A familial study of twins with severe asthenozoospermia identified a homozygous <i><scp>SPAG17</scp></i> mutation by whole‐exome sequencing

Xu, Xiaohui; Sha, Yanwei; Mei, Libin; Ji, Zhiyong; Qiu, Pingping; Ji, Hong; Li, P.; Wang, T.; Li, L.

doi:10.1111/cge.13059

Cited by 47 publications

(27 citation statements)

References 21 publications

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“…This can likely be attributed to nonsense‐mediated decay (NMD) resulting from the frameshift variant c.4127del, p.(Pro1376LeufsTer8). So far, a homozygous missense variant in SPAG17 c.4343G>A p.(Arg1448Gln) has been reported in one patient from a consanguineous family, putting forward SPAG17 as candidate gene for recessive male infertility (Figure S4; Xu et al, 2018). No second (likely) pathogenic SPAG17 variant could be identified however in F1 (III:2) by sequencing of all exons that had coverage below 20x in the WES data, by sequencing of the untranslated regions (UTRs) and by CNV analysis of all exons (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…A decreased expression of SPAG17 could be shown in fibroblasts of F1, II:8. No additional (likely) pathogenic variants could be found in the male infertility gene panel and so far only one homozygous missense variant has been reported in two twin brothers from a consanguineous family with severe asthenozoospermia (Xu et al, 2018). In parallel, homozygous variants in SPAG17 and WDR35 were described in a patient with multiple brain and skeletal anomalies, with a presumed combinatorial effect on the ciliary phenotype (Córdova‐Fletes et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

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Functional characterization of the first missense variant in CEP78 , a founder allele associated with cone‐rod dystrophy, hearing loss, and reduced male fertility

et al. 2020

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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractInactivating variants in the centrosomal CEP78 gene have been found in cone-rod dystrophy with hearing loss (CRDHL), a particular phenotype distinct from Usher syndrome. Here, we identified and functionally characterized the first CEP78 missense variant c.449T>C, p.(Leu150Ser) in three CRDHL families. The variant was found in a biallelic state in two Belgian families and in a compound heterozygous state-in trans with c.1462-1G>T-in a third German family. Haplotype reconstruction showed a founder effect. Homology modeling revealed a detrimental effect of p.(Leu150Ser) on protein stability, which was corroborated in patients' fibroblasts. Elongated primary cilia without clear ultrastructural abnormalities in sperm or nasal brushes suggest impaired cilia assembly. Two affected males from different families displayed sperm abnormalities causing infertility. One of these is a heterozygous carrier of a complex allele in SPAG17, a ciliary gene previously associated with autosomal recessive male infertility. Taken together, our data indicate that a missense founder allele in CEP78 underlies the same sensorineural CRDHL phenotype previously associated with inactivating variants. Interestingly, the CEP78 phenotype has been possibly expanded with male infertility. Finally, CEP78 loss-of-function variants may have an underestimated role in misdiagnosed Usher syndrome, with or without sperm abnormalities. K E Y W O R D S CEP78, cilia, cone-rod dystrophy with hearing loss (CRDHL), founder, male infertility, missense 1000 |

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Functional characterization of the first missense variant in CEP78 , a founder allele associated with cone‐rod dystrophy, hearing loss, and reduced male fertility

et al. 2020

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“…Finally, 23 eligible reports were used in the present systematic review, all of which were original articles. All genes discovered in these studies are listed in Table 1 [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] .…”

Section: Present Systematic Reviewmentioning

confidence: 99%

“…More recently, Wang et al [44] used whole exome-sequencing to identify an additional four consanguineous Chinese men with frameshift truncating mutations in DNAH1 , further establishing this gene’s role in flagellar development and motility during spermatogenesis. Further, Xu et al [45] identified homozygous mutations in two siblings of consanguineous parents with mutations affecting a highly conserved residue in sperm-associated antigen 17 ( SPAG17 ) causing asthenospermia. Functional studies showed this mutation causes significantly decreased SPAG17 expression in the patients’ spermatozoa, consistent with a functional role in motility [45] .…”

Section: Motility Anomalies (Asthenospermia and Flagellar Abnormalitimentioning

confidence: 99%

A systematic review on the genetics of male infertility in the era of next-generation sequencing

Robay

Abbasi

Akil

et al. 2018

Arab Journal of Urology

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ObjectivesTo identify the role of next-generation sequencing (NGS) in male infertility, as advances in NGS technologies have contributed to the identification of novel genes responsible for a wide variety of human conditions and recently has been applied to male infertility, allowing new genetic factors to be discovered.Materials and methodsPubMed was searched for combinations of the following terms: ‘exome’, ‘genome’, ‘panel’, ‘sequencing’, ‘whole-exome sequencing’, ‘whole-genome sequencing’, ‘next-generation sequencing’, ‘azoospermia’, ‘oligospermia’, ‘asthenospermia’, ‘teratospermia’, ‘spermatogenesis’, and ‘male infertility’, to identify studies in which NGS technologies were used to discover variants causing male infertility.ResultsAltogether, 23 studies were found in which the primary mode of variant discovery was an NGS-based technology. These studies were mostly focused on patients with quantitative sperm abnormalities (non-obstructive azoospermia and oligospermia), followed by morphological and motility defects. Combined, these studies uncover variants in 28 genes causing male infertility discovered by NGS methods.ConclusionsMale infertility is a condition that is genetically heterogeneous, and therefore remarkably amenable to study by NGS. Although some headway has been made, given the high incidence of this condition despite its detrimental effect on reproductive fitness, there is significant potential for further discoveries.

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“…Recently, SPAG17 variants were reported to cause primary ciliary dyskinesia in human patients (Andjelkovic, Minic et al 2018). These variants are linked to male infertility due to severe asthenozoospermia (Xu, Sha et al 2018), and affect almost all stages of spermatogenesis in mice (Kazarian, Son et al 2018).…”

Section: Introductionmentioning

confidence: 99%

A novel hypomorphic allele ofSpag17causes primary ciliary dyskinesia phenotypes in mice

Abdelhamed

Lukacs

Cindrić

et al. 2020

Preprint

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Primary ciliary dyskinesia (PCD) is a human condition of dysfunctional motile cilia characterized by recurrent lung infection, infertility, organ laterality defects, and partially penetrant hydrocephalus. We recovered a mouse mutant from a forward genetic screen that developed all the phenotypes of PCD. Whole exome sequencing identified this primary ciliary dyskinesia only (Pcdo) allele to be a nonsense mutation (c.5236A>T) in the Spag17 coding sequence creating a premature stop codon at position 1746 (K1746*). The Pcdo variant abolished different isoforms of SPAG17 in the Pcdo mutant testis but not in the brain. Our data indicate differential requirements for SPAG17 in different motile cilia cell types. SPAG17 is required for proper development of the sperm flagellum, and is essential for either development or stability of the C1 microtubule structure within cilia, but not the brain ependymal cilia. We identified changes in ependymal cilia beating frequency but these did not apparently alter lateral ventricle cerebrospinal fluid (CSF) flow. Aqueductal (Aq) stenosis resulted in significantly slower and abnormally directed CSF flow and we suggest this is the root cause of the hydrocephalus. The Spag17Pcdo homozygous mutant mice are generally viable to adulthood, but have a significantly shortened life span with chronic morbidity. Our data indicate that the c.5236A>T Pcdo variant is a hypomorphic allele of Spag17 gene that causes phenotypes related to motile, but not primary, cilia. Spag17Pcdo is a novel and useful model for elucidating the molecular mechanisms underlying development of PCD in the mouse.

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A familial study of twins with severe asthenozoospermia identified a homozygous SPAG17 mutation by whole‐exome sequencing

Cited by 47 publications

References 21 publications

Functional characterization of the first missense variant in CEP78 , a founder allele associated with cone‐rod dystrophy, hearing loss, and reduced male fertility

Functional characterization of the first missense variant in CEP78 , a founder allele associated with cone‐rod dystrophy, hearing loss, and reduced male fertility

A systematic review on the genetics of male infertility in the era of next-generation sequencing

A novel hypomorphic allele ofSpag17causes primary ciliary dyskinesia phenotypes in mice

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