Background: Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder with a high risk for arterial, bowel, and uterine rupture, caused by heterozygous pathogenic variants in . The aim of this cohort study is to provide further insights into the natural history of vEDS and describe genotype-phenotype correlations in a Dutch multicenter cohort to optimize patient care and increase awareness of the disease.
Methods: Individuals with vEDS throughout the Netherlands were included.
Objectives: The primary aim was to gain insight into the growth of the aortic root in children and young adults with Marfan syndrome (MFS). Furthermore, we aimed to identify a clinical profile of patients with MFS who require an aortic root replacement at a young age with specific interest in age, sex, height and fibrillin-1 () genotype.
Methods: Aortic root dimensions of 97 patients with MFS between 0 year and 20 years and 30 controls were serially assessed with echocardiography.
Purpose: Heterozygous pathogenic/likely pathogenic (P/LP) variants in the ACTA2 gene confer a high risk for thoracic aortic aneurysms and aortic dissections. This retrospective multicenter study elucidates the clinical outcome of ACTA2-related vasculopathies.
Methods: Index patients and relatives with a P/LP variant in ACTA2 were included.
Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available.
View Article and Find Full Text PDFBackground: Musculocontractural Ehlers-Danlos syndrome is caused by biallelic loss-of-function variants in (mcEDS-) or (mcEDS-). Although 48 patients in 33 families with mcEDS- have been reported, the spectrum of pathogenic variants, accurate prevalence of various manifestations and detailed natural history have not been systematically investigated.
Methods: We collected detailed and comprehensive clinical and molecular information regarding previously reported and newly identified patients with mcEDS- through international collaborations.
Recessive loss-of-function variants in a putative zinc transporter gene, were first associated with a connective tissue disorder that is now called "Ehlers-Danlos syndrome, spondylodysplastic form type 3" (SCD-EDS, OMIM 612350) in 2008. Nine individuals have been described. We describe here four additional affected individuals from three consanguineous families and the follow up of two of the original cases.
View Article and Find Full Text PDFDisease-causing variants in TGFB3 cause an autosomal dominant connective tissue disorder which is hard to phenotypically delineate because of the small number of identified cases. The purpose of this retrospective cross-sectional multicenter study is to elucidate the genotype and phenotype in an international cohort of TGFB3 patients. Eleven (eight novel) TGFB3 disease-causing variants were identified in 32 patients (17 families).
View Article and Find Full Text PDFAm J Med Genet C Semin Med Genet
December 2019
CHD8 has been reported as an autism susceptibility/intellectual disability gene but emerging evidence suggests that it additionally causes an overgrowth phenotype. This study reports 27 unrelated patients with pathogenic or likely pathogenic CHD8 variants (25 null variants, two missense variants) and a male:female ratio of 21:6 (3.5:1, p < .
View Article and Find Full Text PDFContext: The two major forms of circulating thyroid hormones (THs) are T3 and T4. T3 is regarded as the biologically active hormone because it binds to TH receptors (TRs) with greater affinity than T4. However, it is currently unclear what structural mechanisms underlie this difference in affinity.
View Article and Find Full Text PDFThe original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.
View Article and Find Full Text PDFMitochondrial disorders, characterized by clinical symptoms and/or OXPHOS deficiencies, are caused by pathogenic variants in mitochondrial genes. However, pathogenic variants in some of these genes can lead to clinical manifestations which overlap with other neuromuscular diseases, which can be caused by pathogenic variants in non-mitochondrial genes as well. Mitochondrial pathogenic variants can be found in the mitochondrial DNA (mtDNA) or in any of the 1,500 nuclear genes with a mitochondrial function.
View Article and Find Full Text PDFLoss-of-function mutations in the recycling endosomal (Na,K)/H exchanger gene SLC9A6/NHE6 result in overacidification and dysfunction of endosomal-lysosomal compartments, and cause a neurodevelopmental and degenerative form of X-linked intellectual disability called Christianson Syndrome (CS). However, knowledge of the disease heterogeneity of CS is limited. Here, we describe the clinical features and underlying molecular and cellular mechanisms associated with a CS patient carrying a de novo missense variant (p.
View Article and Find Full Text PDFPurpose: Several studies have reported diagnostic yields up to 57% for rapid exome or genome sequencing (rES/GS) as a single test in neonatal intensive care unit (NICU) patients, but the additional yield of rES/GS compared with other available diagnostic options still remains unquantified in this population.
Methods: We retrospectively evaluated all genetic NICU consultations in a 2-year period.
Results: In 132 retrospectively evaluated NICU consultations 27 of 32 diagnoses (84.
Simultaneous analysis of multiple genes using next-generation sequencing (NGS) technology has become widely available. Copy-number variations (CNVs) in disease-associated genes have emerged as a cause for several hereditary disorders. CNVs are, however, not routinely detected using NGS analysis.
View Article and Find Full Text PDFBackground: Thoracic aortic aneurysm (TAA) is a potentially life-threatening disorder with a strong genetic component. The number of genes implicated in TAA has increased exponentially over the last decade. Approximately 20% of patients with TAA have a positive family history.
View Article and Find Full Text PDFThe Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor-β (TGF-β) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF-β signaling.
View Article and Find Full Text PDFBackground: Several genetic causes of ectopia lentis (EL), with or without systemic features, are known. The differentiation between syndromic and isolated EL is crucial for further treatment, surveillance and counseling of patients and their relatives. Next generation sequencing (NGS) is a powerful tool enabling the simultaneous, highly-sensitive analysis of multiple target genes.
View Article and Find Full Text PDFSMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS.
View Article and Find Full Text PDFSevere recessive mitochondrial myopathy caused by FBXL4 gene mutations may present prenatally with polyhydramnios and cerebellar hypoplasia. Characteristic dysmorphic features are: high and arched eyebrows, triangular face, a slight upslant of palpebral fissures, and a prominent pointed chin. Metabolic investigations invariably show increased serum lactate and pyruvate levels.
View Article and Find Full Text PDFBackground: Hypospadias is associated with twinning. The incidence of hypospadias in monochorionic and dichorionic male twins is, however, yet to be determined.
Methods: All medical records of monochorionic and dichorionic twins admitted to our neonatal nursery between January 2004 and August 2013 were reviewed for the presence of hypospadias.
We report three families with arterial aneurysms and dissections in which variants predicted to be pathogenic were identified in SMAD2. Moreover, one variant occurred de novo in a proband with unaffected parents. SMAD2 is a strong candidate gene for arterial aneurysms and dissections given its role in the TGF-β signaling pathway.
View Article and Find Full Text PDFCopy number variations (CNVs) on the short arm of chromosome 19 are relatively rare. We present a patient with a tandem de novo 3.9 Mb duplication of 19p13.
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