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A study was conducted to analyze the role of FOXF1 in human lung and intrinsic pulmonary vascular development by describing inactivating mutations in patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV). Findings reveal that patients with deletions harboring FOXF1 genes have not only ACD/MPV but also distinct malformations.

Biallelic mutations in FKBP14 cause a recessive form of Ehlers-Danlos syndrome (EDS) characterized by progressive kyphoscoliosis, myopathy, and hearing loss. To date, four children and one adult with this condition have been reported. We recently identified a 42-year-old man with severe kyphoscoliosis, restrictive/obstructive lung disease, short stature, mild hearing loss, decreased muscle mass, and a dissection of the celiac artery at age 41. He also had complete occlusion of the superior mesenteric artery with compensatory flow through an enlarged and tortuous inferior mesenteric artery. He was homozygous for a previously identified FKBP14 mutation, c.362dupC, p.(Glu122Argfs*7). He had no mutations in COL3A1, ACTA2, TGFBR1, TGFBR2, or SMAD3. The FKBP14 mutations in our patient occurred on the same haplotype as others with this same mutation. Although one family member in a previous report was thought to have early vascular complications, it could not be confirmed that she had biallelic mutations in FKBP14. This report expands the phenotype of FKBP14-related EDS to include risk for vascular complications and also raises the question of whether the shared haplotype represents a risk allele or founder mutation. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: The Ehlers–Danlos syndromes (EDS) are genetically and clinically diverse disorders in which affected individuals share a number of physical characteristics, including joint hypermobility, skin extensibility, and tissue friability. Clinical investigations opened the door to identifying the biochemical and molecular etiologies of this diverse but overlapping group of disorders. In this article, we provide an overview of how these disorders inform our understanding of matrix biology, including the role of collagens (types I, III and V), proteoglycans and other proteins. [Copyright &y& Elsevier]

The article focuses on a study related to heritable skin disorder Ehlers–Danlos Syndrome (EDS). It mentions that light and electron microscopy studies identified abnormalities in the structure of collagens in the dermal matrix; and joint hypermobility, skin extensibility, abnormal scarring, and tissue friability are the hallmark diagnostic features of the EDS. It also mentions about virtual absence of hydroxylation of lysyl residues in triple helical collagen molecules.

Despite unprecedented gains in genomic technologies and genotype resolution, there remain tremendous challenges in our ability to capture disease “phenomes.” We propose a previously unreported method for deconvolving human disease into elemental features, thereby creating a third space that interacts with both the disease and genotypic spaces. Using cutaneous and noncutaneous clinical findings available through Johns Hopkins University's Online Mendelian Inheritance in Man (OMIM) database, we set out to deconstruct genetic skin disease (GSD) into its various components, to more fully explore the relationship between these features within the complex phenotypic space and to characterize the genotypic space within which these disorders exist. Using OMIM, we defined the current state of GSD as including 560 distinct disorders associated with 501 unique protein-encoding genes. The most common elemental skin features included cornifying, erosive, and hair/nail phenotypes, and the most common systemic features included those associated with developmental, musculoskeletal, and neurological systems. As a proof of principle, we focused on a single skin feature— café-au-lait macules—and partitioned the disease space into hierarchical groupings on the basis of this finding. Finally, functional analyses among GSD loci were mapped back to skin features, providing insights into pigmentary and auditory features. Phenotypic deconvolution provides a framework for analyzing medical disorders and can aid in the organization and elucidation of biological mechanisms related to human disease. [ABSTRACT FROM AUTHOR]

The role of somatic genetic variants in the pathogenesis of intracranial-aneurysm formation is unknown. We identified a 23-year-old man with progressive, right-sided intracranial aneurysms, ipsilateral to an impressive cutaneous phenotype. The index individual underwent a series of genetic evaluations for known connective-tissue disorders, but the evaluations were unrevealing. Paired-sample exome sequencing between blood and fibroblasts derived from the diseased areas detected a single novel variant predicted to cause a p.Tyr562Cys (g.149505130T>C [GRCh37/hg19]; c.1685A>G) change within the platelet-derived growth factor receptor β gene (PDGFRB), a juxtamembrane-coding region. Variant-allele fractions ranged from 18.75% to 53.33% within histologically abnormal tissue, suggesting post-zygotic or somatic mosaicism. In an independent cohort of aneurysm specimens, we detected somatic-activating PDGFRB variants in the juxtamembrane domain or the kinase activation loop in 4/6 fusiform aneurysms (and 0/38 saccular aneurysms; Fisher's exact test, p < 0.001). PDGFRB -variant, but not wild-type, patient cells were found to have overactive auto-phosphorylation with downstream activation of ERK, SRC, and AKT. The expression of discovered variants demonstrated non-ligand-dependent auto-phosphorylation, responsive to the kinase inhibitor sunitinib. Somatic gain-of-function variants in PDGFRB are a novel mechanism in the pathophysiology of fusiform cerebral aneurysms and suggest a potential role for targeted therapy with kinase inhibitors. [ABSTRACT FROM AUTHOR]

Diagnostic laboratories gather phenotypic data through requisition forms, but there is no consensus as to which data are essential for variant interpretation. The ClinGen Cardiomyopathy Variant Curation Expert Panel defined a phenotypic data set for hypertrophic cardiomyopathy (HCM) variant interpretation, with the goal of standardizing requisition forms. Phenotypic data elements listed on requisition forms from nine leading cardiomyopathy testing laboratories were compiled to assess divergence in data collection. A pilot of 50 HCM cases was implemented to determine the feasibility of harmonizing data collection. Laboratory directors were surveyed to gauge potential for adoption of a minimal data set. Wide divergence was observed in the phenotypic data fields in requisition forms. The 50-case pilot showed that although demographics and assertion of a clinical diagnosis of HCM had 86% to 98% completion, specific phenotypic features, such as degree of left ventricular hypertrophy, ejection fraction, and suspected syndromic disease, were completed only 24% to 44% of the time. Nine data elements were deemed essential for variant classification by the expert panel. Participating laboratories unanimously expressed a willingness to adopt these data elements in their requisition forms. This study demonstrates the value of comparing and sharing best practices through an expert group, such as the ClinGen Program, to enhance variant interpretation, providing a foundation for leveraging cumulative case-level data in public databases and ultimately improving patient care., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

True aneurysms of the internal mammary artery are rare and have been described in association with vasculitis or connective tissue disorders. Herein, we describe 2 cases of familial internal mammary artery aneurysms (IMAs) in 2 sisters with SMAD3 mutation. The older sister presented at the age of 54 years with an incidental diagnosis of a multilobed right IMA and the younger sister presented several years earlier with a ruptured left IMA aneurysm at the age of 49 years. Both sisters had Debakey type I aortic dissections prior to the IMA aneurysm presentation. To our knowledge, this is the first time IMA aneurysms have been described in siblings with SMAD3 mutation. In our experience, endovascular repair is a feasible and safe treatment option. An assessment of the entire arterial tree is recommended in patients diagnosed with SMAD3 mutations., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Genetic testing has shifted from academic laboratories with expertise in specific genes to commercial laboratories that offer tests of a diverse array of genes. The purpose of this comparative study was to determine whether one academic laboratory's model of variant interpretation is similar to that of several commercial laboratories., Methods: The Collagen Diagnostic Laboratory (CDL) received, over a 14-month period, 38 requests to interpret variants originally identified by an outside laboratory (OL). The interpretations by the OL and CDL were compared and discrepancies were assessed., Results: Interpretations from the OL and CDL were concordant in 11 inquiries (29%); discrepancies were moderate in 11 instances (29%) and significant in 16 (42%). Factors that caused discrepancies included the following: (i) private data were not shared in a public database (n = 9); (ii) publicly available allele frequency data were not referenced and used as evidence (n = 5); and (iii) important aspects of protein structure and function were not taken into account (n = 13)., Conclusion: Comprehensive interpretation of sequence variants depends on good functional tests and well-curated variant databases. Provision of clinical information to the clinical laboratory, mandatory submission of identified variants with phenotype data to common resources, and collaboration between clinical laboratories and recognized experts is likely to improve consistency in variant interpretation among clinical laboratories.Genet Med 18 1, 20-24.

Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected to be pathogenic, whereas 52 (1.2%) had likely pathogenic SNVs. For African-ancestry participants, six of 2203 (0.3%) had a pathogenic SNV and six (0.3%) had an expected pathogenic disruptive variant, whereas 13 (0.6%) had likely pathogenic SNVs. Genomic Evolutionary Rate Profiling mammalian conservation score and the Combined Annotation Dependent Depletion summary score of conservation, substitution, regulation, and other evidence were compared across pathogenicity assignments and appear to have utility in variant classification. This work provides a refined estimate of the burden of adult onset, medically actionable incidental findings expected from exome sequencing, highlights challenges in variant classification, and demonstrates the need for a better curated variant interpretation knowledge base., (© 2015 Amendola et al.; Published by Cold Spring Harbor Laboratory Press.)

Purpose: The purpose of this study was to characterize the nature and magnitude of pregnancy risks in women with vascular Ehlers-Danlos syndrome., Methods: Pregnancy-related death rate was determined by a review of pedigrees of families with vascular Ehlers-Danlos syndrome. Maternal morbidity was characterized through semistructured interviews with women with vascular Ehlers-Danlos syndrome or their next of kin., Results: Pregnancy-related deaths occurred in 30 of 565 deliveries (5.3%). There was no difference in Kaplan-Meier survival curves between parous versus nulliparous women with vascular Ehlers-Danlos syndrome. Interviews with 39 women indicated that 46% of deliveries were uncomplicated. The most common pregnancy-related complications were third-/fourth-degree lacerations (20%) and preterm delivery (19%). Life-threatening complications occurred in 14.5% of deliveries and included arterial dissection/rupture (9.2%), uterine rupture (2.6%), and surgical complications (2.6%). There were 5 maternal deaths in 76 deliveries (6.5%)., Conclusion: The risk of pregnancy-related complications is increased in women with vascular Ehlers-Danlos syndrome compared with the general population; however, survival data indicate that pregnancy does not appear to affect overall mortality compared with nulliparous women with vascular Ehlers-Danlos syndrome. The data were insufficient to determine whether mode or timing of delivery influenced risk of complications. Women with vascular Ehlers-Danlos syndrome should be engaged in a shared decision-making process when contemplating pregnancy and pregnancy management.

Purpose: : Approximately 5-10% of patients who undergo genetic testing of BRCA1 and BRCA2 receive a variant of unknown significance (VUS) result. The ambiguous nature of a VUS may increase difficulty in patient understanding and decision making regarding risk reduction and surveillance options, including cancer risk-reducing surgeries. VUS reclassification to benign or deleterious may occur in time; however, clinical decisions may need to be made expeditiously, and some patients may pursue irreversible treatments before VUS reclassification., Methods: : We reviewed the surgical decisions of 107 women postdisclosure of a BRCA VUS result counseled at our institute between 1998 and 2009., Conclusion: : Among women receiving a BRCA VUS result at our center, 11 of 107 (10.3%) pursued cancer risk-reducing mastectomy and 22 of 107 (20.6%) pursued cancer risk-reducing bilateral salpingo-oophorectomy. Reclassification of VUS occurred up to 9 years after testing, and 5 of 22 (22.7%) women followed up for 8 or more years continue to have a VUS result. We discuss considerations for providers of genetic services to discuss with patients who receive a VUS result.