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Aarskog-Scott syndrome: phenotypic and genetic heterogeneity

Aarskog-Scott syndrome: phenotypic and genetic heterogeneity
Aarskog-Scott syndrome: phenotypic and genetic heterogeneity
Aarskog-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
2377-1143
49-59
Jabalameli, M. Reza
d533e702-7a6b-4f2d-8947-352ea1dd769b
Briceno, Ignacio
aaf8caee-1ab9-4291-b3ec-0eadd182b75e
Julio, Martinez
619eb766-678b-442b-9f56-b6b5aa8ba6af
Pengelly, Reuben
af97c0c1-b568-415c-9f59-1823b65be76d
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Collins, Andrew
7daa83eb-0b21-43b2-af1a-e38fb36e2a64
Jabalameli, M. Reza
d533e702-7a6b-4f2d-8947-352ea1dd769b
Briceno, Ignacio
aaf8caee-1ab9-4291-b3ec-0eadd182b75e
Julio, Martinez
619eb766-678b-442b-9f56-b6b5aa8ba6af
Pengelly, Reuben
af97c0c1-b568-415c-9f59-1823b65be76d
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Collins, Andrew
7daa83eb-0b21-43b2-af1a-e38fb36e2a64

Jabalameli, M. Reza, Briceno, Ignacio, Julio, Martinez, Pengelly, Reuben, Ennis, Sarah and Collins, Andrew (2016) Aarskog-Scott syndrome: phenotypic and genetic heterogeneity. AIMS Genetics, 3 (1), 49-59. (doi:10.3934/genet.2016.1.49).

Record type: Article

Abstract

Aarskog-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

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Accepted/In Press date: 20 March 2016
Published date: 29 March 2016
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 391148
URI: http://eprints.soton.ac.uk/id/eprint/391148
ISSN: 2377-1143
PURE UUID: 9f084a6e-cf8b-4791-a283-ca074cb1d7b5
ORCID for M. Reza Jabalameli: ORCID iD orcid.org/0000-0002-7762-0529
ORCID for Reuben Pengelly: ORCID iD orcid.org/0000-0001-7022-645X
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869
ORCID for Andrew Collins: ORCID iD orcid.org/0000-0001-7108-0771

Catalogue record

Date deposited: 26 May 2016 08:23
Last modified: 18 Feb 2021 17:22

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