Novel Compound Heterozygous Variants in the <i>LHCGR</i> Gene in a Genetically Male Patient with Female External Genitalia

Abstract

The LHCGR gene encodes a G-protein coupled receptor that plays a pivotal role in sexual differentiation in males, ovarian development in females and in fertility via its interaction with luteinizing hormone and chorionic gonadotropin. Inactive variants of the LHCGR gene cause Leydig cell hypoplasia (LCH), which is a rare disease and one of the causes of disorder of sexual differentiation (DSD) in males. The aim of this work was to clarify the clinical and molecular characteristics of a 2.75 year old patient with type 1 LCH. Whole exome sequencing was performed for the patient family and variants in the LHCGR gene were validated by Sanger sequencing. Pathogenicity of the missense variant was evaluated by multiple in silico tools. Our Chinese patient, who exhibited DSD, had female external genitalia (normal labia majora and minora, external opening of urethra under the clitoris and blind-ended vagina) and bilateral testis tissues in the inguinal region. Genetic sequencing revealed compound heterozygous variants in the LHCGR gene in the patient, including a novel missense variant in exon 4 (c.349G>A, p.Gly117Arg) and a novel nonsense variant in exon 10 (c.878C>A, p.Ser293*). The missense variant is in the first leucine-rich repeat domain of the LHCGR protein, which is predicted to affect ligand recognition and binding affinity and thus protein function. The patient is molecularly and clinically diagnosed with type 1 LCH, which is caused by novel, compound heterozygous variants of the LHCGR gene. We believe this report will serve to expand the genotypic spectrum of LHCGR variants.

46 XY undervirulized male DSD: Reporting a patient with prenatally diagnosed disorder/difference of sex development (DSD) with heterozygous LHCGR mutations

“…There are more than 77 different inactivating mutations of LHCGR gene which result in hypoplasia of the Leydig cells and decreased or absent production of testosterone. 5 To the best of our knowledge, the c.29_55 deletion has not been previously reported in the literature, and its clinical significance was unknown. While further molecular investigation into the structural and functional ramifications of the c.29_55 mutation could be accomplished in a research setting, the observation here of an infant with a typical female phenotype and absent Leydig cells suggests that when combined with the known inactivating variant, c1868A > C, profound loss of function results.…”

“Waking up” the sleeping metaphor of normality in connection to intersex or DSD: a scoping review of medical literature

“…One paper (Roen et al, 2018 ) expressed its critique on the term “disorder” by placing it between hyphens. The word hermaphrodite was mentioned in 10 of 75 papers (Barham et al, 2016 ; Caputo et al, 2019 ; Greeley et al, 2017 ; Hernández et al, 2016 ; Mirshahvalad et al, 2018 ; Özdemir et al, 2019 ; Rich et al, 2016 ; Schteingart et al, 2019 ; Şimşek et al, 2016 ; Yan et al, 2019 ), often in the context of ovotesticular DSD. Five papers used the outdated term to indicate that this condition was “previously known” as hermaphroditism (Barham et al, 2016 ; Caputo et al, 2019 ; Özdemir et al, 2019 ; Rich et al, 2016 ; Şimşek et al, 2016 ), 4 studies used it as a mere synonym (Greeley et al, 2017 ; Mirshahvalad et al, 2018 ; Schteingart et al, 2019 ; Yan et al, 2019 ) and only one article explicitly stated that the term has been replaced because it was considered stigmatizing (Hernández et al, 2016 ) (see Tables 2 , 3 , 4 , 5 , 6 ).…”

“…Many papers (Caputo et al, 2019;Heo et al, 2018;Hunter et al, 2016;Kearsey & Hutson, 2017;Larios García & Bautista Delgado, 2016;Patil et al, 2019;Poyrazoglu et al, 2017;Raveenthiran, 2017;Rich et al, 2016;Saikia et al, 2019;Schteingart et al, 2019;Şimşek et al, 2016;Singh et al, 2016;Touzon et al, 2019;Wagner-Mahler et al, 2019;Yan et al, 2019) also referred to (ab) normal hormonal levels or (ab)normal hormone production (e.g. testosterone, estrogen, luteinizing hormone (LH), follicle stimulating hormone (FSH), Anti-Müllerian hormone (AMH)), at times with the indication of a reference range (Adrião et al, 2020;Morandi et al, 2018;Raveendran et al, 2019;Şimşek et al, 2016;Sperling & Meyer, 2017;Teasdale & Morton, 2017;Wu et al, 2017;Xu et al, 2018).…”

Primary Amenorrhea Due to Anatomical Abnormalities of the Reproductive Tract: Molecular Insight

“…The hormonal profile of the patients shows low serum T level (basal and stimulated by hCG), normal male range serum AMH level, elevated serum LH and FSH levels, low serum DHT level, normal serum Δ4-A level. In patients with a severe phenotype, nonsense and missense mutations located in the exons of the LHCGR gene, mostly exon 11, were reported [ 64 ]. LCH type I is a very rare disorder.…”