Abstract
AbstractAarskog-Scott syndrome (AAS) is a rare developmental disorder which primarily affects males and has a relative prevalence of 1 in 25,000 in the general population. AAS patients usually present with developmental complications including short stature and facial, skeletal and urogenital anomalies. The spectrum of genotype-phenotype correlations in AAS is unclear and mutations of the FGD1 gene on the proximal short arm of chromosome X account for only 20% of the incidence of the disorder. Failure to identify pathogenic variants in patients referred for FGD1 screening suggests heterogeneity underlying pathophysiology of the condition. Furthermore, overlapping features of AAS with several other developmental disorders increase the complexity of diagnosis. Cytoskeletal signaling may be involved in the pathophysiology of AAS. The FGD1 protein family has a role in activation of CDC42 (Cell Division Control protein 42 homolog) which has a core function in remodeling of extracellular matrix and the transcriptional activation of many modulators of development. Therefore, mutations in components in the EGFR1 (Epidermal Growth Factor Receptor 1) signaling pathway, to which CDC42 belongs, may contribute to pathophysiology. Parallel sequencing strategies (so-called next generation sequencing or high throughput sequencing) enables simultaneous production of millions of sequencing reads that enormously facilitate cost-effective identification of cryptic mutations in heterogeneous monogenic disorders. Here we review the source of phenotypic and genetic heterogeneity in the context of AAS and discuss the applicability of next generation sequencing for identification of novel mutations underlying AAS.
Highlights
Aarskog-Scott syndrome (AAS, OMIM #305400) is a complex developmental disorder initially described by Aarskog in a Finnish pedigree [1] and later by Scott [2]
We review here sources of phenotypic and genetic heterogeneity underlying the condition and discuss the extent to which generation sequencing can be utilized to detect new mutations in AAS
Similarities between the phenotypic faciogenital characteristics of AAS patients and other developmental disorders including Noonan syndrome, SHORT syndrome (Short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly, and teething delay) and Robinow syndrome increase the complexities of diagnosis
Summary
Aarskog-Scott syndrome (AAS, OMIM #305400) ( known as faciogenital dysplasia) is a complex developmental disorder initially described by Aarskog in a Finnish pedigree [1] and later by Scott [2]. Causal genetic variants underlying AAS pathophysiology map to the proximal short arm of chromosome X (Xq11.22) [4] and, to date, 61 different mutations across the 18 exons of the FGD1 gene are reported as pathogenic in the context of the condition. Failure to identify pathogenic variants in patients who are referred for FGD1 mutation analysis must reflect extensive clinical and genetic heterogeneity in AAS. Since it is possible to undertake cost-effective sequencing of genes of clinical interest, exomes, or whole genomes, there is greatly increased confidence that phenotypic overlaps can be resolved and underlying genetic causal variation understood for AAS and AAS-like syndromes.
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