Exp Clin Endocrinol Diabetes 2019; 127(08): 538-544
DOI: 10.1055/a-0681-6608
Article
© Georg Thieme Verlag KG Stuttgart · New York

Targeted Gene Panel Sequencing for Molecular Diagnosis of Kallmann Syndrome and Normosmic Idiopathic Hypogonadotropic Hypogonadism

Ja Hye Kim
1  Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
,
Go Hun Seo
1  Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
,
Gu-Hwan Kim
2  Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
,
Juyoung Huh
3  Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
,
Il Tae Hwang
4  Department of Pediatrics, Hallym University Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
,
Ja-Hyun Jang
5  Green Cross Genome, Yongin, Korea
,
Han-Wook Yoo
1  Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
,
Jin-Ho Choi
1  Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
› Author Affiliations
Further Information

Publication History

received 25 May 2018
revised 09 August 2018

accepted 13 August 2018

Publication Date:
14 September 2018 (online)

Abstract

Background Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is classified either as Kallmann syndrome (KS) with anosmia or normosmic idiopathic hypogonadotropic hypogonadism (nIHH) and caused by mutations in more than 30 different genes. Recent advances in next-generation sequencing technologies have revolutionized the identification of causative genes by using massively parallel sequencing of multiple samples. This study was performed to establish the genetic etiology of IGD using a targeted gene panel sequencing of 69 known human IGD genes.

Methods This study included 28 patients with IGD from 27 independent families. Exomes were captured using customized SureSelect kit (Agilent Technologies) and sequenced on the Miseq platform (Illumina, Inc.), which includes a 163,269 bp region spanning 69 genes.

Results Four pathogenic and six likely pathogenic sequence variants were identified in 11 patients from 10 of the 27 families (37%) included in the study. We identified two known pathogenic mutations in CHD7 and PROKR2 from two male patients (7.4%). Novel sequence variants were also identified in 10 probands (37%) in CHD7, SOX3, ANOS1, FGFR1, and TACR3. Of these, while eight variants (29.6%) were presumed to be pathogenic or likely pathogenic, the remaining two were classified as variants of uncertain significance. Of the two pre-pubertal males with anosmia, one harbored a novel heterozygous splice site variant in FGFR1.

Conclusions The overall diagnostic yield was 37% of the patients who had undergone targeted gene panel sequencing. This approach enables rapid, cost-effective, and comprehensive genetic screening in patients with KS and nIHH.

*These two authors contributed equally.


Supplementary Material