Detection of submicroscopic chromosomal abnormalities using microarray analysis:The value and pitfalls in prenatal and postnatal diagnosis

Chromosomal microarray enables identifying small genomic deletions and duplications that are not routinely seen on karyotyping. Microarray analysis therefore has emerged as a primary diagnostic tool for the evaluation of developmental delay and structural malformations in children in the Netherlands since 2008. When invasive prenatal diagnosis is indicated, because of ultrasound abnormalities and/or an increased risk for common aneuploidies (trisomy 21, 18 or 13) at first trimester screening, microarray analysis instead of conventional karyotyping will be applied when targeted molecular rapid aneuploidy detection reveals no abnormalities. Microarray analysis provides around 12-15% extra diagnosis in cases of mental retardation and/or structural abnormalities and it can provide 6% extra diagnosis in prenatal samples with a normal karyotype. Besides finding evident causative abnormalities, microarray analysis increases the detection rates of VOUS (variants of unknown significance) that, in particular during a pregnancy, induce emotional burden en counselling difficulties. Furthermore, CNVs that are pathogenic but not related with the phenotype (e.g. deletion of an oncogene) may complicate pretest and posttest counselling as well, since these findings may have health consequences for both patient and family members. Clinicians who request microarray analysis should be aware of these implications. In this paper, two prenatal and four postnatal case reports illustrate the ability to identify more clinically relevant abnormalities, but also limitations and coincidental findings in microarray analysis.</p

More Clinical Overlap between 22q11.2 Deletion Syndrome and CHARGE Syndrome than Often Anticipated

CHARGE (coloboma, heart defects, atresia of choanae, retardation of growth and development, genital hypoplasia, and ear abnormalities) and 22q11.2 deletion syndromes are variable, congenital malformation syndromes that show considerable phenotypic overlap. We further explored this clinical overlap and proposed recommendations for the genetic diagnosis of both syndromes. We described 2 patients clinically diagnosed with CHARGE syndrome, who were found to carry a 22q11.2 deletion, and searched the literature for more cases. In addition, we screened our cohort of CHD7 mutation carriers (n = 802) for typical 22q11.2 deletion features and studied CHD7 in 20 patients with phenotypically 22q11.2 deletion syndrome but without haploinsufficiency of TBX1. In total, we identified 5 patients with a clinical diagnosis of CHARGE syndrome and a proven 22q11.2 deletion. Typical 22q11.2 deletion features were found in 30 patients (30/802, 3.7%) of our CHD7 mutation-positive cohort. We found truncating CHD7 mutations in 5/20 patients with phenotypically 22q11.2 deletion syndrome. Differentiating between CHARGE and 22q11.2 deletion syndromes can be challenging. CHD7 and TBX1 probably share a molecular pathway or have common target genes in affected organs. We strongly recommend performing CHD7 analysis in patients with a 22q11.2 deletion phenotype without TBX1 haploinsufficiency and conversely, performing a genome-wide array in CHARGE syndrome patients without a CHD7 mutation

Rapid exome sequencing as a first-tier test in neonates with suspected genetic disorder:results of a prospective multicenter clinical utility study in the Netherlands

The introduction of rapid exome sequencing (rES) for critically ill neonates admitted to the neonatal intensive care unit has made it possible to impact clinical decision-making. Unbiased prospective studies to quantify the impact of rES over routine genetic testing are, however, scarce. We performed a clinical utility study to compare rES to conventional genetic diagnostic workup for critically ill neonates with suspected genetic disorders. In a multicenter prospective parallel cohort study involving five Dutch NICUs, we performed rES in parallel to routine genetic testing for 60 neonates with a suspected genetic disorder and monitored diagnostic yield and the time to diagnosis. To assess the economic impact of rES, healthcare resource use was collected for all neonates. rES detected more conclusive genetic diagnoses than routine genetic testing (20% vs. 10%, respectively), in a significantly shorter time to diagnosis (15 days (95% CI 10–20) vs. 59 days (95% CI 23–98, p &lt; 0.001)). Moreover, rES reduced genetic diagnostic costs by 1.5% (€85 per neonate). Conclusion: Our findings demonstrate the clinical utility of rES for critically ill neonates based on increased diagnostic yield, shorter time to diagnosis, and net healthcare savings. Our observations warrant the widespread implementation of rES as first-tier genetic test in critically ill neonates with disorders of suspected genetic origin.What is Known:• Rapid exome sequencing (rES) enables diagnosing rare genetic disorders in a fast and reliable manner, but retrospective studies with neonates admitted to the neonatal intensive care unit (NICU) indicated that genetic disorders are likely underdiagnosed as rES is not routinely used.• Scenario modeling for implementation of rES for neonates with presumed genetic disorders indicated an expected increase in costs associated with genetic testing.What is New:• This unique prospective national clinical utility study of rES in a NICU setting shows that rES obtained more and faster diagnoses than conventional genetic tests.• Implementation of rES as replacement for all other genetic tests does not increase healthcare costs but in fact leads to a reduction in healthcare costs.</p

First genotype-phenotype study in TBX4 syndrome : gain-of-function mutations causative for lung disease

Rationale: Despite the increased recognition of TBX4-associated pulmonary arterial hypertension (PAH), genotype-phenotype associations are lacking and may provide important insights. Methods: We assembled a multi-center cohort of 137 patients harboring monoallelic TBX4 variants and assessed the pathogenicity of missense variation (n = 42) using a novel luciferase reporter assay containing T-BOX binding motifs. We sought genotype-phenotype correlations and undertook a comparative analysis with PAH patients with BMPR2 causal variants (n = 162) or no identified variants in PAH-associated genes (n = 741) genotyped via the NIHR BioResource - Rare Diseases (NBR). Results: Functional assessment of TBX4 missense variants led to the novel finding of gain-of-function effects associated with older age at diagnosis of lung disease compared to loss-of-function (p = 0.038). Variants located in the T-BOX and nuclear localization domains were associated with earlier presentation (p = 0.005) and increased incidence of interstitial lung disease (p = 0.003). Event-free survival (death or transplantation) was shorter in the T-BOX group (p = 0.022) although age had a significant effect in the hazard model (p = 0.0461). Carriers of TBX4 variants were diagnosed at a younger age (p < 0.001) and had worse baseline lung function (FEV1, FVC) (p = 0.009) compared to the BMPR2 and no identified causal variant groups. Conclusions: We demonstrated that TBX4 syndrome is not strictly the result of haploinsufficiency but can also be caused by gain-of-function. The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains

Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries.

RATIONALE: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. OBJECTIVE: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. METHODS AND RESULTS: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10 CONCLUSIONS: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 nea

Progressive facial hemiatrophy: a complex disorder not only affecting the face. A report in a monozygotic male twin pair

Progressive facial hemiatrophy (PFH) is a ubiquitous disease, characterized by hyperpigmentation of the skin followed by unilateral craniofacial atrophy of subcutaneous tissues, including fat, muscle and bone. Hereditary factors have been postulated to be involved in the aetiology of PFH. Yet, the occurrence of PFH in one of two identical male twins reported here makes this possibility unlikely. PFH usually occurs in the first two decades of life, and the clinical presentation resembles linear scleroderma. PFH may be complicated by autoimmune, neurological, ocular and dental disorders. Management of PFH comprises a long term follow-up of somatic disorders, and prevention of psychological problems. Treatment of PFH is symptomatic and consists of plastic surgery after the disease activity has stopped. Conclusion: The occurrence of PFH in one of a monozygotic twin pair suggests that genetic factors are not involved in its aetiology. Early diagnosis of PFH and accurate follow-up is essential to disclose the occurrence of complications

De ziekte van Gaucher op de kinderleeftijd: presentatie en behandeling

M. Gaucher is a lysosomal storage disorder. Patients present with hepatosplenomegaly or with complaints of the bones. Clinically 3 subtypes can be distinguished; the 'adult' type I is most frequent found. On the basis of 10 case histories the presentation in childhood is reported. Only recently treatment with enzyme replacement therapy became available. The possibilities for the treatment of M. Gaucher are discusse

The Role of Maternal-Fetal Cholesterol Transport in Early Fetal Life:Current Insights

<p>The importance of maternal cholesterol as an exogenous cholesterol source for the growing embryo was first reported in studies of Smith-Lemli-Opitz syndrome. Although most of the fetus's cholesterol is synthesized by the fetus itself, there is now growing evidence that during the first weeks of life, when most organs develop, the fetus largely depends on maternal cholesterol as its cholesterol source. The maternal-fetal cholesterol transport mechanism, by transporters in both the yolk sac and placenta, is becoming better understood. This minireview summarizes current insights on maternal-fetal cholesterol transport based on in vitro and in vivo studies. As the prevalence of maternal diseases, such as diabetes, obesity, and the metabolic syndrome that adversely affect maternal cholesterol levels, is now rapidly reaching epidemic proportions, we urgently need to determine the impact of these maternal conditions on the developing human fetus.</p>