Biallelic Variants in EPHA2 Identified in Three Large Inbred Families with Early-Onset Cataract.

Priya Jarwar,Zubair M Ahmed,Ikram Uddin Ujjan,Ali Muhammad Waryah,Shakeel Ahmed Sheikh,Yar Muhammad Waryah,Saima Riazuddin

doi:10.3390/ijms221910655

Priya Jarwar, Zubair M Ahmed + Show 5 more

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https://doi.org/10.3390/ijms221910655

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Hereditary congenital cataract (HCC) is clinically and genetically heterogeneous. We investigated HCC that segregates in three inbred families (LUCC03, LUCC16, and LUCC24). Ophthalmological examinations revealed cataracts with variability related to the age of onset segregating in a recessive manner in these families. Exome sequencing of probands identified a novel homozygous c.2710delG;p.(Val904Cysfs*36) EPHA2 variant in LUCC03 and a known homozygous c.2353G>A;p.(Ala785Thr) EPHA2 variant in the other two recessive families. EPHA2 encodes a transmembrane tyrosine kinase receptor, which is primarily involved in membrane-transport, cell-cell adhesion, and repulsion signaling processes. Computational structural modeling predicts that substitution of a threonine for an alanine p.(Ala785Thr) results in the formation of three new hydrogen bonds with the neighboring residues, which causes misfolding of EPHA2 in both scenarios. Insights from our study will facilitate counseling regarding the molecular and phenotypic landscape of EPHA2-related HCC.

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Hereditary congenital cataract (HCC) affects every 4 in 10,000 newborns in the UnitedStates, and accounts for 20% of blindness worldwide [1,2]
Pakistani families with HCC [15], three new large consanguineous families were enrolled fromfrom the the remote areas of Sindh province of Pakistan (Figure 1A)
38 genes have been associated with nonsyndromic HCC; it is noteworthy that molecular causes of approximately 50% of the familial cases remain elusive

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Introduction

Hereditary congenital cataract (HCC) affects every 4 in 10,000 newborns in the UnitedStates, and accounts for 20% of blindness worldwide [1,2]. Hereditary congenital cataract (HCC) affects every 4 in 10,000 newborns in the United. The phenotypic presentation of HCC is the opacification of the crystalline lens of the eyes. HCC can be subdivided according to the etiology, anatomical location within the lens (e.g., nuclear) and appearance (e.g., pulverulent) and are usually characterized by a combination of later two attributes [3]. HCC may present as an isolated trait or as part of a syndrome [4]. Non-syndromic CC follows various inheritance patterns: primarily autosomal dominant (accounts for up to 89% of the reported cases), X-linked inheritance that accounts for up to 10% of the cases, and autosomal recessive cataract is relatively rare with a prevalence of 7% in inbred families [5]. Pathological variants in crystalline encoding genes are the most frequent cause of HCC in Chinese populations [6], while the variants in connexin genes are more frequent

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