Further delineation of a recognizable type of syndromic short stature caused by biallelic <scp><i>SEMA3A</i></scp> loss‐of‐function variants

Gileta, Alexander F.; Helgeson, Maria; Leonard, Jacqueline; Pyle, Louise C.; Subramanian, Hari Prasanna; Arndt, Kelly; Hawkes, Colin P.; Gaudio, Daniela del

doi:10.1002/ajmg.a.62023

Cited by 3 publications

(4 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It suggested the mutations at positions 435–457 in the SEMA region are likely to lead to impaired secretion of SEMA3A, and the 435–457 position is very important for the secretion of SEMA3A. Haploin-sufficiency of SEMA3A in humans was sufficient to cause the IHH phenotype [ 3 , 4 , 6 , 12 ].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the patient with SEMA3A variant (T457A) had neither visual impairment nor olfactory defect. Gileta et al screened a nonsense variant (R555 ∗ ) and a deletion of exons 15, 16, and 17 in SEMA3A in a female KS patient [ 12 ]. It seems possible that SEMA3A variants might modify the IHH phenotype, according to the variants at different positions of SEMA3A.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Discovery of a Novel Variant of SEMA3A in a Chinese Patient with Isolated Hypogonadotropic Hypogonadism

Dai

Wang

et al. 2021

International Journal of Endocrinology

View full text Add to dashboard Cite

Semaphorin (SEMA) has an important role in nerve development, organ formation, immune response, angiogenesis, and tumor growth. SEMA can regulate the growth and branching of axons, the morphology of dendrites, and the migration of neurons. The loss-of-function in SEMA and its receptors PLXNs and NRP affect the migration of GnRH neurons, leading to idiopathic hypogonadotropic hypogonadism (IHH). As a member of the SEMA family, SEMA3A has an important role in axonal rejection, dendritic branching, synaptic formation, and neuronal migration. There are more and more SEMA3A variants identified in IHH patients. In this study, we identified a novel SEMA3A variant (c.1369A > G (p.T457A)) in a male nIHH patient. Functional studies indicated that the T457A SEMA3A variant led to the defect of FAK phosphorylation and GN11 cell migration, which strongly argued in favor of its pathogenic effect in the nIHH patient. Our findings substantiated that the 435–457 position of SEMA3A might be very important for the secretion of SEMA3A. Haploin-sufficiency of SEMA3A in humans was sufficient to cause the IHH phenotype. SEMA3A variants might have a role in modifying the IHH phenotype, according to the variants at different positions of SEMA3A. SEMAs and its receptors formed a complex network, and other members of the SEMA-signaling pathway might also be involved in the pathogenesis of IHH.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Discovery of a Novel Variant of SEMA3A in a Chinese Patient with Isolated Hypogonadotropic Hypogonadism

Dai

Wang

et al. 2021

International Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…DSCAM overexpression leads to congenital heart defects [ 56 ] and is probably responsible for the congenital heart defects observed in Down syndrome patients [ 57 ]. Moreover, SEMA3A and PRRX2 mutations also lead to congenital heart defects [ 58 , 59 ]. Next to its function in the heart, both proteins also influence smooth muscle development.…”

Section: Resultsmentioning

confidence: 99%

“…Disturbed insulin/Akt signaling may thus be a determinant for the excessive growth in MFS patients, which deserves further investigation. Interestingly, also SEMA3A mutations may cause short stature, as can be observed in FBN1 mutation patients with acromelic dysplasias [ 58 ]. Moreover, the two genes FAM50B and NAGPA are associated with adolescent idiopathic scoliosis (GeneCards®), which is a common feature in MFS patients [ 78 , 80 ].…”

Section: Discussionmentioning

confidence: 99%

Genome-wide methylation patterns in Marfan syndrome

et al. 2021

View full text Add to dashboard Cite

Background Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene (FBN1). Here, we undertook the first epigenome-wide association study (EWAS) in patients with MFS aiming at identifying DNA methylation loci associated with MFS phenotypes that may shed light on the disease process. Methods The Illumina 450 k DNA-methylation array was used on stored peripheral whole-blood samples of 190 patients with MFS originally included in the COMPARE trial. An unbiased genome-wide approach was used, and methylation of CpG-sites across the entire genome was evaluated. Additionally, we investigated CpG-sites across the FBN1-locus (15q21.1) more closely, since this is the gene defective in MFS. Differentially Methylated Positions (DMPs) and Differentially Methylated Regions (DMRs) were identified through regression analysis. Associations between methylation levels and aortic diameters and presence or absence of 21 clinical features of MFS at baseline were analyzed. Moreover, associations between aortic diameter change, and the occurrence of clinical events (death any cause, type-A or -B dissection/rupture, or aortic surgery) and methylation levels were analyzed. Results We identified 28 DMPs that are significantly associated with aortic diameters in patients with MFS. Seven of these DMPs (25%) could be allocated to a gene that was previously associated with cardiovascular diseases (HDAC4, IGF2BP3, CASZ1, SDK1, PCDHGA1, DIO3, PTPRN2). Moreover, we identified seven DMPs that were significantly associated with aortic diameter change and five DMP’s that associated with clinical events. No significant associations at p < 10–8 or p < 10–6 were found with any of the non-cardiovascular phenotypic MFS features. Investigating DMRs, clusters were seen mostly on X- and Y, and chromosome 18–22. The remaining DMRs indicated involvement of a large family of protocadherins on chromosome 5, which were not reported in MFS before. Conclusion This EWAS in patients with MFS has identified a number of methylation loci significantly associated with aortic diameters, aortic dilatation rate and aortic events. Our findings add to the slowly growing literature on the regulation of gene expression in MFS patients.

show abstract

Genetics of congenital olfactory dysfunction: a systematic review of the literature

et al. 2022

View full text Add to dashboard Cite

Olfaction, as one of our 5 senses, plays an important role in our daily lives. It is connected to proper nutrition, social interaction, and protection mechanisms. Disorders affecting this sense consequently also affect the patients’ general quality of life. Because the underlying genetics of congenital olfactory disorders (COD) have not been thoroughly investigated yet, this systematic review aimed at providing information on genes that have previously been reported to be mutated in patients suffering from COD. This was achieved by systematically reviewing existing literature on 3 databases, namely PubMed, Ovid Medline, and ISI Web of Science. Genes and the type of disorder, that is, isolated and/or syndromic COD were included in this study, as were the patients’ associated abnormal features, which were categorized according to the affected organ(-system). Our research yielded 82 candidate genes/chromosome loci for isolated and/or syndromic COD. Our results revealed that the majority of these are implicated in syndromic COD, a few accounted for syndromic and isolated COD, and the least underly isolated COD. Most commonly, structures of the central nervous system displayed abnormalities. This study is meant to assist clinicians in determining the type of COD and detecting potentially abnormal features in patients with confirmed genetic variations. Future research will hopefully expand this list and thereby further improve our understanding of COD.

show abstract

Further delineation of a recognizable type of syndromic short stature caused by biallelic SEMA3A loss‐of‐function variants

Cited by 3 publications

References 30 publications

Discovery of a Novel Variant of SEMA3A in a Chinese Patient with Isolated Hypogonadotropic Hypogonadism

Discovery of a Novel Variant of SEMA3A in a Chinese Patient with Isolated Hypogonadotropic Hypogonadism

Genome-wide methylation patterns in Marfan syndrome

Genetics of congenital olfactory dysfunction: a systematic review of the literature

Contact Info

Product

Resources

About