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International Journal of Molecular... May 2024Fibrillin-1 and fibrillin-2, encoded by and , respectively, play significant roles in elastic fiber assembly, with pathogenic variants causing a diverse group of...
Fibrillin-1 and fibrillin-2, encoded by and , respectively, play significant roles in elastic fiber assembly, with pathogenic variants causing a diverse group of connective tissue disorders such as Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCD). Different genomic variations may lead to heterogeneous phenotypic features and functional consequences. Recent high-throughput sequencing modalities have allowed detection of novel variants that may guide the care for patients and inform the genetic counseling for their families. We performed clinical phenotyping for two newborn infants with complex congenital heart defects. For genetic investigations, we employed next-generation sequencing strategies including whole-genome Single-Nucleotide Polymorphism (SNP) microarray for infant A with valvular insufficiency, aortic sinus dilatation, hydronephrosis, and dysmorphic features, and Trio whole-exome sequencing (WES) for infant B with dextro-transposition of the great arteries (D-TGA) and both parents. Infant A is a term male with neonatal marfanoid features, left-sided hydronephrosis, and complex congenital heart defects including tricuspid regurgitation, aortic sinus dilatation, patent foramen ovale, patent ductus arteriosus, mitral regurgitation, tricuspid regurgitation, aortic regurgitation, and pulmonary sinus dilatation. He developed severe persistent pulmonary hypertension and worsening acute hypercapnic hypoxemic respiratory failure, and subsequently expired on day of life (DOL) 10 after compassionate extubation. Cytogenomic whole-genome SNP microarray analysis revealed a deletion within the gene spanning exons 7-30, which overlapped with the exon deletion hotspot region associated with neonatal Marfan syndrome. Infant B is a term male prenatally diagnosed with isolated D-TGA. He required balloon atrial septostomy on DOL 0 and subsequent atrial switch operation, atrial septal defect repair, and patent ductus arteriosus ligation on DOL 5. Trio-WES revealed compound heterozygous c.518C>T and c.8230T>G variants in the gene. Zygosity analysis confirmed each of the variants was inherited from one of the parents who were healthy heterozygous carriers. Since his cardiac repair at birth, he has been growing and developing well without any further hospitalization. Our study highlights novel variants and signifies the phenotype-genotype association in two infants affected with complex congenital heart defects with and without dysmorphic features. These findings speak to the importance of next-generation high-throughput genomics for novel variant detection and the phenotypic variability associated with variants, particularly in the neonatal period, which may significantly impact clinical care and family counseling.
Topics: Humans; Fibrillin-1; Marfan Syndrome; Fibrillin-2; Male; Infant, Newborn; Heart Defects, Congenital; High-Throughput Nucleotide Sequencing; Female; Polymorphism, Single Nucleotide; Mutation; Genomics; Phenotype; Exome Sequencing; Adipokines
PubMed: 38791509
DOI: 10.3390/ijms25105469 -
Connective Tissue Research May 2024Congenital contractural arachnodactyly (CCA) is an extremely rare autosomal dominant connective tissue genetic disorder caused by pathogenic variants in FBN2. CCA is...
PURPOSE
Congenital contractural arachnodactyly (CCA) is an extremely rare autosomal dominant connective tissue genetic disorder caused by pathogenic variants in FBN2. CCA is characterized by arachnodactyly, camptodactyly, contracture of major joints, scoliosis, pectus deformities, and crumpled ears, but rarely with lethal cardiovascular manifestations as in Marfan syndrome. It is imperative to conduct a comprehensive analysis and review of the pathogenesis of CCA resulting from pathogenic variants in FBN2 gene.
MATERIALS AND METHODS
Using whole-exome sequencing and Sanger sequencing, we identified a novel pathogenic splice-altering variant (c.4472-3C>A) in intron 34 of FBN2 gene in a CCA pedigree. The transcriptional result of the splicing-altering variant was analyzed by RNA sequencing. We systematically analyzed the clinical manifestations of all reported cases of CCA caused by splicing-altering pathogenic variants and focused on all the pathogenic variants in FBN2 gene that are associated with severe cardiovascular manifestations.
RESULTS
The splice-altering variant (c.4472-3C>A) in FBN2 was demonstrated to result in the exon 35 skipping and cause an in-frame deletion. Furthermore, we identified exons 31 to 35 may be a hotspot region in FBN2 gene associated with severe cardiovascular phenotype.
CONCLUSIONS
This study enriched the pathogenic spectrum of CCA and identified a hotspot region in FBN2 gene associated with severe cardiovascular manifestations. We recommend that patients carrying pathogenic variants in exons 31 to 35 of FBN2 pay more attention to cardiac evaluation.
Topics: Fibrillin-2; Humans; Arachnodactyly; Contracture; Male; Female; Pedigree; Mutation
PubMed: 38602424
DOI: 10.1080/03008207.2024.2340004 -
Cureus Jan 2024Pathogenic variants in mitochondrial calcium uptake 1 ( manifest phenotypically heterogeneously but most frequently in the brain and skeletal muscle. Dolichocephaly,...
Pathogenic variants in mitochondrial calcium uptake 1 ( manifest phenotypically heterogeneously but most frequently in the brain and skeletal muscle. Dolichocephaly, arachnodactyly, diplopia, and distal myopathy have not been reported in carriers of a pathogenic variant. The patient is a 23-year-old female with consanguineous parents (first cousins) who was a carrier of the homozygous variant c.553C>T, phenotypically presenting with developmental delay, intellectual disability, ataxia, dysmorphia (dolichocephaly, arachnodactyly, clinodactyly, hypertelorism, wide nasal bridge), myopathy (ptosis, double vision, strabismus, distal limb weakness, diffuse wasting, hypotonia), hyperextensible joints and hyperkyphosis. Features not previously described were dolichocephaly, arachnodactyly, broad nasal bridge, double vision, and distal myopathy. She was treated with physical therapy, speech therapy, and occupational therapy and received escitalopram and mirtazapine for concomitant depression, anxiety disorder, and insomnia. The presented case shows that the phenotypic heterogeneity of pathogenic variants is even greater than previously assumed. Treatment of -related phenotypes is symptomatic, but these patients benefit from physical therapy, behavioral therapy, speech therapy, and antidepressant treatment.
PubMed: 38380193
DOI: 10.7759/cureus.52672 -
American Journal of Medical Genetics.... Jun 2024Phenotypic features of a hereditary connective tissue disorder, including craniofacial characteristics, hyperextensible skin, joint laxity, kyphoscoliosis,...
Phenotypic features of a hereditary connective tissue disorder, including craniofacial characteristics, hyperextensible skin, joint laxity, kyphoscoliosis, arachnodactyly, inguinal hernia, and diverticulosis associated with biallelic pathogenic variants in EFEMP1 have been previously described in four patients. Genome sequencing on a proband and her mother with comparable phenotypic features revealed that both patients were heterozygous for a stop-gain variant c.1084C>T (p.Arg362*). Complementary RNA-seq on fibroblasts revealed significantly reduced levels of mutant EFEMP1 transcript. Considering the absence of other molecular explanations, we extrapolated that EFEMP1 could be the cause of the patient's phenotypes. Furthermore, nonsense-mediated decay was demonstrated for the mutant allele as the principal mechanism for decreased levels of EFEMP1 mRNA. We provide strong clinical and genetic evidence for the haploinsufficiency of EFEMP1 due to nonsense-medicated decay to cause severe kyphoscoliosis, generalized hypermobility of joints, high and narrow arched palate, and potentially severe diverticulosis. To the best of our knowledge, this is the first report of an autosomal dominant EFEMP1-associated hereditary connective tissue disorder and therefore expands the phenotypic spectrum of EFEMP1 related disorders.
Topics: Humans; Haploinsufficiency; Female; Marfan Syndrome; Extracellular Matrix Proteins; Phenotype; Connective Tissue Diseases; Pedigree; Mutation; Nonsense Mediated mRNA Decay; Male; Adult; Alleles; Genetic Predisposition to Disease; Child
PubMed: 38348595
DOI: 10.1002/ajmg.a.63556 -
Human Genome Variation Feb 2024Congenital contractual arachnodactyly (CCA) is a genetic connective tissue disorder that is characterized by arachnodactyly, kyphoscoliosis, marfanoid habitus, and...
Congenital contractual arachnodactyly (CCA) is a genetic connective tissue disorder that is characterized by arachnodactyly, kyphoscoliosis, marfanoid habitus, and crumpled ears. We report a case of a boy with suspected Marfan syndrome. Genetic analysis revealed c.3207_3217+9del in a heterozygote form of the fibrillin-2 (FBN2) gene. This patient was diagnosed with CCA based on his phenotype, and the pathogenicity of this variant was classified according to cDNA analysis and protein modeling.
PubMed: 38326314
DOI: 10.1038/s41439-024-00264-1 -
Ophthalmic Genetics Jan 2024Variations in have been associated with Brittle Cornea Syndrome that presents with bluish sclera, loss of vision after trivial trauma, arachnodactyly, and joint laxity.
BACKGROUND
Variations in have been associated with Brittle Cornea Syndrome that presents with bluish sclera, loss of vision after trivial trauma, arachnodactyly, and joint laxity.
MATERIALS AND METHODS
Detailed medical and family history, physical examination, and molecular analysis.
RESULTS
A 21-year-old female presented with bluish discoloration of sclera, diminution of vision following trivial trauma in childhood along with hearing loss and systemic features of arachnodactyly and joint laxity. Clinical diagnosis of brittle cornea syndrome was made which was molecularly proven using next-generation sequencing which identified compound heterozygosity in for pathogenic and likely pathogenic nonsense variants. One variant namely NM_001367624.2:c.5882dup was identified in the exon 3 which was novel and classified as likely pathogenic according to American College of Medical Genetics (ACMG) criteria for variant classification. Another variant NM_001367624.2:c.8992C>T in the exon 2 was classified as pathogenic for Brittle Cornea Syndrome 1.
CONCLUSIONS
The report adds to the allelic heterogeneity in causative of Brittle Cornea Syndrome 1 and shall acquaint the physicians about this potentially vision threatening, underdiagnosed, rare syndrome.
PubMed: 38289830
DOI: 10.1080/13816810.2024.2303690 -
Zeitschrift Fur Gastroenterologie Jan 2024Patients with primary sclerosing cholangitis (PSC) carry increased risks for malignancy, among which cholangiocarcinoma (CCA) is the most frequent. We aimed to...
BACKGROUND
Patients with primary sclerosing cholangitis (PSC) carry increased risks for malignancy, among which cholangiocarcinoma (CCA) is the most frequent. We aimed to characterise a cohort of patients with PSC and intrahepatic CCA (iCCA) and to compare this cohort with CCA in different localisations.
METHODS
We performed a retrospective analysis of our medical database from 01.01.2007 to 30.06.2023 and differentiated CCA according to its localisation within the biliary tract into iCCA, perihilar CCA (pCCA), distal CCA (dCCA), and gallbladder carcinoma (GBC).
RESULTS
We identified 8 (28%) patients with iCCA, 14 (48%) patients with pCCA, 6 (21%) patients with GBC, and 1 (3%) patient with dCCA without significant differences in gender distribution and mean age. Mean time between diagnosis of PSC and CCA was 158±84 months for iCCA, 93±94 months for pCCA, and 77±69 months for GBC (p=0.230). At the time of CCA diagnosis, advanced-stage disease was present in 6 (75%) patients with iCCA, 13 (93%) patients with pCCA, and 2 (40%) patients with GBC (p=0.050). Only 5 (63%) patients with iCCA received curatively intended surgery, of whom 4 (80%) patients developed recurrence after a mean time of 38±31 months. Mean survival time in patients with iCCA (35±33 months) lay between patients with pCCA (14±8 months) and patients with GBC (57±58 months), but the difference was not statistically significant (p=0.131).
CONCLUSION
Patients with PSC and iCCA showed an advanced tumour stage at diagnosis and limited long-time survival, which was classified between pCCA with worse prognosis and GBC with better prognosis.
Topics: Humans; Retrospective Studies; Cholangitis, Sclerosing; Cholangiocarcinoma; Gallbladder Neoplasms; Bile Duct Neoplasms; Bile Ducts, Intrahepatic
PubMed: 38195106
DOI: 10.1055/a-2207-5519 -
Archives of Oral Biology Feb 2024describing the clinical features of twelve Egyptian patients with Papillon-Lefever syndrome (PLS). Five novel mutations in the cathepsin C (CTSC) gene are introduced and...
OBJECTIVES
describing the clinical features of twelve Egyptian patients with Papillon-Lefever syndrome (PLS). Five novel mutations in the cathepsin C (CTSC) gene are introduced and the phenotype of the syndrome is expanded by the identification of new clinical features.
DESIGN
the clinical, oro-dental data of twelve Egyptian patients from seven unrelated families are described. Sequence analysis of the CTSC gene was performed to identify the causative mutaions.
RESULTS
Typical PLS features were presented in all patints but with variable severity. One patient showed atypical dental features including dental structural defect, minimal periodontitis, severe gingivitis, and delayed closure of root apices. Another patient presented with arachnodactyly, dystrophic nails, and buphthalmos in the right eye secondary to uncontrolled congenital glaucoma. Mutational analysis of CTSC gene revealed seven distinct homozygous variants including five novel ones: c.285_286delGT (p.Leu96GlufsTer2), c .302 G>C (p.Trp101Ser), c.622_628delCACAGTC (p.H208Efs*11), c.1331delinsAAAAA (p.G444Efs*4) and c .1343 G>A (p.Cys448Tyr). The previously reported missense variant c .757 G>A (p.Ala253Thr) was found in one patient. This variant is very close to the splice region and by functional studies, we proved that it results in exon skipping and early protein truncation (p.R214Sfs*46).
CONCLUSION
We report five novel CTSC variants and describe rare and unusual associated clinical and dental findings such as dental structural defects, delayed closure of root apices, and congenital glaucoma. Therefore, our results expand both the phenotypic and mutational spectrum of PLS.
Topics: Humans; Papillon-Lefevre Disease; Cathepsin C; Egypt; Mutation, Missense; Syndrome; Glaucoma
PubMed: 38104461
DOI: 10.1016/j.archoralbio.2023.105869 -
Genetics Jan 2024The fibrillinopathies represent a group of diseases in which the 10-12 nm extracellular microfibrils are disrupted by genetic variants in one of the genes encoding... (Review)
Review
The fibrillinopathies represent a group of diseases in which the 10-12 nm extracellular microfibrils are disrupted by genetic variants in one of the genes encoding fibrillin molecules, large glycoproteins of the extracellular matrix. The best-known fibrillinopathy is Marfan syndrome, an autosomal dominant condition affecting the cardiovascular, ocular, skeletal, and other systems, with a prevalence of around 1 in 3,000 across all ethnic groups. It is caused by variants of the FBN1 gene, encoding fibrillin-1, which interacts with elastin to provide strength and elasticity to connective tissues. A number of mouse models have been created in an attempt to replicate the human phenotype, although all have limitations. There are also natural bovine models and engineered models in pig and rabbit. Variants in FBN2 encoding fibrillin-2 cause congenital contractural arachnodactyly and mouse models for this condition have also been produced. In most animals, including birds, reptiles, and amphibians, there is a third fibrillin, fibrillin-3 (FBN3 gene) for which the creation of models has been difficult as the gene is degenerate and nonfunctional in mice and rats. Other eukaryotes such as the nematode C. elegans and zebrafish D. rerio have a gene with some homology to fibrillins and models have been used to discover more about the function of this family of proteins. This review looks at the phenotype, inheritance, and relevance of the various animal models for the different fibrillinopathies.
Topics: Animals; Cattle; Humans; Mice; Rats; Rabbits; Swine; Mutation; Caenorhabditis elegans; Models, Genetic; Zebrafish; Fibrillins
PubMed: 37972149
DOI: 10.1093/genetics/iyad189 -
Biochemical Genetics Nov 2023Congenital contractural arachnodactyly (CCA) is a rare connective tissue disorder characterized by arachnodactyly, multiple joint contractures, progressive...
Congenital contractural arachnodactyly (CCA) is a rare connective tissue disorder characterized by arachnodactyly, multiple joint contractures, progressive kyphoscoliosis, pectus deformity and abnormal crumpled ears. FBN2 is the only gene currently known to be associated with CCA. In this study, we report on a prenatal case presented with skeletal, cardiac and spinal malformations. And his father had elongated limbs, contractures of the proximal interphalangeal joints, high myopia and scoliosis. We conducted whole exome sequencing (WES) on the fetus-parental trio and a heterozygous variant (hg19 chr5:127,673,685, c.3598 + 4A > G, NM_001999.4) in intron 27 of the FBN2 gene was successfully identified, inherited from the father. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to evaluate the potential splicing effect of this variant, which confirmed that the variant caused a deletion of exon 27 (126 bp) by disrupting the splice-donor site and destroyed the 17th calcium-binding epidermal growth factor-like (cbEGF) domain. Our research not only finds the etiology of the disease in affected individuals and expands the mutation spectrum of FBN2 gene, but also provides genetic counseling and fertility guidance for this family.
PubMed: 37962692
DOI: 10.1007/s10528-023-10550-2