Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland.
Division of Endocrinology, St. Jude Children's Research Hospital, Memphis, Tennessee.
J Clin Endocrinol Metab. 2020 Aug 1;105(8):2732-9. doi: 10.1210/clinem/dgaa331.
Loss-of-function mutations in the imprinted genes MKRN3 and DLK1 cause central precocious puberty (CPP) but whole gene deletions have not been reported. Larger deletions of the chromosome 15q11-13 imprinted locus, including MKRN3, cause Prader-Willi syndrome (PWS). CPP has been reported in PWS but is not common, and the role of MKRN3 in PWS has not been fully elucidated.
To identify copy number variants in puberty-related, imprinted genes to determine their role in CPP.
Probands with idiopathic CPP had chromosomal microarray (CMA) and targeted deletion/duplication testing for MKRN3 and DLK1.
Sixteen female probands without MKRN3 or DLK1 variants identified by Sanger sequencing were studied. Whole gene deletions of MKRN3 were identified in 2 subjects (13%): a complete deletion of MKRN3 in Patient A (pubertal onset at 7 years) and a larger deletion involving MAGEL2, MKRN3, and NDN in Patient B (pubertal onset 5.5 years). Both were paternally inherited. Patient B had no typical features of PWS, other than obesity, which was also present in her unaffected family.
We identified 2 cases of whole gene deletions of MKRN3 causing isolated CPP without PWS. This is the first report of complete deletions of MKRN3 in patients with CPP, emphasizing the importance of including copy number variant analysis for MKRN3 mutation testing when a genetic diagnosis is suspected. We speculate that there is a critical region of the PWS locus beyond MKRN3, MAGEL2, and NDN that is responsible for the PWS phenotype.
印迹基因 MKRN3 和 DLK1 的功能丧失突变可导致中枢性性早熟（CPP），但尚未报道整个基因缺失。更大的 15q11-13 印迹基因座缺失，包括 MKRN3，可导致 Prader-Willi 综合征（PWS）。PWS 已报道 CPP，但并不常见，MKRN3 在 PWS 中的作用尚未完全阐明。
确定与青春期相关的印迹基因的拷贝数变异，以确定其在 CPP 中的作用。
对特发性 CPP 的先证者进行染色体微阵列（CMA）和 MKRN3 和 DLK1 的靶向缺失/重复检测。
通过 Sanger 测序未发现 MKRN3 或 DLK1 变异的 16 名女性先证者进行了研究。在 2 名患者（13%）中发现 MKRN3 的全基因缺失：患者 A（青春期发病年龄为 7 岁）的 MKRN3 完全缺失，以及患者 B（青春期发病年龄为 5.5 岁）涉及 MAGEL2、MKRN3 和 NDN 的更大缺失。这两个都是父系遗传的。患者 B 除肥胖外，无其他典型的 PWS 特征，而肥胖也存在于她未受影响的家族中。
我们鉴定了 2 例 MKRN3 全基因缺失导致孤立性 CPP 而无 PWS。这是首次报道 CPP 患者的 MKRN3 完全缺失，强调了在怀疑遗传诊断时，MKRN3 突变检测应包括拷贝数变异分析。我们推测，PWS 表型的关键区域位于 MKRN3、MAGEL2 和 NDN 之外的 PWS 基因座。
