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CHD7 missense variants and clinical characteristics of Chinese males with infertility.

ABSTRACT: BACKGROUND:Isolated hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS) are rare genetic diseases that cause male infertility. The chromodomain helicase DNA-binding protein 7 (CHD7) gene is commonly associated with KS and IHH. We speculated that CHD7 variants may be associated with male infertility. METHODS:Two hundred males with azoospermia and 120 with oligozoospermia were recruited. The patients underwent clinical examination and reproductive hormone testing. A panel of genes including CHD7 and others related to spermatogenic failure was sequenced by targeted-gene exome sequencing. RESULTS:Three patients with severe oligozoospermia had CHD7 variants (a detection rate of 0.94% (3/320)). After prediction software analysis, two of the variants c.3464G>A (p.R1155H) and c.4516G>A (p.G1506S) were predicted to be likely pathogenic. Although predicted to be benign, the variants of c.2824A>G (p.T942A) located in the chromodomain 2 could not be excluded as disease causing. The patients with variants had small testicular volumes. In particular, the testes of the patient with a p.G1506S variant varied in size (left, 8 ml; right, 4.5 ml). Two patients (patients 31 and 120) had low E2 levels and two (patients 83 and 120) had low T levels. Ultimately, these variants were classified as "variants of unknown significant" that may be associated with male infertility. CONCLUSIONS:There may be a relationship between the CHD7 gene missense variants and male infertility. These variants are easier to find in patients with azoospermia and severe oligospermia whose testosterone levels are decreased.

SUBMITTER: Li L

PROVIDER: S-EPMC7503206 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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CHD7 missense variants and clinical characteristics of Chinese males with infertility.

Li Leilei L Wang Ruixue R Yu Yang Y Zhang Hongguo H Jiang Yuting Y Yang Xiao X Liu Ruizhi R

Molecular genetics & genomic medicine 20200622 9

<h4>Background</h4>Isolated hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS) are rare genetic diseases that cause male infertility. The chromodomain helicase DNA-binding protein 7 (CHD7) gene is commonly associated with KS and IHH. We speculated that CHD7 variants may be associated with male infertility.<h4>Methods</h4>Two hundred males with azoospermia and 120 with oligozoospermia were recruited. The patients underwent clinical examination and reproductive hormone testing. A panel ...[more]

PMID: 32573075

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Project description:ObjectiveTo determine whether antioxidants improve male fertility, as measured by semen parameters and DNA fragmentation at 3 months and pregnancy resulting in live birth after up to 6 months of treatment, among couples with male factor infertility.DesignMulticenter, double-blind, randomized, placebo-controlled trial with an internal pilot study.SettingNine fertility centers in the United States from December 2015 to December 2018.Patient(s)Men (N = 174) with sperm concentration ≤15 million/mL, motility ≤40%, normal morphology ≤4%, or DNA fragmentation >25%, and female partners who were ovulatory, ≤40 years old, and had documented tubal patency.Intervention(s)Males randomly assigned to receive an antioxidant formulation (n = 85) containing 500 mg of vitamin C, 400 mg of vitamin E, 0.20 mg of selenium, 1,000 mg of l-carnitine, 20 mg of zinc, 1,000 μg of folic acid, 10 mg of lycopene daily, or placebo (n = 86). Treatment lasted for a minimum of 3 months and maximum of 6 months, and couples attempted to conceive naturally during the first 3 months and with clomiphene citrate with intrauterine insemination of the female partner in months 4 through 6.Main outcome measure(s)Primary outcome was live birth; secondary outcomes included pregnancy within 6 months of treatment. For the internal pilot, the primary outcomes were semen parameters and sperm DNA fragmentation index after 3 months of treatment.Result(s)In the Males, Antioxidants, and Infertility (MOXI) study, after 3 months of treatment, the change in sperm concentration differed between the antioxidant group (median -4.0 [interquartile range-12.0, 5.7] million/mL) and placebo group (+2.4 [-9.0, 15.5] million/mL). However, there were no statistically significant differences between the two groups for changes in sperm morphology, motility, or DNA fragmentation. Among the 66 oligospermic men at randomization, sperm concentration did not differ at 3 months between the antioxidant and control groups: 8.5 (4.8, 15.0) million/mL versus 15.0 (6.0, 24.0) million/mL. Of the 75 asthenospermic men, motility did not differ at 3 months: 34% ± 16.3% versus 36.4% ± 15.8%. Among the 44 men with high DNA fragmentation, DNA fragmentation did not differ at 3 months: 29.5% (21.6%, 36.5%) versus 28.0% (20.6%, 36.4%). In the entire cohort, cumulative live birth did not differ at 6 months between the antioxidant and placebo groups: 15% versus 24%.Conclusion(s)Antioxidants do not improve semen parameters or DNA integrity among men with male factor infertility. Although limited by sample size, this study suggests that antioxidant treatment of the male partner does not improve in vivo pregnancy or live-birth rates.Clinical trial registration numberNCT02421887.

Project description:BackgroundCHARGE syndrome is characterized by coloboma, heart defects, choanal atresia, growth retardation, genitourinary malformation and ear abnormalities. The chromodomain helicase DNA-binding protein 7 (CHD7) gene is the major cause of CHARGE syndrome and is inherited in an autosomal dominant manner. Currently, the phenotype spectrum of CHARGE syndrome in neonatal population remain elusive. We aimed to investigate the phenotype spectrum of neonatal patients suspected to have CHARGE syndrome with pathogenic or likely pathogenic variants in the CHD7 gene.MethodsWe pooled next-generation sequencing data from the Neonatal Birth Defects Cohort (NBDC, ClinicalTrials.gov Identifier: NCT02551081) in Children's Hospital of Fudan University. The pathogenicity of novel variants was analyzed by bioinformatic and genetic analyses. Clinical information collection, Sanger sequencing and follow-up interviews were performed when possible. Cranial MRI of these patients was performed, the volumes of different regions of the brain were analyzed.ResultsA total of 12 unrelated patients in our cohort were found with CHD7 variants. Eight patients received a firm clinical diagnosis of CHARGE syndrome (Bergmann criteria, Blake criteria, Verloes criteria and Hale criteria). Three patients did not match any diagnostic criteria, and no patients matched the Verloes criteria. Phenotype spectrum analysis found that feeding difficulty was the dominant feature among this neonatal cohort. Six novel variants in the CHD7 gene (Glu2408*, Lys651*, c.5607 + 1G > T, Leu373Val, Lys2005Asnfs*37 and Gln1991*) were identified, expanding the variant database of the CHD7 gene. Cranial MRI analysis revealed significant volume loss in cingulate gyrus, occipital lobe, and cerebellum and volume gain in the left medial and inferior temporal gyri anterior white matter parts.ConclusionsBased on a relatively unbiased neonatal cohort, we concluded that CHARGE syndrome and CHD7 gene variants should be suspected in newborns who have feeding difficulty, and one or more malformations.Trial registrationNeonatal Birth Defects Cohort (NBDC, ClinicalTrials.gov identifier: NCT02551081 ).

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CHD7 missense variants and clinical characteristics of Chinese males with infertility.

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CHD7 missense variants and clinical characteristics of Chinese males with infertility.

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