Purpose

Consanguineous couples are typically counseled based on familial pathogenic variants identified in affected children. The residual risk for additional autosomal recessive (AR) variants, however, remains largely understudied.

Methods

First, we surveyed pedigrees of 1,859 consanguineous families for evidence of more than one AR disease. Second, we mined our database of 1,773 molecularly tested consanguineous families to identify those with more than one AR disease. Finally, we surveyed 88 women from consanguineous unions who have undergone targeted prenatal testing for a familial AR variant and followed the pregnancy outcome (n = 144).

Results

We found suggestive evidence of more than one AR disease in 1.94% of consanguineous pedigrees surveyed. Of 1,773 molecularly characterized consanguineous families, 2.93% had evidence of at least two AR diseases (3.54% for first cousin or closer and 2.72% for second cousin or more distant). Furthermore, we found that in 2.78% of pregnancies negative for the familial variant, the pregnancy outcome was a child with a different AR disease.

Conclusion

Our results show that when counseling consanguineous couples for a familial AR variant, ~3% residual risk for additional AR variants should be discussed. This suggests that a broader testing strategy in consanguineous couples should be considered.

中文翻译：

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近亲夫妇其他隐性疾病的残余风险

目的

通常根据在受影响儿童中发现的家族性致病变异为近亲夫妇提供咨询。然而，其他常染色体隐性遗传 (AR) 变异的残余风险在很大程度上仍未得到充分研究。

方法

首先，我们调查了 1,859 个近亲家庭的谱系，寻找不止一种 AR 疾病的证据。其次，我们挖掘了包含 1,773 个经过分子测试的近亲家庭的数据库，以识别患有不止一种 AR 疾病的人。最后，我们调查了来自近亲结合的 88 名女性，她们接受了针对家族性 AR 变异的有针对性的产前检测并跟踪妊娠结局 ( n  = 144)。

结果

我们在 1.94% 的被调查的近亲家系中发现了不止一种 AR 疾病的提示性证据。在 1,773 个具有分子特征的近亲家族中，2.93% 有至少两种 AR 疾病的证据（第一个表亲或更近的表亲为 3.54%，第二表亲或更远的为 2.72%）。此外，我们发现在 2.78% 的家族变异阴性妊娠中，妊娠结局是患有不同 AR 疾病的孩子。

结论

我们的结果表明，在为近亲夫妇就家族性 AR 变异进行咨询时，应讨论约 3% 的额外 AR 变异的残余风险。这表明应该考虑对近亲夫妇进行更广泛的测试策略。