scholarly journals Cardiovascular and connective tissue disorder features in FLNA-related PVNH patients: progress towards a refined delineation of this syndrome

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Clarisse Billon ◽  
Salma Adham ◽  
Natalia Hernandez Poblete ◽  
Anne Legrand ◽  
Michael Frank ◽  
...  
Keyword(s):  
Connective Tissue ◽  
Vascular Diseases ◽  
Connective Tissue Disorder ◽  
Neurological Symptoms ◽  
Loss Of Function ◽  
Clinical Presentations ◽  
Major Interest ◽  
Nodular Heterotopia ◽  
Coding Variants

Abstract Background FLNA Loss-of-Function (LoF) causes periventricular nodular heterotopia type 1 (PVNH1), an acknowledged cause of seizures of various types. Neurological symptoms are inconstant, and cardiovascular (CV) defects or connective tissue disorders (CTD) have regularly been associated. We aimed at refining the description of CV and CTD features in patients with FLNA LoF and depicting the multisystemic nature of this condition. Methods We retrospectively evaluated FLNA variants and clinical presentations in FLNA LoF patient with at least one CV or CTD feature, from three cohorts: ten patients from the French Reference Center for Rare Vascular Diseases, 23 patients from the national reference diagnostic lab for filaminopathies-A, and 59 patients from literature review. Results Half of patients did not present neurological symptoms. Most patients presented a syndromic association combining CV and CTD features. CV anomalies, mostly aortic aneurysm and/or dilation were present in 75% of patients. CTD features were present in 75%. Variants analysis demonstrated an enrichment of coding variants in the CH1 domain of FLNA protein. Conclusion In FLNA LoF patients, the absence of seizures should not be overlooked. When considering a diagnosis of PVNH1, the assessment for CV and CTD anomalies is of major interest as they represent interlinked features. We recommend systematic study of FLNA within CTD genes panels, regardless of the presence of neurological symptoms.

scholarly journals Loss-of-Function Variants in EFEMP1 Cause a Recognizable Connective Tissue Disorder Characterized by Cutis Laxa and Multiple Herniations

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 510
Author(s):  
Maxim Verlee ◽  
Aude Beyens ◽  
Alper Gezdirici ◽  
Elif Yilmaz Gulec ◽  
Lore Pottie ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Connective Tissue ◽  
Connective Tissue Disorder ◽  
Heterogeneous Group ◽  
Cutis Laxa ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
Genes Encoding ◽  
Hereditary Disorders ◽  
Musculoskeletal Systems

Hereditary disorders of connective tissue (HDCT) compromise a heterogeneous group of diseases caused by pathogenic variants in genes encoding different components of the extracellular matrix and characterized by pleiotropic manifestations, mainly affecting the cutaneous, cardiovascular, and musculoskeletal systems. We report the case of a 9-year-old boy with a discernible connective tissue disorder characterized by cutis laxa (CL) and multiple herniations and caused by biallelic loss-of-function variants in EFEMP1. Hence, we identified EFEMP1 as a novel disease-causing gene in the CL spectrum, differentiating it from other HDCT.

scholarly journals Identification of three novel homozygous variants in COL9A3 causing autosomal-recessive Stickler Syndrome

2021 ◽  
Author(s):  
Aboulfazl Rad ◽  
Maryam Najafi ◽  
Fatemeh Suri ◽  
Soheila Abedini ◽  
Stephen Loum ◽  
...  
Keyword(s):  
Connective Tissue ◽  
Molecular Genetics ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Connective Tissue Disorder ◽  
Stickler Syndrome ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
Autosomal Dominant Fashion

Abstract Background: Stickler syndrome (STL) is a rare, clinically and molecularly heterogeneous connective tissue disorder. Pathogenic variants occurring in a variety of genes cause STL, mainly inherited in an autosomal dominant fashion. Autosomal recessive STL is ultra-rare with only four families with biallelic COL9A3 variants reported to date. Results: Here, we report three unrelated families clinically diagnosed with STL carrying different novel biallelic loss of function variants in COL9A3. Further, we have collected COL9A3 genotype-phenotype associations from the literature. Conclusion: Our report substantially expands the molecular genetics and clinical basis of autosomal recessive STL and provides an overview about allelic COL9A3 disorders.

scholarly journals Genetic architecture of schizophrenia: a review of major advancements

2021 ◽  
pp. 1-10
Author(s):  
Sophie E. Legge ◽  
Marcos L. Santoro ◽  
Sathish Periyasamy ◽  
Adeniran Okewole ◽  
Arsalan Arsalan ◽  
...  
Keyword(s):  
Genetic Architecture ◽  
Association Studies ◽  
Copy Number Variants ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Genetic Loci ◽  
Significant Enrichment ◽  
High Heritability ◽  
Coding Variants

Abstract Schizophrenia is a severe psychiatric disorder with high heritability. Consortia efforts and technological advancements have led to a substantial increase in knowledge of the genetic architecture of schizophrenia over the past decade. In this article, we provide an overview of the current understanding of the genetics of schizophrenia, outline remaining challenges, and summarise future directions of research. World-wide collaborations have resulted in genome-wide association studies (GWAS) in over 56 000 schizophrenia cases and 78 000 controls, which identified 176 distinct genetic loci. The latest GWAS from the Psychiatric Genetics Consortium, available as a pre-print, indicates that 270 distinct common genetic loci have now been associated with schizophrenia. Polygenic risk scores can currently explain around 7.7% of the variance in schizophrenia case-control status. Rare variant studies have implicated eight rare copy-number variants, and an increased burden of loss-of-function variants in SETD1A, as increasing the risk of schizophrenia. The latest exome sequencing study, available as a pre-print, implicates a burden of rare coding variants in a further nine genes. Gene-set analyses have demonstrated significant enrichment of both common and rare genetic variants associated with schizophrenia in synaptic pathways. To address current challenges, future genetic studies of schizophrenia need increased sample sizes from more diverse populations. Continued expansion of international collaboration will likely identify new genetic regions, improve fine-mapping to identify causal variants, and increase our understanding of the biology and mechanisms of schizophrenia.

scholarly journals Functional tests to guide management in an adult with loss of function of type-1 angiotensin II receptor

2021 ◽  
Author(s):  
Daan H. H. M. Viering ◽  
Anneke P. Bech ◽  
Jeroen H. F. de Baaij ◽  
Eric J. Steenbergen ◽  
A. H. Jan Danser ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Collecting Duct ◽  
Perinatal Period ◽  
Tubular Dysfunction ◽  
Loss Of Function ◽  
Angiotensin Ii Receptor ◽  
Salt Wasting ◽  
Truncating Mutation ◽  
Urinary Potassium

AbstractBackgroundGenetic loss of function ofAGT(angiotensinogen),REN(renin),ACE(angiotensin-converting enzyme), orAGTR1(type-1 angiotensin II receptor) leads to renal tubular dysgenesis (RTD). This syndrome is almost invariably lethal. Most surviving patients reach stage 5 chronic kidney disease at a young age.MethodsHere, we report a 28-year-old male with a homozygous truncating mutation inAGTR1(p.Arg216*), who survived the perinatal period with a mildly impaired kidney function. In contrast to classic RTD, kidney biopsy showed proximal tubules that were mostly normal. During the subsequent three decades, we observed evidence of both tubular dysfunction (hyperkalemia, metabolic acidosis, salt-wasting and a urinary concentrating defect) and glomerular dysfunction (reduced glomerular filtration rate, currently ~30 mL/min/1.73 m2, accompanied by proteinuria). To investigate the recurrent and severe hyperkalemia, we performed a patient-tailored functional test and showed that high doses of fludrocortisone induced renal potassium excretion by 155%. Furthermore, fludrocortisone lowered renal sodium excretion by 39%, which would have a mitigating effect on salt-wasting. In addition, urinary pH decreased in response to fludrocortisone. Opposite effects on urinary potassium and pH occurred with administration of amiloride, further supporting the notion that a collecting duct is present and able to react to fludrocortisone.ConclusionsThis report provides living proof that even truncating loss-of-function mutations inAGTR1are compatible with life and relatively good GFR and provides evidence for the prescription of fludrocortisone to treat hyperkalemia and salt-wasting in such patients.

scholarly journals A Novel Mutation of ATP7B Gene in a Case of Wilson Disease

Medicina ◽  
2021 ◽  
Vol 57 (2) ◽  
pp. 123
Author(s):  
Cigdem Yuce Kahraman ◽  
Ali Islek ◽  
Abdulgani Tatar ◽  
Özlem Özdemir ◽  
Adil Mardinglu ◽  
...  
Keyword(s):  
Wilson Disease ◽  
Novel Mutation ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Compound Heterozygous ◽  
Atp7b Gene ◽  
Loss Of Function ◽  
Clinical Presentations ◽  
The Family ◽  
The Brain

Wilson disease (WD) (OMIM# 277900) is an autosomal recessive inherited disorder characterized by excess copper (Cu) storage in different human tissues, such as the brain, liver, and the corneas of the eyes. It is a rare disorder that occurs in approximately 1 in 30,000 individuals. The clinical presentations of WD are highly varied, primarily consisting of hepatic and neurological conditions. WD is caused by homozygous or compound heterozygous mutations in the ATP7B gene. The diagnosis of the disease is complicated because of its heterogeneous phenotypes. The molecular genetic analysis encourages early diagnosis, treatment, and the opportunity to screen individuals at risk in the family. In this paper, we reported a case with a novel, hotspot-located mutation in WD. We have suggested that this mutation in the ATP7B gene might contribute to liver findings, progressing to liver failure with a loss of function effect. Besides this, if patients have liver symptoms in childhood and/or are children of consanguineous parents, WD should be considered during the evaluation of the patients.

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