A at chromosome 10q24.33 as a candidate gene for nsCL/P. To date, support for this gene as a cleft gene has been restricted to data from zebrafish and a knockout mouse model. The present GWAS was the first to implicate SH3PXD2A in non-syndromic cleft formation in humans. In summary, although performed in a relatively small sample, the present GWAS generated novel insights into nsCL/P etiology.

Objective: With the replacement of karyotyping by chromosomal microarray (CMA) in invasive prenatal diagnosis, new challenges have arisen. By building a national database, we standardize the classification and reporting of prenatally detected copy number variants (CNVs) across Belgian genetic centers. This database, which will link genetic and ultrasound findings with postnatal development, forms a unique resource to investigate the pathogenicity of variants of uncertain significance and to refine the phenotypic spectrum of pathogenic and susceptibility CNVs., Methods: The Belgian MicroArray Prenatal (BEMAPRE) consortium is a collaboration of all genetic centers in Belgium. We collected data from all invasive prenatal procedures performed between May 2013 and July 2016., Results: In this three-year period, 13 266 prenatal CMAs were performed. By national agreement, a limited number of susceptibility CNVs and no variants of uncertain significance were reported. Added values for using CMA versus conventional karyotyping were 1.8% in the general invasive population and 2.7% in cases with an ultrasound anomaly. Of the reported CNVs, 31.5% would have remained undetected with non-invasive prenatal test as the first-tier test., Conclusion: The establishment of a national database for prenatal CNV data allows for a uniform reporting policy and the investigation of the prenatal and postnatal genotype-phenotype correlation., (© 2018 John Wiley & Sons, Ltd.)

Purpose: Idiopathic infantile nystagmus (IIN; OMIM 31700) with X-linked inheritance is one of the most common forms of infantile nystagmus. Up to date, three X-linked loci have been identified, Xp11.4-p11.3 (calcium/calmodulin-dependent serine protein kinase [CASK]), Xp22 (GPR143), and Xq26-q27 (FRMD7), respectively. Here, we investigated the role of mutations and copy number variations (CNV) of FRMD7 and GPR143 in the molecular pathogenesis of IIN in 49 unrelated Belgian probands., Methods: We set up a comprehensive molecular genetic workflow based on Sanger sequencing, targeted next generation sequencing (NGS) and CNV analysis using multiplex ligation-dependent probe amplification (MLPA) for FRMD7 (NM&#95;194277.2) and GPR143 (NM&#95;000273.2)., Results: In 11/49 probands, nine unique FRMD7 changes were found, five of which are novel: frameshift mutation c.2036del, missense mutations c.801C>A and c.875T>C, splice-site mutation c.497+5G>A, and one genomic rearrangement (1.29 Mb deletion) in a syndromic case. Additionally, four known mutations were found: c.70G>A, c.886G>C, c.910C>T, and c.660del. The latter was found in three independent families. In silico predictions and segregation testing of the novel mutations support their pathogenic effect. No GPR143 mutations or CNVs were found in the remainder of the probands (38/49)., Conclusions: Overall, genetic defects of FRMD7 were found in 11/49 (22.4%) probands, including the first reported genomic rearrangement of FRMD7 in IIN, expanding its mutational spectrum. Finally, we generate a discovery cohort of IIN patients potentially harboring either hidden a variation of FRMD7 or mutations in genes at known or novel loci sustaining the genetic heterogeneity of IIN., (Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.)

After their successful introduction in postnatal testing, genome-wide arrays are now rapidly replacing conventional karyotyping in prenatal diagnostics. While previous studies have demonstrated the advantages of this method, we are confronted with difficulties regarding the technology and the ethical dilemmas inherent to genomic arrays. These include indication for testing, array design, interpretation of variants and how to deal with variants of unknown significance and incidental findings. The experiences with these issues reported in the literature are most often from single centres. Here, we report on a national consensus approach how microarray is implemented in all genetic centres in Belgium. These recommendations are subjected to constant re-evaluation based on our growing experience and can serve as a useful tool for those involved in prenatal diagnosis., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Microduplication 22q11.2 is a recently discovered genomic disorder. So far, targeted research on the cognitive and behavioral characteristics of individuals with this microduplication is limited. Therefore, 11 Flemish children (3-13 years old) with a microduplication 22q 1.2 were investigated in order to describe their clinical, developmental and behavioral characteristics. We measured their general intelligence, visual-motor capacities, attention, behavioral problems and characteristics of autism. In addition, there was an interview with the parents on developmental history and we reviewed available information from other specialists. The results show that the cognitive and behavioral phenotype of the children with microduplication 22q.11.2 is very wide and heterogeneous. Some of the children have a cognitively nearly normal development whereas others are more severely affected. All children had some degree of developmental delay and some of them have an intellectual disability. The most common clinical features include congenital malformations such as heart defects and cleft lip, feeding problems, hearing impairment and facial dysmorphism. The most common non-medical problems are learning difficulties, motor impairment, attention deficits, social problems and behavioral problems. There is no correlation between the size of the duplication and the phenotype.

X-linked mental retardation (XLMR) is a heterogeneous disorder that can be classified as either non-specific (MRX), when mental retardation is the only feature, or as syndromic mental retardation (MRXS). Genetic defects underlying XLMR are being identified at a rapid pace, often starting from X-chromosomal aberrations and XLMR families with a well-defined linkage interval. Here, we present a new family with a syndromic form of XLMR, including mild mental retardation, short stature, microcephaly and hypogonadism. Two-point linkage analysis with 24 polymorphic markers spanning the entire X chromosome was carried out. We could assign the causative gene to a 6 cM interval in Xp22.1-p21.3, with a maximum LOD score of 2.61 for markers DXS989 and DXS1061 at theta = 0.00. No mutations were found in the presented family for two known MRX genes mapping to this interval, ARX and IL1RAPL-1. These data indicate that the interval Xp22.1-p21.3 contains at least one additional MRXS gene.

The identification of all people with a diagnosis of Prader-Willi syndrome (PWS) confirmed by DNA methylation analysis living in Flanders was attempted through contact with the four genetic centres and the PWS Association. The birth incidence for the period 1993-2001 was 1:26 676, the minimum prevalence at 31 December 2001 was 1:76 574. A decreasing number of cases with age was found, which can be explained by a number of missing cases in the older population, a higher neonatal mortality in the past and an increasing mortality with age. Childhood death is usually sudden and associated with respiratory infection and high temperature, while the cause of death in adults is considered to be circulatory or respiratory in origin.

Parenting, family contexts, and personality characteristics in youngsters with VCFS: The personality profiles for 48 youths with Velo-Cardio-Facial syndrome (VCFS) were described using the California Child Q-Set (CCQ). Associations between personality characteristics and parenting (i.e., Control and Warmth vs. Anger) and family contexts (i.e., Experienced Family Stress, Marital Conflict and Parental Consistency) were investigated. Personality characteristics were found to be related to parenting (in particular, Parental Warmth vs. Anger) but not to family contexts. Parents who reported more Parental Warmth (and less Anger) in interactions had children with higher Agreeableness, Conscientiousness and Emotional Stability and with lower Irritability and Dependency. Parental Control was positively related to children's Dependency and negatively to children's Conscientiousness. Compared to fathers, mothers exerted more Control. Differences in parenting and family contexts were related to the mode of inheritance but not to IQ, age, gender, and cardiac defects. Families in which a familial deletion occurred reported higher levels of Marital Conflict and lower Warmth in the parent-child interactions.

School-aged children with del22q11.2 tend to show a typical learning and neuropsychological profile, which is characterised by a VIQ-PIQ discrepancy (in favour of the VIQ) and significantly better scores for reading (decoding) and spelling compared to mathematics. To the best of our knowledge, there exists no systematic research on the pre-academic and early academic skills that might underpin these learning difficulties. The purpose of the current study was to investigate more systematically these pre-academic and early academic skills in borderline to normal intelligent (FSIQ > 70) children with del22q11.2 in the last year of kindergarten and first grade of primary school in Flanders. In the kindergarten group, meta-linguistic awareness and counting skills were examined. In the group of first graders, children were tested on reading, spelling and mathematics. Thirteen children (mean age: 6 years 4 months (SD = 0.84); 9 boys, 4 girls) participated in this study. In the present study, there were no differences in intelligence and academic outcomes between boys and girls, and no differences in IQ and academic achievement between children with cardiac defects or severe velopharyngeal insufficiency (VPI) and children without these deficits. With regard to pre-academic achievement in general, a characteristic profile with clearly better results for meta-linguistic awareness in comparison to counting skills was found, but this difference is not statistically significant. Concerning early academic achievement, children with del22q11.2, as a group, perform (despite their somewhat lower general intelligence) on average compared with their age-related peers. However, at an individual level--especially within the domain of counting skills and mathematics--there is a wide variability, with some children showing remarkable learning difficulties already at an early age.

The personality profile of 48 youngsters (24 males and 24 females, mean age 8 years, 5 months) with Velo-Cardio-Facial Syndrome (VCFS) was compared with a group of 240 non VCFS control youngsters (matched on age and gender), and, in addition, with groups of youngsters with Prader-Willi (PWS), Fragile X (FXS), and Williams Syndromes (WS). Personality characteristics of each youngster were rated by both parents, using the California Child Q-set (CCQ). The scores on eight personality dimensions were compared, i.e., Extraversion, Agreeableness, Conscientiousness, Emotional Stability, Openness, Motor Activity, Irritability, and Dependency. Moreover, Individual differences in personality of VCFS youngsters were related to IQ level, presence or absence of cardiac defects, and de novo versus familial origin of VCFS. The personality profile of VCFS youngsters was markedly different from all non-VCFS groups. Compared to the 240 control children, they were equally extravert and agreeable, less conscientious and emotional stable and more Irritable and dependent. Some personality characteristics in youngsters with VCFS were related to IQ and Age, but not to cardiac defects or de novo versus familial genetic origin of the 22q11 deletion.

The velo-cardio-facial syndrome (VCFS) is a leading cause of velopharyngeal dysfunction and cleft palate and caused by a submicroscopic deletion in the long arm of chromosome 22 (band 22q11). During the last 5 years, 130 patients with a 22q11 deletion were diagnosed in Leuven. Most patients presented a wide variety of the classical features of the velo-cardio-facial syndrome. Velopharyngeal dysfunction was almost always present whereas an isolated cleft lip/palate was observed in a minority of patients. The velopharyngeal function can be evaluated by the classic combination of indirect and direct techniques. Because of the frequent occurrence of the velo-cardio-facial syndrome, estimated at around 1/4000 live births, and given the extremely broad clinical spectrum which makes clinical diagnosis difficult, screening of patients with velopharyngeal dysfunction for a deletion 22q11 is indicated.

The combination of X-linked mental retardation (XLMR) and neurological disorders occurs in a number of syndromes. Differential diagnosis mostly depends on clinical data and mapping of responsible genes by linkage analysis. We present a Belgian family with severe XLMR and a progressive neurological disorder with ataxia, spasticity and convulsions. Biochemical investigations, neuroimaging and neuropathology were normal. Linkage analysis pointed to region Xq27-28 as the probable locus for the genetic defect. The sequence of the L1CAM cDNA, a possible candidate gene, proved to be normal in the patients. This suggests the presence of a genetic factor on Xq27-28, different from L1CAM, which can lead to severe XLMR and a progressive neurological disorder.