Department of Genetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Department of Pediatrics, Hadassah Ein-Kerem Medical Center, Jerusalem, Israel.
Eur J Hum Genet. 2021 Mar;29(3):455-462. doi: 10.1038/s41431-020-00756-y. Epub 2020 Nov 22.
Consanguinity, commonplace in many regions around the globe, is associated with an increased risk of autosomal recessive (AR) genetic disorders. Consequently, consanguineous couples undergoing preimplantation genetic diagnosis (PGD) for one Mendelian disorder may be at increased risk for a child with a second, unrelated AR genetic disorder. We examined the yield of exome analysis for carrier screening of additional AR disorders, beyond the primary diagnosis, amongst consanguineous vs. non-consanguineous populations. Parental samples from trio exomes of 102 consanguineous families and 105 non-consanguineous controls were evaluated for shared carrier status, after disregarding the primary molecular diagnosis. Results were sub-classified according to disease severity. Secondary shared carrier status for pathogenic and likely pathogenic variants leading to AR disorders of moderate to profound severity was identified in 10/102 (9.8%) consanguineous couples, as compared to 1/105 (0.95%) non-consanguineous couples (χ = 8.0565, p value < 0.005). Higher inbreeding coefficient values, calculated from individual exomes, correlated with secondary shared carrier status for diseases of moderate to profound severity (r = 0.17, p value < 0.0125). Our results indicate that consanguineous couples undergoing PGD are at increased risk for a second genetic disease of moderate to profound severity. This study represents an underestimate of the rate of secondary shared carrier status due to inability to detect deep intronic variants, no assessment of copy number variants, and false negative results stemming from stringent variant interpretation. False positive results may result from inaccuracies in public databases. Additional studies in consanguineous populations will determine whether exome-based carrier screening should be recommended to all couples undergoing PGD.
血缘关系在全球许多地区都很常见，与常染色体隐性（AR）遗传疾病的风险增加有关。因此，进行单基因疾病胚胎植入前遗传学诊断（PGD）的血缘夫妇，可能会增加生育第二个非相关 AR 遗传疾病患儿的风险。我们研究了外显子组分析在血缘和非血缘人群中，对主要诊断以外的其他 AR 疾病携带者筛查的效果。在排除主要分子诊断后，对 102 个血缘家庭和 105 个非血缘对照组的三联体外显子父母样本进行了共享携带者状态评估。结果根据疾病严重程度进行了细分。在 10/102（9.8%）对血缘夫妇中，发现了与 AR 疾病中度至重度严重程度相关的致病性和可能致病性变异的二次共享携带者状态，而在 1/105（0.95%）非血缘夫妇中未发现（χ²=8.0565，p 值<0.005）。从个体外显子计算得出的更高的近交系数值，与中度至重度严重疾病的二次共享携带者状态相关（r=0.17，p 值<0.0125）。我们的结果表明，进行 PGD 的血缘夫妇有更高的生育中度至重度遗传疾病的风险。由于无法检测到深内含子变异、未评估拷贝数变异以及严格的变异解释导致假阴性结果，本研究仅代表二次共享携带者状态的低估率。假阳性结果可能源于公共数据库的不准确性。在血缘人群中进行的进一步研究将确定是否应建议所有进行 PGD 的夫妇进行基于外显子组的携带者筛查。
