Search

The application of next-generation sequencing to fetal pathology has proved to increase the diagnostic yield in fetuses with abnormal ultrasounds. We retrospectively reviewed genetic data of 30 selected cases studied through targeted resequencing of OMIM genes. In our experience, clinical data proved to be essential to support diagnostic reasoning and enhance variants' assessment. The molecular diagnosis was reached in 19/30 (63%) cases. Only in 7/19 cases the molecular diagnosis confirmed the initial diagnostic hypothesis, showing the relevance of the genotype-first approach. According to the genotype-phenotype correlation, we were able to divide the solved cases into three groups: i) the correlation is well established but it was missed due to lack of specificity, unusual presentation or recent description; ii) the clinical presentation is much more severe than currently known for the underlying condition; iii) the correlation does not recapitulate the entire phenotype, possibly due to the fetal presentation or multiple coexisting conditions. Moreover, we found a higher proportion of recessive diagnosis in abnormal fetuses compared to cohorts of individuals with developmental delay. Our findings suggest that fetal pathology may be enriched in rare alleles and/or in unusual combinations, counter-selected in postnatal genomes and thus contributing to both phenotypic extremeness and atypical presentation., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Knowledge on the influence of specific genotypes on the phenotypic expression of hypertrophic cardiomyopathy (HCM) is emerging. The objective of this study was to evaluate the genotype-phenotype relation in HCM patients and to construct a score to predict the genetic yield based to improve counseling. Unrelated HCM patients who underwent genetic testing were included in the analysis. Multivariate logistic regression was performed to identify variables that predict a positive genetic test. A weighted score was constructed based on the odds ratios. In total, 378 HCM patients were included of whom 141 carried a mutation (global yield 37%), 181 were mutation negative and 56 only carried a variant of unknown significance. We identified age at diagnosis <45 years, familial HCM, familial sudden death, arrhythmic syncope, maximal wall thickness ≥20 mm, asymmetrical hypertrophy and the absence of negative T waves in the lateral ECG leads as significant predictors of a positive genetic test. When we included these values in a risk score we found very high correlation between the score and the observed genetic yield (Pearson r = 0.98). MYBPC3 mutation carriers more frequently suffered sudden cardiac death compared to troponin complex mutations carriers (p = 0.01) and a similar trend was observed compared to MYH7 mutation carriers (p = 0.08) and mutation negative patients (p = 0.11). To conclude, a simple score system based on clinical variables can predict the genetic yield in HCM index patients, aiding in counseling HCM patients. MYBPC3 mutation carriers had a worse outcome regarding sudden cardiac death., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: Catatonia is a motor dysregulation syndrome co-occurring with a variety of psychiatric and medical disorders. Response to treatment with benzodiazepines and electroconvulsive therapy suggests a neurobiological background. The genetic etiology however remains largely unexplored. Copy Number Variants (CNV), known to predispose to neurodevelopmental disorders, may play a role in the etiology of catatonia., Methods: This study is exploring the genetic field of catatonia through CNV analysis in a cohort of psychiatric patients featuring intellectual disability and catatonia. Fifteen adults admitted to a psychiatric inpatient unit and diagnosed with catatonia were selected for array Comparative Genomic Hybridization analysis at 200 kb resolution. We introduced a CNV interpretation algorithm to define detected CNVs as benign, unclassified, likely pathogenic or causal with regard to catatonia., Results: Co-morbid psychiatric diagnoses in these patients were autism, psychotic or mood disorders. Eight patients were found to carry rare CNVs, which could not be classified as benign, comprising 6 duplications and 2 deletions. Microdeletions on 22q13.3, considered causal for catatonia, were detected in 2 patients. Duplications on 16p11.2 and 22q11.2 were previously implicated in psychiatric disorders, but not in catatonia, and were therefore considered likely pathogenic. Driven by the identification of a rare 14q11.2 duplication in one catatonic patient, additional patients with overlapping duplications were gathered to delineate a novel susceptibility locus for intellectual disability and psychiatric disorders on 14q11.2, harboring the gene SUPT16H. Three remaining variants respectively on 2q36.1, 16p13.13 and 17p13.3 were considered variants of unknown significance., Conclusion: The identification of catatonia-related copy number changes in this study, underscores the importance of genetic research in patients with catatonia. We confirmed that 22q13.3 deletions, affecting the gene SHANK3, predispose to catatonia, and we uncover 14q11.2 duplications as a novel susceptibility factor for intellectual and psychiatric disorders., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Congenital heart defects (CHD) are associated with the recurrent 10q22q23 deletion syndrome and with partially overlapping distal 10q23.2.q23.31 microdeletions. We report on a de novo intragenic deletion of the BMPR1A gene in a normally developing adolescent boy with short stature, delayed puberty, facial dysmorphism and an atrioventricular septal defect. Based on this finding, complemented with computational prioritization data and molecular evidence in literature, the critical region for CHD on 10q23 can be downsized to a single gene, BMPR1A. Although loss-of-function mutations in BMPR1A typically result in juvenile polyposis syndrome, none of the patients with the typical 10q22q23 microdeletion syndrome, comprising this gene, were reported to have juvenile polyposis thus far. We reason that, even in the absence of juvenile polyposis syndrome, sequencing and copy number analysis of BMPR1A should be considered in patients with (atrioventricular) septal defects, especially when associated with facial dysmorphism and anomalous growth., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Loeys-Dietz syndrome (LDS; OMIM:609192) is an autosomal dominant disorder characterized by hypertelorism, bifid uvula or cleft palate, and arterial tortuosity with widespread vascular aneurysms and a high risk of aortic dissection at an early age. LDS results from mutations in the transforming growth factor beta-receptor I and II (TGFBR1 and TGFBR2) genes, altering the transmission of the subcellular TGF-β signal, mediated by increased activation of Smad2. We report on a 17-year-old boy with pubertas tarda, a bifid uvula, camptodactyly and facial dysmorphic features, suggestive of LDS. Mutation analysis of TGFBR1 and TGFBR2 was normal. By means of molecular karyotyping two previously unreported chromosomal imbalances were detected: a 120 kb deletion on chromosome 22q13.31q13.32, inherited from an unaffected parent, and a de novo 14.6 Mb duplication on chromosome 9q22.32q31.3, comprising TGFBR1. We hypothesize that copy number gain of TGFBR1 contributes to the phenotype., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

In 1991, a large family was described with an autosomal dominant inheritance of otological and branchial manifestations which was termed branchio-otic syndrome type 2 (BOS2). This trait was mapped by linkage analysis in this family to a region of 23-31 Mb on chromosome 1q25.1q32.1. In the present report we describe the clinical features of two patients with a deletion in this region: one patient has a deletion but no otological or branchial manifestations, the other patient manifests mild conductive hearing loss resulting from bilaterally malformed middle ear ossicles, as well as a preauricular pit. Mapping of the deletion breakpoints allowed to delineate the region involved in BOS2 to a 5.25 Mb region containing 27 protein-coding genes. A detailed medical history of both patients is provided and they are compared with the literature on other detected interstitial deletions of 1q25q32. These findings will aid in the identification of the genetic cause underlying BOS2.

Complex chromosomal rearrangements [CCRs] are considered very rare, but are being detected with an increasing frequency because of the enhanced resolution of novel molecular karyotyping techniques like array-CGH. This report describes a patient carrying a unique CCR involving one duplication and two triplications in a 3.2 Mb region on 19p13.11. The patient presented with microcephaly, velopharyngeal insufficiency, dysmorphism, mental retardation and a muscular ventricular septal defect. We show that CCRs are likely to be more frequent than hitherto appreciated. This has important consequences for genotype-phenotype correlations and warrants caution before labelling imbalances as "simple".