Pathogenic mosaic variants in congenital hypogonadotropic hypogonadism.,Genetics in Medicine

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Pathogenic mosaic variants in congenital hypogonadotropic hypogonadism.
Genetics in Medicine ( IF 6.6 ) Pub Date : 2020-07-29 , DOI: 10.1038/s41436-020-0896-0
James S Acierno _{1,

2} , Cheng Xu ₁ , Georgios E Papadakis _{1,

3} , Nicolas J Niederländer ₁ , Jesse D Rademaker _{1,

2} , Jenny Meylan ₁ , Andrea Messina ₁ , Zofia Kolesinska _{1,

4} , Richard Quinton ₅ , Mariarosaria Lang-Muritano ₆ , Deborah Bartholdi ₇ , Irene Halperin ₈ , Christian De Geyter ₉ , Jérôme Bouligand _{10,

11,

12} , Lucia Bartoloni ₁ , Jacques Young _{3,

11,

12} , Federico A Santoni ₁ , Nelly Pitteloud ₁

Affiliation

Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital, Lausanne, Switzerland.
Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
Department of Reproductive Endocrinology, Assistance Publique-Hôpitaux de Paris, Bicêtre Hôpital, Le Kremlin-Bicêtre, France.
Department of Pediatric Endocrinology and Rheumatology, Poznan University of Medical Sciences, Poznan, Poland.
Translational & Clinical Research Institute, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, UK.
Division of Pediatric Endocrinology and Diabetology and Children's Research Centre, University Children's Hospital, Zurich, Switzerland.
Department of Human Genetics, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
Department of Endocrinology, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.
Reproductive Medicine and Gynecological Endocrinology (RME), University Hospital, University of Basel, Basel, Switzerland.
Department of Molecular Genetics, Pharmacogenomics, and Hormonology, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
University of Paris-Saclay, Paris-Saclay Medical School, Le Kremlin-Bicetre, France.
INSERM Unité 1185, Le Kremlin-Bicêtre, France.

Purpose

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder resulting in absent puberty and infertility. The genetic architecture is complex with multiple loci involved, variable expressivity, and incomplete penetrance. The majority of cases are sporadic, consistent with a disease affecting fertility. The current study aims to investigate mosaicism as a genetic mechanism for CHH, focusing on de novo rare variants in CHH genes.

Methods

We evaluated 60 trios for de novo rare sequencing variants (RSV) in known CHH genes using exome sequencing. Potential mosaicism was suspected among RSVs with altered allelic ratios and confirmed using customized ultradeep sequencing (UDS) in multiple tissues.

Results

Among the 60 trios, 10 probands harbored de novo pathogenic variants in CHH genes. Custom UDS demonstrated that three of these de novo variants were in fact postzygotic mosaicism—two in FGFR1 (p.Leu630Pro and p.Gly348Arg), and one in CHD7 (p.Arg2428*). Statistically significant variation across multiple tissues (DNA from blood, buccal, hair follicle, urine) confirmed their mosaic nature.

Conclusions

We identified a significant number of de novo pathogenic variants in CHH of which a notable number (3/10) exhibited mosaicism. This report of postzygotic mosaicism in CHH patients provides valuable information for accurate genetic counseling.

中文翻译：

先天性低促性腺激素性腺功能减退症的致病性镶嵌变异。

目的

先天性低促性腺激素性腺功能减退症（CHH）是一种罕见的疾病，会导致青春期缺失和不育。遗传结构复杂，涉及多个基因座、可变表达性和不完全外显率。大多数病例是散发的，与影响生育能力的疾病一致。目前的研究旨在研究嵌合现象作为 CHH 的遗传机制，重点关注 CHH 基因中的从头罕见变异。

方法

我们使用外显子组测序评估了 60 个三重奏组的已知 CHH 基因中的从头罕见测序变体 (RSV)。在等位基因比率改变的 RSV 中怀疑存在潜在的嵌合，并在多个组织中使用定制的超深度测序 (UDS) 进行了确认。

结果

在这 60 名三重奏中，10 名先证者携带 CHH 基因中的从头致病变异。定制 UDS 表明，这些从头变体中的三个实际上是合子后嵌合体——两个在FGFR1（p.Leu630Pro 和 p.Gly348Arg）中，一个在CHD7中（p.Arg2428*）。多个组织（来自血液、口腔、毛囊、尿液的 DNA）的统计学显着差异证实了它们的镶嵌性质。