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ELife Jan 2021Shprintzen-Goldberg syndrome (SGS) is a multisystemic connective tissue disorder, with considerable clinical overlap with Marfan and Loeys-Dietz syndromes. These...
Shprintzen-Goldberg syndrome (SGS) is a multisystemic connective tissue disorder, with considerable clinical overlap with Marfan and Loeys-Dietz syndromes. These syndromes have commonly been associated with enhanced TGF-β signaling. In SGS patients, heterozygous point mutations have been mapped to the transcriptional co-repressor SKI, which is a negative regulator of TGF-β signaling that is rapidly degraded upon ligand stimulation. The molecular consequences of these mutations, however, are not understood. Here we use a combination of structural biology, genome editing, and biochemistry to show that SGS mutations in SKI abolish its binding to phosphorylated SMAD2 and SMAD3. This results in stabilization of SKI and consequently attenuation of TGF-β responses, both in knockin cells expressing an SGS mutation and in fibroblasts from SGS patients. Thus, we reveal that SGS is associated with an attenuation of TGF-β-induced transcriptional responses, and not enhancement, which has important implications for other Marfan-related syndromes.
Topics: Arachnodactyly; Craniosynostoses; DNA-Binding Proteins; Female; Humans; Male; Marfan Syndrome; Mutation; Proto-Oncogene Proteins; Signal Transduction; Transforming Growth Factor beta
PubMed: 33416497
DOI: 10.7554/eLife.63545 -
Neurology. Genetics Aug 2021To determine whether mutations reported for can cause mixed neurodevelopmental disorders, we performed both functional studies on variant pathogenicity and ZDHHC15...
OBJECTIVE
To determine whether mutations reported for can cause mixed neurodevelopmental disorders, we performed both functional studies on variant pathogenicity and ZDHHC15 function in animal models.
METHODS
We examined protein function of 4 identified variants in ZDHHC15 in a yeast complementation assay and locomotor defects of loss-of-function genotypes in a model.
RESULTS
Although we assessed multiple patient variants, only 1 (p.H158R) affected protein function. We report a patient with a diagnosis of hypotonic cerebral palsy, autism, epilepsy, and intellectual disability associated with this bona fide damaging X-linked variant. Features include tall forehead with mild brachycephaly, down-slanting palpebral fissures, large ears, long face, facial muscle hypotonia, high-arched palate with dental crowding, and arachnodactyly. The patient had mild diminished cerebral volume, with left-sided T2/FLAIR hyperintense periatrial ovoid lesion. We found that loss-of-function mutations in orthologs of this gene cause flight and coordinated movement defects in .
CONCLUSIONS
Our findings support a functional expansion of this gene to a role in motor dysfunction. Although mutations represent a rare cause of neurodevelopmental disability, candidate variants need to be carefully assessed before pathogenicity can be determined.
PubMed: 34345675
DOI: 10.1212/NXG.0000000000000602 -
BMC Medical Genomics Feb 2022Linkeropathies refers to a series of extremely rare hereditary connective tissue diseases affected by various glycosyltransferases in the biosynthesis of proteoglycans.... (Review)
Review
BACKGROUND
Linkeropathies refers to a series of extremely rare hereditary connective tissue diseases affected by various glycosyltransferases in the biosynthesis of proteoglycans. We report for the first time two heterozygous variants of B3GAT3 in a Chinese infant, in whom Marfan syndrome was suspected at birth.
CASE PRESENTATION
A 2-month-old boy from a non-consanguineous Chinese family without a family history presented severe phenotypes of joint dislocation, obvious flexion contractures of the elbow, arachnodactyly with slightly adducted thumbs, cranial dysplasia, foot abnormalities and aortic root dilation; Marfan syndrome was suspected at birth. Our patient was the youngest, at the age of 2 months, to experience aortic root dilation. Two B3GAT3 variants, NM_012200.2, c.752T>C, p.V251A and c.47C>A, p.S16*, with heterozygosity were identified in the patient by whole-exome sequencing; the variants were inherited from his parents. During close follow-up, significant changes in the cranial profile and obvious external hydrocephalus were present at the age of 7 months, which differs from previously reported cases.
CONCLUSION
We diagnosed a patient with congenital heart defects at an early age with a B3GAT3-related disorder instead of Marfan syndrome and expanded the spectrum of B3GAT3-related disorders. We also provide a literature review of reported B3GAT3 cases; for at least one of the variants, this is the first report of genotype-phenotype correlations in individuals with cardiovascular defects being related to the acceptor substrate-binding subdomain of B3GAT3.
Topics: Genetic Association Studies; Glucuronosyltransferase; Heterozygote; Humans; Phenotype; Exome Sequencing
PubMed: 35151321
DOI: 10.1186/s12920-022-01160-9 -
Philosophical Transactions of the Royal... Oct 2023Over 240 million people are infected with schistosomiasis. Detecting eggs in stool using Kato-Katz thick smears (Kato-Katzs) is highly specific but lacks sensitivity....
Over 240 million people are infected with schistosomiasis. Detecting eggs in stool using Kato-Katz thick smears (Kato-Katzs) is highly specific but lacks sensitivity. The urine-based point-of-care circulating cathodic antigen test (POC-CCA) has higher sensitivity, but issues include specificity, discrepancy between batches and interpretation of trace results. A semi-quantitative G-score and latent class analyses making no assumptions about trace readings have helped address some of these issues. However, intra-sample and inter-sample variation remains unknown for POC-CCAs. We collected 3 days of stool and urine from 349 and 621 participants, from high- and moderate-endemicity areas, respectively. We performed duplicate Kato-Katzs and one POC-CCA per sample. In the high-endemicity community, we also performed three POC-CCA technical replicates on one urine sample per participant. Latent class analysis was performed to estimate the relative contribution of intra- (test technical reproducibility) and inter-sample (day-to-day) variation on sensitivity and specificity. Within-sample variation for Kato-Katzs was higher than between-sample, with the opposite true for POC-CCAs. A POC-CCA G3 threshold most accurately assesses individual infections. However, to reach the WHO target product profile of the required 95% specificity for prevalence and monitoring and evaluation, a threshold of G4 is needed, but at the cost of reducing sensitivity. This article is part of the theme issue 'Challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs'.
Topics: Humans; Animals; Uganda; Point-of-Care Systems; Reproducibility of Results; Schistosoma mansoni; Neglected Diseases
PubMed: 37598698
DOI: 10.1098/rstb.2022.0275 -
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 -
Global Medical Genetics Jun 2022Geroderma osteodysplasticum (GO; MIM 231070) is characterized by a typical progeroid facial appearance, wrinkled, lax skin, joint laxity, skeletal abnormalities with...
Geroderma osteodysplasticum (GO; MIM 231070) is characterized by a typical progeroid facial appearance, wrinkled, lax skin, joint laxity, skeletal abnormalities with variable degree of osteopenia, frequent fractures, scoliosis, bowed long bones, vertebral collapse, and hyperextensible fingers. The disorder results from mutations in the GORAB-golgin, RAB6 interacting. This gene encodes a member of the golgin family, a group of coiled-coil proteins on golgin that maps to chromosome 1q24. The encoded protein has a function in the secretory pathway, was identified by terminal kinase-like protein, and thus, it may function in mitosis. Mutations in this gene have been associated with GO. Herein, we describe the clinical presentation of one young male patient from related Saudi parents. Mutations, a homozygous frameshift mutation (c.306dup p.(pro 103 Thrfs*20)). Interestingly, phenotypic variability was observed in this patient with GO features that were more atypical than the cases reported in the literature as he looks tall stature where most of the cases reported were short and arachnodactyly fingers which mimic other syndromes.
PubMed: 35707774
DOI: 10.1055/s-0041-1740468 -
BMC Medical Genomics Jul 2022Osteogenesis imperfecta (OI) is the most common monogenic disease of the skeletal system and is usually caused by mutations in the COL1A1 or COL1A2 genes. Congenital...
BACKGROUND
Osteogenesis imperfecta (OI) is the most common monogenic disease of the skeletal system and is usually caused by mutations in the COL1A1 or COL1A2 genes. Congenital contractural arachnodactyly syndrome (CCA) is an autosomal dominant hereditary disease of connective tissue. To date, the FBN2 gene is the only gene reported to cause CCA. Researchers found that COL1A2 and FBN2 are both involved in the extracellular matrix organization pathway. These findings suggest that these two genes play an important role in a similar mechanism and may trigger a synergistic effect.
METHODS
Trio-whole-exome sequencing (Trio-WES) was performed to analyse the underlying genetic cause of a proband with OI in a Chinese family. Sanger sequencing was used to validate the mutations in 3 members of the family with OI with varying degrees of severity of skeletal abnormalities and the members with no clinical signs.
RESULT
A c.3304G > C mutation in the COL1A2 gene (p.Gly1102Arg) and a novel c.4108G > T mutation in the FBN2 gene (p.Glu1370*) were detected in the proband, an affected member of the family. The affected individuals with both mutations present a more severe phenotype, while affected individuals present a milder phenotype if only the mutation in COL1A2 is detected (c.3304G > C). The unaffected individual in this family did not have any mutations in the COL1A2 gene or FBN2 gene.
CONCLUSION
Our study is the first clinical report to indicate that patients carrying concomitant mutations in both the COL1A2 and FBN2 genes may present with more severe skeletal abnormalities. Furthermore, our study suggests the possibility of synergistic effects between the COL1A2 and FBN2 genes.
Topics: Arachnodactyly; Collagen Type I; Contracture; Fibrillin-2; Humans; Mutation; Osteogenesis Imperfecta; Phenotype
PubMed: 35804365
DOI: 10.1186/s12920-022-01296-8 -
Dental and Medical Problems 2019The Shprintzen-Goldberg syndrome (SGS) is an autosomal dominant disorder with multiple congenital abnormalities. It is the result of de novo gene mutations. Recently,...
The Shprintzen-Goldberg syndrome (SGS) is an autosomal dominant disorder with multiple congenital abnormalities. It is the result of de novo gene mutations. Recently, mutations in the SKI gene are considered to be related to this syndrome. This gene is responsible for the manufacturing of protein which regulates the transforming growth factor beta (TGF-β) signaling pathway. There are characteristic craniofacial, skeletal, neurological, and connective tissue abnormalities associated with SGS. This is a case report of a 6-year-old male child who reported to the Department of Pediatric Dentistry at the Government Dental College and Hospital, Aurangabad, India, with decayed teeth. He had craniofacial, skeletal, cardiovascular, and other abnormalities suggestive of SGS. The patient had a tall forehead with plagiocephaly and a high-arched palate with hypoplastic teeth. His ears were apparently low-set with posterior rotation. The child had eyes with proptosis, myopia, hypertelorism, and down-slanting palpebral fissures. The child had moderate mental retardation with craniofacial features typical of this syndrome. The Shprintzen-Goldberg syndrome has many similarities with the Marfan syndrome (MFS) or the Loeys-Dietz syndrome (LDS) due to considerable phenotypic overlapping.
Topics: Arachnodactyly; Child; Craniosynostoses; Humans; India; Male; Marfan Syndrome; Plagiocephaly
PubMed: 31577075
DOI: 10.17219/dmp/109111 -
Severe neonatal Marfan syndrome with a novel mutation in the intron of the FBN1 gene: A case report.Medicine Feb 2021Marfan syndrome (MFS) has been defined as a genetic disorder that affects various systems such as the musculoskeletal, orbital, and cardiovascular systems. Neonatal MFS...
RATIONALE
Marfan syndrome (MFS) has been defined as a genetic disorder that affects various systems such as the musculoskeletal, orbital, and cardiovascular systems. Neonatal MFS is considered rare and the most severe form of MFS is characterized by rapidly progressive atrioventricular valve dysfunction, often leading to death during early childhood due to congestive heart failure.
PATIENT CONCERNS
A newborn with neonatal MFS and severe cardiac involvement. He presented various severe clinical features such as arachnodactyly, camptodactyly, elbow and knee joint contracture, senile facial appearance, and deep settling with down-slanting palpebral fissure, hypoplastic ear cartilage, sagging mouth, brachycephaly, and ectopia lentis.
DIAGNOSIS
Genetic analysis revealed a novel mutation at nucleotide 3964 (c.3964 + 1 G > T) in intron 32 of the fibrillin-1 gene. This mutation is identified to be in the so-called neonatal region of fibrillin-1 exon 24 to 32, as reported previously.
INTERVENTIONS
The patient was managed medically for improving the low cardiac output according to severe mitral regurgitation and aortic regurgitation. Afterload reduction, full sedation, and use of diuretic were attempted to improve the oliguria and heart failure.
OUTCOMES
Despite the medical management, aortic regurgitation, mitral regurgitation, pulmonary hypertension, and cardiac contractility got worse. Surgical treatment is essential to prolong the patient's life, however, considerations for the grave progression of the disease make families decide to continue palliative care instead of surgical treatment. A few months after birth, he presented with rapidly progressive aortic regurgitation, mitral regurgitation, and congestive heart failure leading to death.
CONCLUSIONS
This review demonstrated the prominent characteristics of neonatal MFS mutations, it would be helpful for the recognition of novel neonatal MFS variants and valuable for the understanding of the genotype-phenotype correlations and using the plans for managements and counseling in neonatal MFS.
Topics: Cardiovascular Abnormalities; Cardiovascular System; Congenital Abnormalities; Exons; Fatal Outcome; Fibrillin-1; Fibrillins; Heart Failure; Humans; Infant, Newborn; Introns; Male; Marfan Syndrome; Mutation; Oliguria
PubMed: 33578525
DOI: 10.1097/MD.0000000000024301 -
Cureus Nov 2022Marfan syndrome (MFS), an inherited connective tissue disorder, is caused by a mutation in the FBN1 gene. MFS is characterized by manifestations in the musculoskeletal...
Marfan syndrome (MFS), an inherited connective tissue disorder, is caused by a mutation in the FBN1 gene. MFS is characterized by manifestations in the musculoskeletal system (joint laxity, scoliosis), the cardiovascular system (aortic dilation), and the ocular system (ectopic lens). We report a case of a 37-year-old male with a genetically confirmed MFS. His mother and brother were also both confirmed cases of MFS. While the patient exhibited the characteristic physical features of MFS in general appearance, he did not show any cardiac manifestations of the disease. This report highlights a case of the familial occurrence of MFS and emphasizes the importance of recognizing the forme fruste of MFS.
PubMed: 36505128
DOI: 10.7759/cureus.31231