Kırkgöz Tarık, Kaygusuz Sare Betül, Alavanda Ceren, Helvacıoğlu Didem, Abalı Zehra Yavaş, Tosun Büşra Gürpınar, Eltan Mehmet, Menevşe Tuba Seven, Guran Tulay, Arman Ahmet, Turan Serap, Bereket Abdullah
Department of Pediatric Endocrinology and Diabetes, Marmara University School of Medicine, Istanbul, Türkiye.
Department of Medical Genetics, Marmara University School of Medicine, Istanbul, Türkiye.
J Pediatr Endocrinol Metab. 2023 Mar 9;36(4):401-408. doi: 10.1515/jpem-2022-0645. Print 2023 Apr 25.
Central precocious puberty (CPP) develops as a result of early stimulation of the hypothalamic-pituitary-gonadal (HPG) axis. The loss-of-function mutations in the Makorin-ring-finger3 (MKRN3) gene appear to be the most common molecular cause of familial CPP. We aimed to identify MKRN3 gene mutations in our CPP cohort and to investigate the frequency of MKRN3 mutations.
102 patients with CPP included. 53 of them had family history of CPP in the first and/or second-degree relatives. MKRN3 gene was analyzed by next-generation sequencing.
Possible pathogenic variants were found in 2/53 patients with family history of CPP (3.8%) and 1/49 patient without family history (2%). A novel heterozygous c.1A>G (p.Met1Val) mutation, a novel heterozygous c.683_684delCA (p.Ser228*) and a previously reported c.482dupC (Ala162Glyfs*) frameshift variations were detected. The two novel variants are predicted to be pathogenic in silico analyses.
In our cohort, possible pathogenic variants in MKRN3 gene were detected in 2.9% of the total cohort, 3.8% of the familial and 2% of the nonfamilial cases, slightly lower than that reported in the literature. Two novel variants detected contribute to the molecular repertoire of MKRN3 defects in CPP. Classical pattern of paternal inheritance has been demonstrated in all three cases. However, the father of the patient 3 did not have history of CPP suggesting that the father inherited this variant from his mother and had phenotype skipping. Therefore, we emphasize that the absence of history of CPP in the father does not exclude the possibility of a MKRN3 mutation.
中枢性性早熟（CPP）是下丘脑 - 垂体 - 性腺（HPG）轴过早受到刺激所致。Makorin 环指蛋白 3（MKRN3）基因功能丧失突变似乎是家族性 CPP 最常见的分子病因。我们旨在鉴定我们的 CPP 队列中的 MKRN3 基因突变，并调查 MKRN3 突变的频率。
纳入 102 例 CPP 患者。其中 53 例在一级和/或二级亲属中有 CPP 家族史。通过二代测序分析 MKRN3 基因。
在 53 例有 CPP 家族史的患者中有 2 例（3.8%）以及 49 例无家族史的患者中有 1 例（2%）发现了可能的致病变异。检测到一个新的杂合 c.1A>G（p.Met1Val）突变、一个新的杂合 c.683_684delCA（p.Ser228*）以及一个先前报道的 c.482dupC（Ala162Glyfs*）移码变异。这两个新变异在计算机分析中被预测为致病的。
在我们的队列中，MKRN3 基因的可能致病变异在总队列中占 2.9%，家族性病例中占 3.8%，非家族性病例中占 2%，略低于文献报道。检测到的两个新变异丰富了 CPP 中 MKRN3 缺陷的分子谱。在所有三例中均证实了经典的父系遗传模式。然而，患者 3 的父亲没有 CPP 病史，提示父亲从其母亲那里继承了该变异且出现了表型跳跃。因此，我们强调父亲没有 CPP 病史并不排除 MKRN3 突变的可能性。
