Autosomal dominant Marfan syndrome caused by a previously reported recessive <i>FBN1</i> variant

Overwater, Eline; Efrat, Rifka; Barge-Schaapveld, Daniela Q.C.M.; Lakeman, Phillis; Weiss, Marjan M.; Maugeri, Alessandra; Tintelen, Peter van; Houweling, Arjan C.

doi:10.1002/mgg3.518

Cited by 6 publications

(7 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pathogenic FBN1 variants cause MFS but can also be found in patients presenting with apparently isolated features. For instance, the c.1453C>T, p.(Arg485-Cys) mutation in FBN1 has been identified in both autosomal dominant and recessive diseases characterized by a high extent of phenotypic variability [41,42]. Hence, it is reasonable to postulate that the c.2649G>A allele, which has been associated with MFS, could also account for the isolated CS in our study.…”

Section: Discussionmentioning

confidence: 63%

Identification of novel FBN1 variations implicated in congenital scoliosis

et al. 2019

View full text Add to dashboard Cite

Congenital scoliosis (CS) is a form of scoliosis caused by congenital vertebral malformations. Genetic predisposition has been demonstrated in CS. We previously reported that TBX6 loss-of-function causes CS in a compound heterozygous model; however, this model can explain only 10% of CS. Many monogenic and polygenic CS genes remain to be elucidated. In this study, we analyzed exome sequencing (ES) data of 615 Chinese CS from the Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) project. Cosegregation studies for 103 familial CS identified a novel heterozygous nonsense variant, c.2649G>A (p.Trp883Ter) in FBN1. The association between FBN1 and CS was then analyzed by extracting FBN1 variants from ES data of 574 sporadic CS and 828 controls; 30 novel variants were identified and prioritized for further analyses. A mutational burden test showed that the deleterious FBN1 variants were significantly enriched in CS subjects (OR = 3.9, P = 0.03 by Fisher's exact test). One missense variant, c.2613A>C (p.Leu871Phe) was recurrent in two unrelated CS subjects, and in vitro functional experiments for the variant suggest that FBN1 may contribute to CS by upregulating the transforming growth factor beta (TGF-β) signaling. Our study expanded the phenotypic spectrum of FBN1, and provided nove insights into the genetic etiology of CS. Members of the Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study are listed below Acknowledgements.

show abstract

Section: Discussionmentioning

confidence: 63%

Identification of novel FBN1 variations implicated in congenital scoliosis

et al. 2019

View full text Add to dashboard Cite

show abstract

“…ES revealed that he carried two pathogenic variants, including a de novo variant in COL1A1 (c.1081C>T p.Arg361Ter) and a maternally inherited variant in FBN1 (c.1453C>T p.Arg485Cys) (Table 1). These two reported variants led to dual molecular diagnosis consisting of osteogenesis imperfecta type I and Marfan syndrome (13,14). Although reported patients with osteogenesis imperfecta type I often present short stature (15), the stature of this patient is relatively high tall (Height: 185cm) (Figure 1.B , Table 1), which might be related with his second diagnosis of Marfan syndrome.…”

Section: Casementioning

confidence: 81%

“…Although reported patients with osteogenesis imperfecta type I often present short stature (15), the stature of this patient is relatively high tall (Height: 185cm) (Figure 1.B , Table 1), which might be related with his second diagnosis of Marfan syndrome. Although FBN1 variant has been reported and considered as a pathogenic variant (14), no other features of Marfan Syndrome such as dolichostenomelia, arachnodactyly, joint laxity, velvety skin, ectopia lentis and cardiovascular manifestations were identi ed. This patient exempli ed the apparently contrary effects of two monogenic disease on the same trait (height in this case).…”

Section: Casementioning

confidence: 99%

Epidemiology and Phenotypic Characteristics of Dual Molecular Diagnosis Cases in Skeletal Abnormality

Lian

Sun

Chen

et al. 2021

Preprint

View full text Add to dashboard Cite

Background Skeletal abnormality is a heterogeneous group of disorders that affects the composition and structure of bone and cartilage. In our previous studies, we have revealed that a substantial proportion of cases with early-onset scoliosis could be explained by monogenic disorders such as Marfan syndrome and Ehlers-Danlos syndrome. More recently complex phenotypes caused by more than one genetic defect (i.e., dual molecular diagnosis) have also been reported in skeletal abnormalities. To explore the molecular epidemiology and phenotypic characteristics of dual diagnosis in skeletal abnormalities, we described cases with dual molecular diagnosis from the Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study.Results In total, 1108 patients with skeletal abnormality from the DISCO study underwent Exome Sequencing. We identified eight probands with dual molecular diagnosis, including three (0.7%) from individuals with early-onset scoliosis (EOS), three (0.5%) from individuals with short stature, and two (2%) from individuals with congenital hand/foot deformity (CHFA). Other skeletal abnormalities observed in these individuals included bone fracture and interphalangeal joint contracture. All the eight probands have dual diagnosis of two autosomal dominant (AD) diseases. A total of 16 variants in 12 genes were identified. A substantial rate (5 of 10) of the identified causal variants were of de novo origin. The frequently observed molecular diagnoses (observed in more than one patient) include Osteogenesis Imperfecta Type I (COL1A1, MIM:166200), Neurofibromatosis, Type I (NF1, MIM:162200) and Marfan Syndrome (FBN1, MIM:154700). These patients with dual molecular diagnosis often present blended phenotypes of two diseases, which significantly complicate their diagnostic process. Conclusions This study revealed the molecular epidemiology and complex diagnostic odyssey of dual molecular diagnosis through analyzing the clinical traits of skeletal abnormalities in eight patients.

show abstract

“…ES identified two pathogenic variants, including a de novo variant in COL1A1 (c.1081C > T, p.Arg361Ter) and a maternally inherited variant in FBN1 (c.1453C > T, p.Arg485Cys) (Table 1 ). These two reported variants led to dual molecular diagnosis consisting of osteogenesis imperfecta type I and Marfan syndrome [ 16 , 17 ]. Although patients with osteogenesis imperfecta type I often present with short stature [ 18 ], the patient was tall (Height: 185 cm), which might be related with his second diagnosis of Marfan syndrome.…”

Section: Resultsmentioning

confidence: 99%

Delineation of dual molecular diagnosis in patients with skeletal deformity

Sun

Chen

Wang

et al. 2022

Orphanet J Rare Dis

View full text Add to dashboard Cite

Background Skeletal deformity is characterized by an abnormal anatomical structure of bone and cartilage. In our previous studies, we have found that a substantial proportion of patients with skeletal deformity could be explained by monogenic disorders. More recently, complex phenotypes caused by more than one genetic defect (i.e., dual molecular diagnosis) have also been reported in skeletal deformities and may complicate the diagnostic odyssey of patients. In this study, we report the molecular and phenotypic characteristics of patients with dual molecular diagnosis and variable skeletal deformities. Results From 1108 patients who underwent exome sequencing, we identified eight probands with dual molecular diagnosis and variable skeletal deformities. All eight patients had dual diagnosis consisting of two autosomal dominant diseases. A total of 16 variants in 12 genes were identified, 5 of which were of de novo origin. Patients with dual molecular diagnosis presented blended phenotypes of two genetic diseases. Mendelian disorders occurred more than once include Osteogenesis Imperfecta Type I (COL1A1, MIM:166200), Neurofibromatosis, Type I (NF1, MIM:162200) and Marfan Syndrome (FBN1, MIM:154700). Conclusions This study demonstrated the complicated skeletal phenotypes associated with dual molecular diagnosis. Exome sequencing represents a powerful tool to detect such complex conditions.

show abstract

Autosomal dominant Marfan syndrome caused by a previously reported recessive FBN1 variant

Cited by 6 publications

References 21 publications

Identification of novel FBN1 variations implicated in congenital scoliosis

Identification of novel FBN1 variations implicated in congenital scoliosis

Epidemiology and Phenotypic Characteristics of Dual Molecular Diagnosis Cases in Skeletal Abnormality

Delineation of dual molecular diagnosis in patients with skeletal deformity

Contact Info

Product

Resources

About