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American Journal of Medical Genetics Mar 1984We describe a male infant with the Aarskog syndrome and his equally prominently affected mother. The propositus and his mother have a balanced X-autosome translocation...
We describe a male infant with the Aarskog syndrome and his equally prominently affected mother. The propositus and his mother have a balanced X-autosome translocation which originated in her. We postulate that the mother's translocation resulted in a presumed de novo point mutation for the Aarskog locus and that she has nonrandom inactivation of her structurally normal X. The full expression of the syndrome in the mother is compared to the partial expression in reported females. It is concluded that the Aarskog syndrome is an X-linked disorder and that the locus for the syndrome is at Xq13.
Topics: Abnormalities, Multiple; Adult; Child, Preschool; Chromosome Banding; Chromosome Mapping; Chromosomes, Human, 6-12 and X; Facial Expression; Female; Fingers; Growth Disorders; Humans; Karyotyping; Male; Penis; Phenotype; Sex Factors; Syndrome; Toes; Translocation, Genetic; X Chromosome
PubMed: 6711610
DOI: 10.1002/ajmg.1320170307 -
European Journal of Pediatrics Oct 2014Aarskog syndrome (AAS) is an X-linked human disease that affects the skeletal formation and embryonic morphogenesis and is caused by mutations in the FGD1 gene. Patients...
UNLABELLED
Aarskog syndrome (AAS) is an X-linked human disease that affects the skeletal formation and embryonic morphogenesis and is caused by mutations in the FGD1 gene. Patients typically show distinctive skeletal and genital developmental abnormalities, but a broad spectrum of clinical phenotypes has been observed. We report here on the clinical and molecular analysis of a family that reveals a novel FGD1 mutation in a 9-year-old boy displaying extreme craniofacial dysplasia associated with attention deficit hyperactivity disorder. Sequencing of FGD1 revealed a novel mutation in exon 7 at position c.1468 C > T in the index patient, leading to a stop codon in the highly conserved RhoGEF gene domain. His mother and maternal grandmother were also found to be heterozygous for this FGD1 mutation.
CONCLUSION
Our results identify a novel mutation of FDG1 in a family with Aarskog syndrome and underscore the phenotypical variability of this condition.
Topics: Attention Deficit Disorder with Hyperactivity; Child; Dwarfism; Face; Female; Genetic Diseases, X-Linked; Genetic Markers; Genitalia, Male; Guanine Nucleotide Exchange Factors; Hand Deformities, Congenital; Heart Defects, Congenital; Humans; Male; Pedigree; Phenotype; Point Mutation
PubMed: 24770546
DOI: 10.1007/s00431-014-2317-3 -
Molecular and Cellular Biology Nov 2011Podosomes are dynamic actin-rich adhesion plasma membrane microdomains endowed with extracellular matrix-degrading activities. In aortic endothelial cells, podosomes are...
The Aarskog-Scott syndrome protein Fgd1 regulates podosome formation and extracellular matrix remodeling in transforming growth factor β-stimulated aortic endothelial cells.
Podosomes are dynamic actin-rich adhesion plasma membrane microdomains endowed with extracellular matrix-degrading activities. In aortic endothelial cells, podosomes are induced by transforming growth factor β (TGF-β), but how this occurs is largely unknown. It is thought that, in endothelial cells, podosomes play a role in vessel remodeling and/or in breaching anatomical barriers. We demonstrate here that, in bovine aortic endothelial cells, that the Cdc42-specific guanine exchange factor (GEF) Fgd1 is expressed and regulated by TGF-β to induce Cdc42-dependent podosome assembly. Within 15 min of TGF-β stimulation, Fgd1, but none of the other tested Cdc42 GEFs, undergoes tyrosine phosphorylation, associates with Cdc42, and translocates to the subcortical cytoskeleton via a cortactin-dependent mechanism. Small interfering RNA-mediated Fgd1 knockdown inhibits TGF-β-induced Cdc42 activation. Fgd1 depletion also reduces podosome formation and associated matrix degradation and these defects are rescued by reexpression of Fgd1. Although overexpression of Fgd1 does not promote podosome formation per se, it enhances TGF-β-induced matrix degradation. Our results identify Fgd1 as a TGF-β-regulated GEF and, as such, the first GEF to be involved in the process of cytokine-induced podosome formation. Our findings reveal the involvement of Fgd1 in endothelial cell biology and open up new avenues to study its role in vascular pathophysiology.
Topics: Actins; Animals; Aorta; Blood Vessels; Cattle; Cortactin; Dwarfism; Endothelial Cells; Extracellular Matrix; Face; Genetic Diseases, X-Linked; Genitalia, Male; Guanine Nucleotide Exchange Factors; Hand Deformities, Congenital; Heart Defects, Congenital; RNA Interference; RNA, Small Interfering; Signal Transduction; Transforming Growth Factor beta; cdc42 GTP-Binding Protein
PubMed: 21911474
DOI: 10.1128/MCB.05474-11 -
Human Mutation Mar 2013Aarskog-Scott syndrome (ASS) is a rare disorder with characteristic facial, skeletal, and genital abnormalities. Mutations in the FGD1 gene (Xp11.21) are responsible for...
Aarskog-Scott syndrome (ASS) is a rare disorder with characteristic facial, skeletal, and genital abnormalities. Mutations in the FGD1 gene (Xp11.21) are responsible for ASS. However, mutation detection rates are low. Here, we report a family with ASS where conventional Sanger sequencing failed to detect a pathogenic change in FGD1. To identify the causative gene, we performed whole-exome sequencing in two patients. An initial analysis did not reveal a likely candidate gene. After relaxing our filtering criteria, accepting larger intronic segments, we unexpectedly identified a branch point (BP) variant in FGD1. Analysis of patient-derived RNA showed complete skipping of exon 13, leading to premature translation termination. The BP variant detected is one of very few reported so far proven to affect splicing. Our results show that besides digging deeper to reveal nonobvious variants, isolation and analysis of RNA provides a valuable but under-appreciated tool to resolve cases with unknown genetic defects.
Topics: Abnormalities, Multiple; Dwarfism; Exome; Exons; Face; Female; Genetic Diseases, X-Linked; Genitalia, Male; Guanine Nucleotide Exchange Factors; Hand Deformities, Congenital; Heart Defects, Congenital; Humans; Male; Mutation; Phenotype; Polymorphism, Single Nucleotide; Sequence Analysis, DNA; Sequence Analysis, RNA
PubMed: 23169394
DOI: 10.1002/humu.22252 -
Clinical Genetics Jul 1989
Topics: Child; Facial Expression; Genetic Linkage; Genitalia, Male; Humans; Hungary; Male; Syndactyly; Syndrome; X Chromosome
PubMed: 2548775
DOI: 10.1111/j.1399-0004.1989.tb03370.x -
NMC Case Report Journal Jul 2015A 44-year-old male with Aarskog syndrome (AS) presented with subarachnoid hemorrhage secondary to ruptured posterior communicating artery aneurysm. AS, also known as...
A 44-year-old male with Aarskog syndrome (AS) presented with subarachnoid hemorrhage secondary to ruptured posterior communicating artery aneurysm. AS, also known as faciogenital dysplasia, is an X-linked, autosomal dominant or autosomal recessive congenital developmental disorder. This syndrome is characterized by short stature in association with a variety of multiple anomalies in musculoskeletal, neurological, and urogenital systems. Cerebrovascular abnormalities such as anomalous cerebral venous drainage, dysplastic internal carotid artery, and basilar artery malformation have been reported to be associated with AS. To our knowledge this represents the first case of a ruptured intracranial aneurysm in a patient with AS.
PubMed: 28663972
DOI: 10.2176/nmccrj.2014-0022 -
Clinical Genetics Apr 1988The first Danish case of Aarskog syndrome is reported. The child had attended several specialized out-patient clinics before the diagnosis was suggested. This underlines...
The first Danish case of Aarskog syndrome is reported. The child had attended several specialized out-patient clinics before the diagnosis was suggested. This underlines the need for dysmorphology in paediatrics.
Topics: Abnormalities, Multiple; Body Height; Child, Preschool; Denmark; Genes, Recessive; Genetic Linkage; Humans; Male; Syndrome; X Chromosome
PubMed: 3359689
DOI: 10.1111/j.1399-0004.1988.tb03455.x -
The Journal of Pediatrics Jun 1975Prominent physical features of the Aarskog syndrome are short stature, telecanthus, ptosis, short broad nose, long philtrum, thin upper vermilion border and pouty lower...
Prominent physical features of the Aarskog syndrome are short stature, telecanthus, ptosis, short broad nose, long philtrum, thin upper vermilion border and pouty lower lip, low-set jug-handle ears, short broad hands with clawlike positioning of the fingers, broad feet with bulbous toes, ventral scrotal folds, cryptorchidism, and hernias. Four families with 20 affected males are reported. Pedigree analysis is compatible with X-linked recessive inheritance with occasional partial expression in heterozygote females. The fact that seven sons, all unaffected, have been born to affected males argues against the alternative hypothesis of autosomal sex-influenced inheritance.
Topics: Abnormalities, Multiple; Adolescent; Adult; Aged; Child; Chromosome Aberrations; Chromosome Disorders; Dermatoglyphics; Face; Female; Foot Deformities, Congenital; Genes, Recessive; Genitalia, Male; Hand Deformities, Congenital; Heterozygote; Humans; Male; Middle Aged; Pedigree; Sex Chromosomes; Syndrome; Toes
PubMed: 1127528
DOI: 10.1016/s0022-3476(75)80219-8 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Aug 2021To detect pathogenic variant of the FGD1 gene in a boy with Aarskog-Scott syndrome.
OBJECTIVE
To detect pathogenic variant of the FGD1 gene in a boy with Aarskog-Scott syndrome.
METHODS
Genetic variant was detected by high-throughput sequencing. Suspected variant was verified by Sanger sequencing. The nature and impact of the candidate variant were predicted by bioinformatic analysis.
RESULTS
The child was found to harbor a novel c.1906C>T hemizygous variant of the FGD1 gene, which has led to conversion of Arginine to Tryptophane at codon 636(p.Arg636Trp). The same variant was found in his mother but not father. Based on the American College of Medical Genetics and Genomics guidelines, the c.1906C>T variant of FGD1 gene was predicted to be likely pathogenic(PM1+PM2+PM5+PP2+PP3+PP4).
CONCLUSION
The novel c.1906C>T variant of the FGD1 gene may underlay the Aarskog-Scott syndrome in this child. Above finding has enabled diagnosis for the boy.
Topics: Child; Dwarfism; Face; Genetic Diseases, X-Linked; Genitalia, Male; Guanine Nucleotide Exchange Factors; Hand Deformities, Congenital; Heart Defects, Congenital; Humans; Male; Mutation
PubMed: 34365618
DOI: 10.3760/cma.j.cn511374-20200605-00408 -
Journal of Autism and Developmental... Apr 1999
Topics: Autistic Disorder; Body Height; Child; Child, Preschool; Communication Disorders; Diagnosis, Differential; Genetic Linkage; Humans; Hyperkinesis; Hypertelorism; Intellectual Disability; Male; Syndrome; X Chromosome
PubMed: 10382140
DOI: 10.1023/a:1023005029949