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Cold Spring Harbor Molecular Case... Oct 2022Neonatal Marfan syndrome (nMFS) is a rare and severe form of Marfan syndrome (MFS) with a poor prognosis, that presents with a highly variable phenotype, particularly...
Neonatal Marfan syndrome (nMFS) is a rare and severe form of Marfan syndrome (MFS) with a poor prognosis, that presents with a highly variable phenotype, particularly regarding skeletal, ocular, and cardiovascular manifestations. Mutations in the fibrillin-1 () gene are known as the principal cause of MFS and MFS-related syndromes. Here, we report on a full-term female neonate with postnatal characteristics suggestive of nMFS, including severe cardiovascular disease resulting in cardiorespiratory failure and death by 4 mo of age. We identified a novel large genomic in-frame deletion of exons 42-45, c.(5065 + 1_5066 - 1)_(5545 + 1_5546 - 1)del. Large in-frame deletions between exons 24 and 53 have been associated with severe MFS. The deletion in our patient differs from the region associated with the majority of nMFS cases, exons 24-32.
Topics: Female; Humans; Exons; Fibrillin-1; Marfan Syndrome; Mutation; Phenotype; Sequence Deletion
PubMed: 36307213
DOI: 10.1101/mcs.a006213 -
Molecular Genetics & Genomic Medicine Apr 2021Congenital contractural arachnodactyly (CCA) is a rare autosomal dominant condition caused by mutations in the fibrillin 2 gene (FBN2). The primary clinical symptoms of...
BACKGROUND
Congenital contractural arachnodactyly (CCA) is a rare autosomal dominant condition caused by mutations in the fibrillin 2 gene (FBN2). The primary clinical symptoms of CCA include multiple flexion contractures, arachnodactyly, dolichostenomelia, scoliosis, abnormal pinnae, muscular hypoplasia, and crumpled ears.
METHODS
We used whole-exome sequencing technology to examine an arthrogryposis multiplex congenita and used Sanger sequencing technology to genetically confirm its family.
RESULTS
FBN2 c.3344A>T(p.D1115V) was identified in this family with CCA in a pedigree. Prenatal diagnosis and counseling were carried out simultaneously to avoid the birth of the sick fetus.
CONCLUSION
The study is on FBN2 variant in CCA, which potentially having implications for genetic counseling and clinical management, our study may provide new insights into the cause and diagnosis of CCA.
Topics: Adult; Amniocentesis; Arachnodactyly; Contracture; Female; Fibrillin-2; Humans; Male; Mutation, Missense; Pedigree; Pregnancy; Whole Genome Sequencing
PubMed: 33638605
DOI: 10.1002/mgg3.1638 -
Orphanet Journal of Rare Diseases Dec 2018Galloway-Mowat syndrome (GAMOS) is a rare autosomal recessive disease characterized by the combination of glomerulopathy with early-onset nephrotic syndrome and...
BACKGROUND
Galloway-Mowat syndrome (GAMOS) is a rare autosomal recessive disease characterized by the combination of glomerulopathy with early-onset nephrotic syndrome and microcephaly with central nervous system anomalies. Given its clinical heterogeneity, GAMOS is believed to be a genetically heterogenous group of disorders. Recently, it has been reported that mutations in KEOPS-encoding genes, including the OSGEP gene, were responsible for GAMOS.
RESULTS
Overall, 6 patients from 5 different Taiwanese families were included in our study; the patients had an identical OSGEP gene mutation (c.740G > A transition) and all exhibited a uniform clinical phenotype with early-onset nephrotic syndrome, craniofacial and skeletal dysmorphism, primary microcephaly with pachygyria, and death before 2 years of age. We reviewed their clinical manifestations, the prenatal and postnatal presentations and ultrasound findings, results of imaging studies, associated anomalies, and outcome on follow-up. All individuals were found to have an "aged face" comprising peculiar facial dysmorphisms. Arachnodactyly or camptodactyly were noted in all patients. Neurological findings consisted of microcephaly, hypotonia, developmental delay, and seizures. Brain imaging studies all showed pachygyria and hypomyelination. All patients developed early-onset nephrotic syndrome. The proteinuria was steroid-resistant and eventually resulted in renal function impairment. Prenatal ultrasound findings included microcephaly, intrauterine growth restriction, and oligohydramnios. Fetal MRI in 2 patients confirmed the gyral and myelin abnormalities.
CONCLUSIONS
Our study suggests that a careful review of the facial features can provide useful clues for an early and accurate diagnosis. Prenatal ultrasound findings, fetal MRI, genetic counseling, and mutation analysis may be useful for an early prenatal diagnosis.
Topics: Arachnodactyly; Female; Hernia, Hiatal; Humans; Lissencephaly; Male; Metalloendopeptidases; Microcephaly; Mutation; Nephrosis; Nephrotic Syndrome; Prenatal Diagnosis; Retrospective Studies; Taiwan
PubMed: 30558655
DOI: 10.1186/s13023-018-0961-9 -
BMC Bioinformatics Sep 2022In Alzheimer's Diseases (AD) research, multimodal imaging analysis can unveil complementary information from multiple imaging modalities and further our understanding of...
BACKGROUND
In Alzheimer's Diseases (AD) research, multimodal imaging analysis can unveil complementary information from multiple imaging modalities and further our understanding of the disease. One application is to discover disease subtypes using unsupervised clustering. However, existing clustering methods are often applied to input features directly, and could suffer from the curse of dimensionality with high-dimensional multimodal data. The purpose of our study is to identify multimodal imaging-driven subtypes in Mild Cognitive Impairment (MCI) participants using a multiview learning framework based on Deep Generalized Canonical Correlation Analysis (DGCCA), to learn shared latent representation with low dimensions from 3 neuroimaging modalities.
RESULTS
DGCCA applies non-linear transformation to input views using neural networks and is able to learn correlated embeddings with low dimensions that capture more variance than its linear counterpart, generalized CCA (GCCA). We designed experiments to compare DGCCA embeddings with single modality features and GCCA embeddings by generating 2 subtypes from each feature set using unsupervised clustering. In our validation studies, we found that amyloid PET imaging has the most discriminative features compared with structural MRI and FDG PET which DGCCA learns from but not GCCA. DGCCA subtypes show differential measures in 5 cognitive assessments, 6 brain volume measures, and conversion to AD patterns. In addition, DGCCA MCI subtypes confirmed AD genetic markers with strong signals that existing late MCI group did not identify.
CONCLUSION
Overall, DGCCA is able to learn effective low dimensional embeddings from multimodal data by learning non-linear projections. MCI subtypes generated from DGCCA embeddings are different from existing early and late MCI groups and show most similarity with those identified by amyloid PET features. In our validation studies, DGCCA subtypes show distinct patterns in cognitive measures, brain volumes, and are able to identify AD genetic markers. These findings indicate the promise of the imaging-driven subtypes and their power in revealing disease structures beyond early and late stage MCI.
Topics: Alzheimer Disease; Arachnodactyly; Brain; Cognitive Dysfunction; Contracture; Fluorodeoxyglucose F18; Genetic Markers; Humans; Magnetic Resonance Imaging; Positron-Emission Tomography
PubMed: 36175853
DOI: 10.1186/s12859-022-04946-x -
Scientific Reports Mar 2022MASS phenotype is a connective tissue disorder clinically overlapping with Marfan syndrome and caused by pathogenic variants in FBN1. We report four patients from three...
MASS phenotype is a connective tissue disorder clinically overlapping with Marfan syndrome and caused by pathogenic variants in FBN1. We report four patients from three families presenting with a MASS-like phenotype consisting of tall stature, arachnodactyly, spinal deformations, dural ectasia, pectus and/or feet deformations, osteoarthritis, and/or high arched palate. Gene panel sequencing was negative for FBN1 variants. However, it revealed likely pathogenic missense variants in three individuals [c.3936G > T p.(Lys1312Asn), c.193G > A p.(Asp65Asn)] and a missense variant of unknown significance in the fourth patient [c.4013G > A p.(Ser1338Asn)] in propeptide coding regions of COL2A1. Pathogenic COL2A1 variants are associated with type II collagenopathies comprising a remarkable clinical variablility. Main features include skeletal dysplasia, ocular anomalies, and auditory defects. A MASS-like phenotype has not been associated with COL2A1 variants before. Thus, the identification of likely pathogenic COL2A1 variants in our patients expands the phenotypic spectrum of type II collagenopathies and suggests that a MASS-like phenotype can be assigned to various hereditary disorders of connective tissue. We compare the phenotypes of our patients with related disorders of connective tissue and discuss possible pathomechanisms and genotype-phenotype correlations for the identified COL2A1 variants. Our data recommend COL2A1 sequencing in FBN1-negative patients suggestive for MASS/Marfan-like phenotype (without aortopathy).
Topics: Collagen Type II; Genotype; Humans; Marfan Syndrome; Mitral Valve Prolapse; Mutation; Myopia; Phenotype; Skin Diseases
PubMed: 35296718
DOI: 10.1038/s41598-022-08476-7 -
Journal of Assisted Reproduction and... Nov 2016To investigate the usefulness of preimplantation genetic diagnosis (PGD) for the patient affected by congenital contractural arachnodactyly (CCA) and spinal and bulbar...
PURPOSE
To investigate the usefulness of preimplantation genetic diagnosis (PGD) for the patient affected by congenital contractural arachnodactyly (CCA) and spinal and bulbar muscular atrophy (SBMA).
METHODS
Multiple displacement amplification (MDA) was performed for whole genome amplification (WGA) of biopsied trophectoderm (TE) cells. Direct mutation detection by sequencing and next-generation sequencing (NGS)-based single nucleotide polymorphism (SNP) haplotyping were used for CCA diagnosis. Direct sequencing of the PCR products and sex determination by amplification of sex-determining region Y (SRY) gene were used for SBMA diagnosis. After PGD, the unaffected blastocyst (B4) was transferred in the following frozen embryo transfer (FET).
RESULTS
In this PGD cycle, sixteen MII oocytes were inseminated by ICSI with testicular spermatozoa. Four blastocysts (B4, B5, B10, B13) were utilized for TE cell biopsy on day 5 after ICSI. After PGD, B4 was unaffected by CCA and SBMA. B5 was affected by CCA and carried SBMA. B10 was unaffected by CCA and carried SBMA. B13 was affected by CCA and unaffected by SBMA. B4 was the only unaffected blastocyst and transferred into the uterus for the subsequent FET cycle. The accuracy of PGD was confirmed by amniocentesis at 21 weeks of gestation. A healthy boy weighing 2850 g was born by cesarean section at the 38th week of gestation.
CONCLUSIONS
PGD is a valid screening tool for patienst affected of CCA and SBMA to prevent transmission of these genetic diseases from parents to children.
Topics: Arachnodactyly; Contracture; Embryo Transfer; Female; Humans; Male; Muscular Disorders, Atrophic; Mutation; Polymorphism, Single Nucleotide; Preimplantation Diagnosis; Sex-Determining Region Y Protein; Spermatozoa
PubMed: 27393415
DOI: 10.1007/s10815-016-0760-y -
Journal of Clinical Pathology Jul 1964Pathological findings are described in four cases of a new aminoaciduria in which homocystine is excreted in the urine. All the patients were mentally retarded children....
Pathological findings are described in four cases of a new aminoaciduria in which homocystine is excreted in the urine. All the patients were mentally retarded children. Three of them presented diagnostic features of Marfan's syndrome. Necropsy on one case and biopsy findings in the others are described. Fatty change occurs in the liver. The most striking lesions are vascular. Metachromatic medial degeneration of the aorta and of the elastic arteries in the necropsied case are considered in relation to Marfan's syndrome. Other changes, particularly thrombosis which is prevalent in homocystinuria, suggest the possibility of a platelet defect. The findings are discussed in respect of an upset in the metabolism of sulphur-containing amino-acids and with particular reference to Marfan's syndrome.
Topics: Adolescent; Amino Acid Metabolism, Inborn Errors; Amino Acids; Arachnodactyly; Child; Cystine; Fatty Liver; Homocystinuria; Humans; Intellectual Disability; Intracranial Embolism; Intracranial Embolism and Thrombosis; Kidney; Marfan Syndrome; Pathology; Renal Aminoacidurias; Thrombosis; Vascular Diseases
PubMed: 14195630
DOI: 10.1136/jcp.17.4.427 -
Frontiers in Genetics 2023Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder with clinical features of arthrogryposis, arachnodactyly, crumpled...
Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder with clinical features of arthrogryposis, arachnodactyly, crumpled ears, scoliosis, and muscular hypoplasia. The heterozygous pathogenic variants in have been shown to cause CCA. Fibrillin-2 is related to the elasticity of the tissue and has been demonstrated to play an important role in the constitution of extracellular microfibrils in elastic fibers, providing strength and flexibility to the connective tissue that sustains the body's joints and organs. We recruited two Chinese families with arachnodactyly and bilateral arthrogryposis of the fingers. Whole-exome sequencing (WES) and co-segregation analysis were employed to identify their genetic etiologies. Three-dimensional protein models were used to analyze the pathogenic mechanism of the identified variants. We have reported two CCA families and identified two novel missense variants in (NM_001999.3: c.4093T>C, p.C1365R and c.2384G>T, p.C795F). The structural models of the mutant FBN2 protein in rats exhibited that both the variants could break disulfide bonds. We detected two variants in two families with CCA. Our description expands the genetic profile of CCA and emphasizes the pathogenicity of disulfide bond disruption in FBN2.
PubMed: 36936417
DOI: 10.3389/fgene.2023.1035887 -
Clinical Genetics Feb 2020Genome-scale high-throughput sequencing enables the detection of unprecedented numbers of sequence variants. Variant filtering and interpretation are facilitated by...
Genome-scale high-throughput sequencing enables the detection of unprecedented numbers of sequence variants. Variant filtering and interpretation are facilitated by mutation databases, in silico tools, and population-based reference datasets such as ExAC/gnomAD, while variants are classified using the ACMG/AMP guidelines. These methods, however, pose clinically relevant challenges. We queried the gnomAD dataset for (likely) pathogenic variants in genes causing autosomal-dominant disorders. Furthermore, focusing on the fibrillinopathies Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA), we screened 500 genomes of our patients for co-occurring variants in FBN1 and FBN2. In gnomAD, we detected 2653 (likely) pathogenic variants in 253 genes associated with autosomal-dominant disorders, enabling the estimation of variant-filtering thresholds and disease predisposition/prevalence rates. In our database, we discovered two families with hitherto unreported co-occurrence of FBN1/FBN2 variants causing phenotypes with mixed or modified MFS/CCA clinical features. We show that (likely) pathogenic gnomAD variants may be more frequent than expected and are challenging to classify according to the ACMG/AMP guidelines as well as that fibrillinopathies are likely underdiagnosed and may co-occur. Consequently, selection of appropriate frequency cutoffs, recognition of digenic variants, and variant classification represent considerable challenges in variant interpretation. Neglecting these challenges may lead to incomplete or missed diagnoses.
Topics: Adolescent; Adult; Aged; Alleles; Arachnodactyly; Child; Contracture; Databases, Genetic; Female; Fibrillin-1; Fibrillin-2; Frameshift Mutation; Genetic Association Studies; Genetic Variation; Genotype; Humans; INDEL Mutation; Male; Marfan Syndrome; Middle Aged; Pedigree; Phenotype; Whole Genome Sequencing
PubMed: 31506931
DOI: 10.1111/cge.13640 -
BMJ Case Reports Jan 2021Patients with syndromic craniosynostosis are usually associated with the complexity of the malformation complex. We describe here detailed oculo-motility disorder and a...
Patients with syndromic craniosynostosis are usually associated with the complexity of the malformation complex. We describe here detailed oculo-motility disorder and a remarkable finding of hypoplastic bilateral media recti on imaging and its intraoperative absence in patients with phenotypic features resembling Shprintzen-Goldberg syndrome (SGS). SGS is a rare congenital disorder with craniosynostosis affecting multiple systems including mentation and having a considerable overlap of its phenotypic features with Marfan syndrome. Large A-pattern exotropia found in these patients may be related to the craniofacial features and their bearing on extraocular muscle development and function. In this paper, we aimed to sensitise ophthalmologists and strabismologists concerning the necessity to recognise syndromic associations of patients with craniosynostosis presenting with a large squint, be aware of the intraoperative surprises and consider the challenges in its management.
Topics: Arachnodactyly; Child; Craniosynostoses; Humans; Male; Marfan Syndrome; Oculomotor Muscles
PubMed: 33461988
DOI: 10.1136/bcr-2019-233557