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<p>Anophthalmia/microphthalmia (A/M) are rare congenital ocular malformations involving the absence or underdevelopment of the eyes, and they display considerable clinical and genetic heterogeneity. Establishing a genetic diagnosis for A/M is critical because it facilitates early intervention, informed genetic counseling, and the prevention of disease transmission in high-risk families. This study explored the genotypic and phenotypic landscape of A/M in 10 Pakistani families meeting specific criteria: confirmed A/M phenotype, residence in Khyber Pakhtunkhwa, no prior genetic testing, and informed consent. Whole-exome sequencing (WES) and segregation analysis in families identified a novel missense variant in <i>SMOC1</i> (c.406T&gt;G, p.Cys136Gly) in a family with Waardenburg anophthalmia syndrome (WAS). Additionally, causative variants in <i>VSX2</i> (c.598C&gt;T, p.Arg200Ter) and <i>ALDH1A3</i> (c.172dup, p.Glu58GlyfsTer5) were detected, potentially representing founder variants&#xa0;in the Pashtun ethnic group. Moreover, a likely pathogenic variant in <i>FOXE3</i> (c.145G&gt;T, p.Gly49Ter) and a variant of uncertain significance in <i>STRA6</i> (c.1399C&gt;T, p.Arg467Cys), which exhibited incomplete penetrance, were also identified. In addition, segregation analysis of the causal genetic variants in the 5 families revealed a carrier frequency of 60.86% among the phenotypically unaffected family members. Notably, the average size of autozygous regions among probands was substantial (282.62 Mb), indicating a high degree of consanguinity and familial relatedness due to endogamous practices. However, no causative variants were identified in five families, each with a single affected member, with unilateral A/M&#xa0;in the majority of cases. These findings support the value of genetic diagnostics in reproductive counseling and highlight the utility of broader genomic approaches to improve diagnostic outcomes in unresolved cases.</p>

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Genotypic and phenotypic spectrum of anophthalmia/microphthalmia in families from Khyber Pakhtunkhwa, Pakistan

  • 期刊论文

  • 发表日期：

    2025年8月18日

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  • Muhammad Dawood,
  • Xinran Ji,
  • Irfan U. Shah,
  • Niamat Khan,
  • Shifeng Xue,
  • Shamim Saleha

摘要

Anophthalmia/microphthalmia (A/M) are rare congenital ocular malformations involving the absence or underdevelopment of the eyes, and they display considerable clinical and genetic heterogeneity. Establishing a genetic diagnosis for A/M is critical because it facilitates early intervention, informed genetic counseling, and the prevention of disease transmission in high-risk families. This study explored the genotypic and phenotypic landscape of A/M in 10 Pakistani families meeting specific criteria: confirmed A/M phenotype, residence in Khyber Pakhtunkhwa, no prior genetic testing, and informed consent. Whole-exome sequencing (WES) and segregation analysis in families identified a novel missense variant in SMOC1 (c.406T>G, p.Cys136Gly) in a family with Waardenburg anophthalmia syndrome (WAS). Additionally, causative variants in VSX2 (c.598C>T, p.Arg200Ter) and ALDH1A3 (c.172dup, p.Glu58GlyfsTer5) were detected, potentially representing founder variants in the Pashtun ethnic group. Moreover, a likely pathogenic variant in FOXE3 (c.145G>T, p.Gly49Ter) and a variant of uncertain significance in STRA6 (c.1399C>T, p.Arg467Cys), which exhibited incomplete penetrance, were also identified. In addition, segregation analysis of the causal genetic variants in the 5 families revealed a carrier frequency of 60.86% among the phenotypically unaffected family members. Notably, the average size of autozygous regions among probands was substantial (282.62 Mb), indicating a high degree of consanguinity and familial relatedness due to endogamous practices. However, no causative variants were identified in five families, each with a single affected member, with unilateral A/M in the majority of cases. These findings support the value of genetic diagnostics in reproductive counseling and highlight the utility of broader genomic approaches to improve diagnostic outcomes in unresolved cases.