A novel nonsense mutation in the STS gene in a Pakistani family with X-linked recessive ichthyosis: including a very rare case of two homozygous female patients

Abstract

Background: X-linked ichthyosis (XLI; OMIM# 308100) is a recessive keratinization disorder characterized by the presence of dark brown, polygonal, adherent scales on different parts of the body surface. It almost exclusively affects males and the estimated prevalence ranges from 1:2000-6000 in males worldwide. Extracutaneous manifestations are frequent including corneal opacities, cryptorchidism, neuropsychiatric symptoms or others. Up to 90% of XLI cases are caused by recurrent hemizygous microdeletion encompassing entire STS gene on chromosome Xp22.3, while only a minority of patients shows partial deletions or loss of function point mutations in STS. Larger deletions also involving contiguous genes are identified in syndromic patients. Methods: Here, we report clinical and genetic findings of a large Pakistani family having 16 affected individuals including 2 females with XLI. Molecular karyotyping and direct DNA sequencing of coding region of the STS gene was performed. Results: The clinical manifestations in affected individuals involved generalized dryness and scaling of the skin with polygonal, dark scales of the skin on scalp, trunk, limbs, and neck while sparing face, palms and soles. There were no associated extra-cutaneous features such as short stature, cryptorchidism, photophobia, corneal opacities, male baldness, and behavioral, cognitive, or neurological phenotypes including intellectual disability, autism or attention deficit hyperactivity disorder. Molecular karyotyping was normal and no copy number variation was found. Sanger sequencing identified a novel hemizygous nonsense mutation (c.287G > A; p.W96*), in exon 4 of STS gene in all affected male individuals. In addition, two XLI affected females in the family were found to be homozygous for the identified variant. Conclusions: This study is useful for understanding the genetic basis of XLI in the patients studied, for extending the known mutational spectrum of STS, diagnosis of female carriers and for further application of mutation screening in the genetic counseling of this family.

Biallelic mutations in FLG, TGM1, and STS genes segregated with different types of ichthyoses in eight families of Pakistani origin

“…The XLI families (F, G, H) displayed the dark brown, polygonal scales, widespread on the whole body, face, neck, arms, trunk, abdomen, and legs with generalized dryness, which closely matched clinical findings of the previous Pakistani studies 28 . Our XLI patients also showed heat intolerance as an additional phenotype.…”

“…31 Only a few cases of XLI in Pakistani population, caused by the STS gene, have been reported. 28 STS participates in the control of barrier permeability and desquamation by hydrolyzing steroid sulphates to their unconjugated counterparts. Lack of STS activity causes the stratum corneum to accumulate cholesterol sulphate, which impairs skin permeability and causes hyperkeratosis and corneocyte cohesiveness.…”

“…Additionally, a few numbers of functionally significant point mutations and complete deletions were found (Pakistan Genetic Mutation Database, PGMD: https://pakmutation.kust.edu.pk/). 31 Only a few cases of XLI in Pakistani population, caused by the STS gene, have been reported 28 . STS participates in the control of barrier permeability and desquamation by hydrolyzing steroid sulphates to their unconjugated counterparts.…”

Prenatally detected six duplications at Xp22.33-p11.22: a case report

“…The Xp22.33-p11.22 region contains several critical genes, such as steroid sulfatase ( STS ), anosmin 1 ( ANOS1 ), X chromosomal neuroligins ( NLGN4X ), haloacid dehydrogenase-like hydrolase domain-containing protein 1 ( HDHD 1, also named PUDP ) and G-protein coupled receptor 143 ( GPR143 ) [ 9 ]. STS belongs to the sulfatase family and hydrolyses several 3β-hydroxysteroid sulphates, which serve as metabolic precursors for oestrogens, androgens, and cholesterol [ 10 ]. Large deletions/duplications of the STS gene are associated with X-linked ichthyosis ( XLI) and are inherited in a recessive manner on the X chromosome [ 11 ].…”