Abstract：
Inherited retinal dystrophies (IRDs) are characterized by photoreceptor dysfunction or degeneration. Clinical and phenotypic overlap between IRDs makes the genetic diagnosis very challenging and comprehensive genomic approaches for accurate diagnosis are frequently required. While there are previous studies on IRDs in Pakistan, causative genes and variants are still unknown for a significant portion of patients. Therefore, there is a need to expand the knowledge of the genetic spectrum of IRDs in Pakistan. Here, we recruited 52 affected and 53 normal individuals from 15 consanguineous Pakistani families presenting non-syndromic and syndromic forms of IRDs. We employed single molecule Molecular Inversion Probes (smMIPs) based panel sequencing and whole genome sequencing to identify the probable disease-causing variants in these families. Using this approach, we obtained a 93% genetic solve rate and identified 16 (likely) causative variants in 14 families, of which seven novel variants were identified in ATOH7, COL18A1, MERTK, NDP, PROM1, PRPF8 and USH2A while nine recurrent variants were identified in CNGA3, CNGB1, HGSNAT, NMNAT1, SIX6 and TULP1. The novel MERTK variant and one recurrent TULP1 variant explained the intra-familial locus heterogeneity in one of the screened families while two recurrent CNGA3 variants explained compound heterozygosity in another family. The identification of variants in known disease-associated genes emphasizes the utilization of time and cost-effective screening approaches for rapid diagnosis. The timely genetic diagnosis will not only identify any associated systemic issues in case of syndromic IRDs, but will also aid in the acceleration of personalized medicine for patients affected with IRDs.
摘要：
遗传性视网膜营养不良(IRD)的特征在于光感受器功能障碍或退化。IRD之间的临床和表型重叠使得遗传诊断非常具有挑战性,并且经常需要用于准确诊断的综合基因组方法。虽然以前有关于巴基斯坦IRD的研究，相当一部分患者的致病基因和变异仍然未知.因此,有必要扩大对巴基斯坦IRD遗传谱的认识。这里,我们从15个存在非综合征型和综合征型IRD的巴基斯坦近亲家庭中招募了52名患者和53名正常人.我们采用基于单分子分子倒置探针(smMIP)的小组测序和全基因组测序来鉴定这些家族中可能的致病变异。使用这种方法，我们获得了93%的遗传解决率，并在14个家庭中确定了16个（可能的）致病变异，其中在ATOH7、COL18A1、MERTK、NDP,PROM1，PRPF8和USH2A，而在CNGA3，CNGB1，HGSNAT，NMNAT1、SIX6和TULP1。新的MERTK变体和一个复发的TULP1变体解释了一个筛选家族的家族内基因座异质性，而两个复发的CNGA3变体解释了另一个家族的复合杂合性。已知疾病相关基因中变异的鉴定强调了利用时间和成本有效的筛选方法进行快速诊断。及时的基因诊断不仅会在综合征性IRD的情况下识别任何相关的系统性问题，但也将有助于加速对IRD患者的个性化医疗。
