Division of Endocrinology and Diabetes, Children's Mercy Hospitals and Clinics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri.
Division of Nephrology, Children's Mercy Hospitals and Clinics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri.
Endocrinology. 2020 May 1;161(5). doi: 10.1210/endocr/bqz015.
Differences of sex development (DSDs) are a constellation of conditions that result in genital ambiguity or complete sex reversal. Although determining the underlying genetic variants can affect clinical management, fewer than half of undermasculinized males ever receive molecular diagnoses. Next-generation sequencing (NGS) technology has improved diagnostic capabilities in several other diseases, and a few small studies suggest that it may improve molecular diagnostic capabilities in DSDs. However, the overall diagnostic rate that can be achieved with NGS for larger groups of patients with DSDs remains unknown. In this study, we aimed to implement a tiered approach to genetic testing in undermasculinized males seen in an interdisciplinary DSD clinic to increase the molecular diagnosis rate in this group. We determined the diagnosis rate in patients undergoing all clinically available testing. Patients underwent a stepwise approach to testing beginning with a karyotype and progressing through individual gene testing, microarray, panel testing, and then to whole-exome sequencing (WES) if no molecular cause was found. Deletion/duplication studies were also done if deletions were suspected. Sixty undermasculinized male participants were seen in an interdisciplinary DSD clinic from 2008 to 2016. Overall, 37/60 (62%) of patients with Y chromosomes and 46% of those who were 46XY received molecular diagnoses. Of the 46,XY patients who underwent all available genetic testing, 18/28 (64%) achieved molecular diagnoses. This study suggests that the addition of WES testing can result in a higher rate of molecular diagnoses compared to genetic panel testing.
性别发育差异（DSD）是一组导致生殖器模糊或完全性别反转的病症。虽然确定潜在的基因突变会影响临床管理，但不到一半的未男性化男性接受分子诊断。下一代测序（NGS）技术已经提高了其他几种疾病的诊断能力，一些小型研究表明，它可能会提高 DSD 中的分子诊断能力。然而，对于更大的 DSD 患者群体，使用 NGS 可以实现的总体诊断率仍然未知。在这项研究中，我们旨在为在多学科 DSD 诊所中看到的未男性化男性实施分层遗传测试方法，以提高该组的分子诊断率。我们确定了接受所有临床可用测试的患者的诊断率。患者采用逐步测试方法，从核型开始，然后逐个基因测试、微阵列、面板测试，如果未发现分子原因，则进行全外显子组测序（WES）。如果怀疑有缺失，还进行缺失/重复研究。2008 年至 2016 年，有 60 名未男性化男性在多学科 DSD 诊所就诊。总体而言，有 Y 染色体的 60 名患者中有 37/60（62%）和 46%的 46，XY 患者获得了分子诊断。在接受所有可用遗传测试的 46，XY 患者中，18/28（64%）获得了分子诊断。这项研究表明，与基因组测试相比，添加 WES 测试可以提高分子诊断率。
