Noonan syndrome-causing genes: Molecular update and an assessment of the mutation rate

AbstractNoonan syndrome is a common autosomal dominant disorder characterized by short stature, congenital heart disease and facial dysmorphia with an incidence of 1/1000 to 2500 live births. Up to now, several genes have been proven to be involved in the disturbance of the transduction signal through the RAS-MAP Kinase pathway and the manifestation of Noonan syndrome. The first gene described was PTPN11, followed by SOS1, RAF1, KRAS, BRAF, NRAS, MAP2K1, and RIT1, and recently SOS2, LZTR1, and A2ML1, among others. Progressively, the physiopathology and molecular etiology of most signs of Noonan syndrome have been demonstrated, and inheritance patterns as well as genetic counseling have been established. In this review, we summarize the data concerning clinical features frequently observed in Noonan syndrome, and then, we describe the molecular etiology as well as the physiopathology of most Noonan syndrome-causing genes. In the second part of this review, we assess the mutational rate of Noonan syndrome-causing genes reported up to now in most screening studies. This review should give clinicians as well as geneticists a full view of the molecular aspects of Noonan syndrome and the authentic prevalence of the mutational events of its causing-genes. It will also facilitate lay the groundwork for future molecular diagnosis research, and the development of novel treatment strategies

GATA4 molecular screening and assessment of environmental risk factors in a Moroccan cohort with tetralogy of Fallot

Background: Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect (CHD) with an incidence of 1/3600 live births. This disorder was associated with mutations in the transcription factors involved in cardiogenesis, like Nk2 homeobox5 (NKX2-5), GATA binding protein4 (GATA4) and T-BOX1 (TBX1). GATA4 contributes particularly to heart looping and differentiation of the second heart field.Objectives: The aim of this study was to screen a Moroccan cohort with tetralogy of Fallot for GATA4 mutations, and to assess environmental risk factors that could be involved in the occurrence of this disorder.Methods: Thirty-one non-syndromic TOF patients, enrolled between 5th April 2014 and 18th June 2015, were screened for GATA4 mutations using direct sequencing of GATA4 coding exons. Statistical assessment of different risk factors, which is a retrospective study, was carried out using Chi-square and Fisher’s exact tests. Results: We identified seven exonic variants in nine patients (two missense and five synonymous variants); in addition of eight intronic variants. Assessment of environmental risk factors shows significant association of maternal passive smoking with TOF in the Moroccan population.Conclusion: The present study allowed, for the first time, the molecular and environmental characterisation of Moroccan TOF population. Our findings emphasise particularly the strong association of passive smoking with the emergence of tetralogy of Fallot.Keywords: Tetralogy of Fallot, GATA4, molecular screening, risk factors

GATA4 molecular screening and assessment of environmental risk factors in a Moroccan cohort with tetralogy of Fallot

Background: Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect (CHD) with an incidence of 1/3600 live births. This disorder was associated with mutations in the transcription factors involved in cardiogenesis, like Nk2 homeobox5 (NKX2-5), GATA binding protein4 (GATA4) and T-BOX1 (TBX1). GATA4 contributes particularly to heart looping and differentiation of the second heart field. Objectives: The aim of this study was to screen a Moroccan cohort with tetralogy of Fallot for GATA4 mutations, and to assess environmental risk factors that could be involved in the occurrence of this disorder. Methods: Thirty-one non-syndromic TOF patients, enrolled between 5th April 2014 and 18th June 2015, were screened for GATA4 mutations using direct sequencing of GATA4 coding exons. Statistical assessment of different risk factors, which is a retrospective study, was carried out using Chi-square and Fisher\u2019s exact tests. Results: We identified seven exonic variants in nine patients (two missense and five synonymous variants); in addition of eight intronic variants. Assessment of environmental risk factors shows significant association of maternal passive smoking with TOF in the Moroccan population. Conclusion: The present study allowed, for the first time, the molecular and environmental characterisation of Moroccan TOF population. Our findings emphasise particularly the strong association of passive smoking with the emergence of tetralogy of Fallot

Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot

Purpose: Rare genetic variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), have been reported in patients with tetralogy of Fallot (TOF). However, their role in disease causality and pathogenesis remains unclear. Methods: We conducted exome sequencing in a familial case of TOF and large-scale genetic studies, including burden testing, in >1,500 patients with TOF. We studied gene-targeted mice and conducted cell-based assays to explore the role of KDR genetic variation in the etiology of TOF. Results: Exome sequencing in a family with two siblings affected by TOF revealed biallelic missense variants in KDR. Studies in knock-in mice and in HEK 293T cells identified embryonic lethality for one variant when occurring in the homozygous state, and a significantly reduced VEGFR2 phosphorylation for both variants. Rare variant burden analysis conducted in a set of 1,569 patients of European descent with TOF identified a 46-fold enrichment of protein-truncating variants (PTVs) in TOF cases compared to controls (P = 7 × 10-11). Conclusion: Rare KDR variants, in particular PTVs, strongly associate with TOF, likely in the setting of different inheritance patterns. Supported by genetic and in vivo and in vitro functional analysis, we propose loss-of-function of VEGFR2 as one of the mechanisms involved in the pathogenesis of TOF

Correction to: Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot (Genetics in Medicine, (2021), 23, 10, (1952-1960), 10.1038/s41436-021-01212-y)

Due to a processing error the author’s Doris Škorić-Milosavljević, Najim Lahrouchi, Alex V. Postma, Connie R. Bezzina were assigned to affiliation 38. However, affiliation 38 does not exist. In addition, the affiliations of Najim Lahrouchi, Elisabeth M. Lodder, and Connie R. Bezzina should be number 1 instead of number 2. The correct affiliation is Department of Clinical and Experimental Cardiology, Amsterdam University Medical Center, Amsterdam, The Netherlands. The original article has been corrected

Williams-Beuren syndrome in diverse populations

Williams–Beuren syndrome (WBS) is a common microdeletion syndrome characterized by a 1.5Mb deletion in 7q11.23. The phenotype of WBS has been well described in populations of European descent with not as much attention given to other ethnicities. In this study, individuals with WBS from diverse populations were assessed clinically and by facial analysis technology. Clinical data and images from 137 individuals with WBS were found in 19 countries with an average age of 11 years and female gender of 45%. The most common clinical phenotype elements were periorbital fullness and intellectual disability which were present in greater than 90% of our cohort. Additionally, 75% or greater of all individuals with WBS had malar flattening, long philtrum, wide mouth, and small jaw. Using facial analysis technology, we compared 286 Asian, African, Caucasian, and Latin American individuals with WBS with 286 gender and age matched controls and found that the accuracy to discriminate between WBS and controls was 0.90 when the entire cohort was evaluated concurrently. The test accuracy of the facial recognition technology increased significantly when the cohort was analyzed by specific ethnic population (P-value < 0.001 for all comparisons), with accuracies for Caucasian, African, Asian, and Latin American groups of 0.92, 0.96, 0.92, and 0.93, respectively. In summary, we present consistent clinical findings from global populations with WBS and demonstrate how facial analysis technology can support clinicians in making accurate WBS diagnoses