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.

中文翻译：

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巴基斯坦家庭中与X连锁隐性鱼鳞病相关的STS基因中的一个新的无意义突变：包括两名非常罕见的纯合女性患者。

背景技术X连锁鱼鳞病（XLI； OMIM＃308100）是一种隐性角化病，其特征在于在体表的不同部分上存在暗褐色的多边形粘附鳞片。它几乎只影响男性，估计全世界的患病率在1：2000-6000之间。皮外表现很常见，包括角膜混浊，隐睾，神经精神症状或其他。高达90％的XLI病例是由Xp22.3染色体上包含整个STS基因的复发性半合子微缺失引起的，而只有少数患者在STS中显示出部分缺失或功能点突变。在综合征患者中鉴定出也涉及连续基因的较大缺失。方法在这里，我们报告了一个巴基斯坦大家庭的临床和遗传发现，该家庭有16位受影响的个体，其中包括2位XLI女性。进行了STS基因编码区的分子核型分析和直接DNA测序。结果受影响个体的临床表现包括皮肤普遍干燥和脱屑，头皮，躯干，四肢和颈部皮肤呈多边形，深色鳞片，而脸部，手掌和脚底则稀疏。没有相关的皮肤外特征，例如身材矮小，隐睾症，畏光，角膜混浊，男性秃发以及行为，认知或神经系统表型，包括智力障碍，自闭症或注意力缺陷多动障碍。分子核型分析是正常的，没有发现拷贝数变异。Sanger测序在所有受影响的男性个体的STS基因外显子4中鉴定出一个新的半合子无意义突变（c.287G> A； p.W96 *）。此外，发现该家族中两名受XLI感染的雌性对于确定的变体是纯合的。结论本研究对于了解所研究患者的XLI遗传基础，扩展STS已知突变谱，诊断女性携带者以及将突变筛查进一步应用于该家庭的遗传咨询中非常有用。