Spermatogenic failure 16 (SPGF16) is autosomal recessive male infertility caused by biallelic loss-of-function variants in SUN5, a testis-specific SUN domain protein of the sperm nuclear envelope. Affected men are otherwise healthy and present with acephalic spermatozoa syndrome: the ejaculate contains mostly headless flagella, a minority of tail-less heads, and a few intact spermatozoa with an abnormal head-tail junction. SUN5 sits in the posterior nuclear envelope at the implantation fossa, where it is thought to form a LINC (linker of nucleoskeleton and cytoskeleton) bridge that holds the head-tail coupling apparatus against the nucleus. Without it, the coupling apparatus separates from the nucleus during spermatid elongation and the break lies between the nucleus and the proximal centriole. Nonsense, frameshift, splice-site, missense and whole-gene deletion alleles are reported, and SUN5 is the most frequently mutated gene in acephalic spermatozoa syndrome, with a founder splice-site duplication common in men of North African origin. Intracytoplasmic sperm injection (ICSI) with the detached heads has mostly given good fertilization and pregnancy rates.
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Conditions with similar clinical presentations that must be differentiated from Spermatogenic Failure 16:
name: Spermatogenic Failure 16
creation_date: "2026-10-31T12:00:00Z"
category: Mendelian
synonyms:
- SPGF16
- spermatogenic failure type 16
- SUN5 azoospermia
- azoospermia caused by mutation in SUN5
- SUN5-related acephalic spermatozoa syndrome
description: >-
Spermatogenic failure 16 (SPGF16) is autosomal recessive male infertility
caused by biallelic loss-of-function variants in SUN5, a testis-specific SUN
domain protein of the sperm nuclear envelope. Affected men are otherwise
healthy and present with acephalic spermatozoa syndrome: the ejaculate
contains mostly headless flagella, a minority of tail-less heads, and a few
intact spermatozoa with an abnormal head-tail junction. SUN5 sits in the
posterior nuclear envelope at the implantation fossa, where it is thought to
form a LINC (linker of nucleoskeleton and cytoskeleton) bridge that holds the
head-tail coupling apparatus against the nucleus. Without it, the coupling
apparatus separates from the nucleus during spermatid elongation and the
break lies between the nucleus and the proximal centriole. Nonsense,
frameshift, splice-site, missense and whole-gene deletion alleles are
reported, and SUN5 is the most frequently mutated gene in acephalic
spermatozoa syndrome, with a founder splice-site duplication common in men
of North African origin. Intracytoplasmic sperm injection (ICSI) with the
detached heads has mostly given good fertilization and pregnancy rates.
disease_term:
preferred_term: spermatogenic failure 16
term:
id: MONDO:0014961
label: spermatogenic failure 16
parents:
- Spermatogenic Failure
- Genetic Disease
notes: >-
MONDO cross-references this disease as OMIM 617187 and records SUN5 as its
causal gene. MONDO's text definition calls the disease an azoospermia, but
every reported patient produces spermatozoa; the defect is sperm
decapitation, not absent sperm. No GeneReviews chapter or ClinGen
gene-disease validity assertion for SUN5 is in the committed Bookshelf index
or the cached ClinGen export, so no validity tier is recorded. Sun5 knockout
mouse sperm look round-headed on light microscopy, but these are headless
tails with a retained cytoplasmic droplet, not globozoospermia.
inheritance:
- name: Autosomal recessive
description: >-
Disease requires two SUN5 loss-of-function alleles, either homozygous
(often in consanguineous families or with a founder allele) or compound
heterozygous, including a point variant in trans with a deletion of the
whole gene.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:27640305
reference_title: "Biallelic SUN5 Mutations Cause Autosomal-Recessive Acephalic Spermatozoa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In summary, these results demonstrate that biallelic SUN5 mutations cause male infertility due to autosomal-recessive acephalic spermatozoa syndrome."
explanation: Biallelic variants in eight unrelated men establish recessive inheritance.
- reference: PMID:34159570
reference_title: "Novel Mutation and Deletion in SUN5 Cause Male Infertility with Acephalic Spermatozoa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "one compound heterozygous including one reported missense mutation (c.1043A>T; p.N348I) and a large deletion that contains partial EFCAB8 ( NM_001143967 .1) and BPIFB2 ( NM_025227 ) and complete SUN5 ( NM_080675 )"
explanation: A point variant in trans with a whole-gene deletion is the compound heterozygous form of recessive inheritance.
pathophysiology:
- name: Loss of SUN5 Protein
description: >-
Nonsense, frameshift and splice-site alleles truncate SUN5 or remove its
transcript, a 5-kb deletion-insertion removes exon 8, and a large deletion
removes the whole gene. Several missense variants in the SUN domain alter
folding and localization, and patient sperm carrying them also lack the
protein. SUN5 is a testis-specific inner nuclear membrane protein that, in
mature sperm, sits at the implantation fossa where the tail attaches to the
head.
biological_scale: MOLECULAR
genes:
- preferred_term: SUN5
term:
id: hgnc:16252
label: SUN5
genetic_context:
variant_origin: GERMLINE
functional_impact_category: LOSS_OF_FUNCTION
molecular_functions:
- preferred_term: protein-membrane adaptor activity (SUN domain bridge across the nuclear envelope)
modifier: DECREASED
term:
id: GO:0043495
label: protein-membrane adaptor activity
cellular_components:
- preferred_term: nuclear inner membrane
term:
id: GO:0005637
label: nuclear inner membrane
downstream:
- target: Disrupted SUN5 Nuclear Envelope Anchoring Complex
causal_link_type: DIRECT
evidence:
- reference: PMID:33848337
reference_title: "Pathogenesis of acephalic spermatozoa syndrome caused by SUN5 variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Furthermore, the distribution of outer dense fiber protein 1 (ODF1) and Nesprin3 was altered in sperm of ASS patients with SUN5 variants."
explanation: Patient sperm lacking SUN5 also mislocalize its partners Nesprin3 and ODF1.
- target: Impaired Germ Cell Nuclear mRNA Export
causal_link_type: DIRECT
evidence:
- reference: PMID:39108207
reference_title: "SUN5, a testis-specific nuclear membrane protein, participates in recruitment and export of nuclear mRNA in spermatogenesis."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In Sun5-knockout mice ( Sun5 -/-), poly(A) + RNA accumulates in the nuclei of germ cells, leading to reduced sperm counts, decreased sperm motility and disrupted sperm head-to-tail junctions."
explanation: Loss of Sun5 in mice causes nuclear retention of germ-cell mRNA.
evidence:
- reference: PMID:27640305
reference_title: "Biallelic SUN5 Mutations Cause Autosomal-Recessive Acephalic Spermatozoa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SUN5 variants lead to absent, significantly reduced, or truncated SUN5, and certain variants altered SUN5 distribution in the head-tail junction of the sperm."
explanation: Patient variants abolish, reduce or truncate SUN5 in sperm.
- reference: PMID:28541472
reference_title: "Homozygous deletion of SUN5 in three men with decapitated spermatozoa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We found all three men to be homozygous for a deletion-insertion variant (GRCh38 - chr20:32995761_32990672delinsTGGT) that removes 5090 base pairs including exon 8 of SUN5, predicting the frameshift, p.(Leu143Serfs*30), and the inactivation of SUN5."
explanation: A second family with two clear loss-of-function alleles.
- reference: PMID:28541472
reference_title: "Homozygous deletion of SUN5 in three men with decapitated spermatozoa."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We also show that the p.Gly114Arg variant has a strong inhibitory effect on splicing in HeLa cells, evidence that homozygozity for p.Gly114Arg causes acephalic spermatozoa syndrome through loss of SUN5 function."
explanation: A variant first read as missense acts by disrupting splicing.
- reference: PMID:29298896
reference_title: "Mechanistic insights into acephalic spermatozoa syndrome-associated mutations in the human SUN5 gene."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Furthermore, we observed that many SUN5 mutations affect the secondary structure of the protein and influence its folding and cellular localization."
explanation: Missense variants act by misfolding and mislocalizing SUN5.
- reference: PMID:33671757
reference_title: "Identification and Characterization of the Most Common Genetic Variant Responsible for Acephalic Spermatozoa Syndrome in Men Originating from North Africa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Immunofluorescence assays performed on sperm cells from three mutated subjects revealed a total absence of SUN5, thus demonstrating the deleterious impact of the identified variant on protein expression."
explanation: The North African founder splice variant abolishes SUN5 in sperm.
- reference: PMID:34159570
reference_title: "Novel Mutation and Deletion in SUN5 Cause Male Infertility with Acephalic Spermatozoa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our results showed that SUN5 could not be detected in the patients' spermatozoa and the exogenous expression level of the mutant protein was decreased in transfected HEK-293T cells."
explanation: Missense, splice and deletion genotypes all leave sperm without SUN5.
- name: Disrupted SUN5 Nuclear Envelope Anchoring Complex
description: >-
At the posterior nuclear envelope SUN5 binds partners on both sides of the
envelope: lamin B1 inside the nucleus, and the KASH protein Nesprin3, the
centriole-associated septin SEPTIN12, ODF1 and the linker CENTLEIN outside
it. Cryo-electron tomography of mammalian sperm shows a regular hexagonal
protein lattice in the nuclear envelope at the base of the head, proposed
to be formed by these LINC complexes. Losing SUN5 dissolves this complex
and Nesprin3 loses its posterior localization. The partner data come
mainly from Sun5 knockout mice and transfected cells, with altered
Nesprin3 and ODF1 staining confirmed in patient sperm.
biological_scale: MOLECULAR
cellular_components:
- preferred_term: posterior nuclear envelope (implantation fossa)
term:
id: GO:0005635
label: nuclear envelope
downstream:
- target: Defective Sperm Head-Tail Coupling
causal_link_type: DIRECT
evidence:
- reference: PMID:38870534
reference_title: "SUN5 interacts with nuclear membrane LaminB1 and cytoskeletal GTPase Septin12 mediating the sperm head-and-tail junction."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The disruption of the LaminB1/SUN5/Septin12 complex by Sun5 deficiency caused separation of the Septin12-proximal centriole from the nucleus, leading to the breakage of the head-to-tail junction."
explanation: Loss of the SUN5-anchored complex separates the proximal centriole from the nucleus.
- reference: PMID:33848337
reference_title: "Pathogenesis of acephalic spermatozoa syndrome caused by SUN5 variant."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "When gene variants resulted in a loss of SUN5, the 'triplet' structure disappears and then the head-tail junction becomes fragile, leading to the occurrence of ASS."
explanation: Proposed model in which loss of the SUN5-Nesprin3-ODF1 complex weakens the junction.
evidence:
- reference: PMID:34268309
reference_title: "SUN5 Interacting With Nesprin3 Plays an Essential Role in Sperm Head-to-Tail Linkage: Research on Sun5 Gene Knockout Mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Further coimmunoprecipitation (Co-IP) and immunofluorescence assays confirmed that Sun5 and Nesprin3 were indeed bona fide interaction partners that formed the linker of the nucleoskeleton and cytoskeleton (LINC) complex participating in the connection of the head and tail of spermatozoa."
explanation: SUN5 and Nesprin3 form a LINC complex at the head-tail junction.
- reference: PMID:34268309
reference_title: "SUN5 Interacting With Nesprin3 Plays an Essential Role in Sperm Head-to-Tail Linkage: Research on Sun5 Gene Knockout Mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Nesprin3 was located posterior and anterior to the nucleus during spermiogenesis in wild-type mice, whereas it lost its localization at the implantation fossa of the posterior region in Sun5-/- mice."
explanation: Without Sun5, Nesprin3 is lost from the posterior nuclear envelope.
- reference: PMID:38870534
reference_title: "SUN5 interacts with nuclear membrane LaminB1 and cytoskeletal GTPase Septin12 mediating the sperm head-and-tail junction."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Further studies demonstrated that SUN5 connected the nucleus by interacting with LaminB1 and connected the proximal centriole by interacting with Septin12."
explanation: SUN5 bridges the nuclear lamina and the proximal centriole.
- reference: PMID:34389728
reference_title: "The missing linker between SUN5 and PMFBP1 in sperm head-tail coupling apparatus."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We demonstrate that CENTLEIN directly interacts with both SUN5 and PMFBP1, two proteins localized in the HTCA and related with acephalic spermatozoa syndrome."
explanation: CENTLEIN links SUN5 on the head side to PMFBP1 on the tail side.
- reference: PMID:29298896
reference_title: "Mechanistic insights into acephalic spermatozoa syndrome-associated mutations in the human SUN5 gene."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We also found that SUN5 interacts with the coupling apparatus protein DnaJ heat shock protein family (Hsp40) member B13 (DNAJB13) during spermatogenesis, and the substitutions in the SUN5 SUN domain impair its interaction with DNAJB13."
explanation: SUN domain substitutions weaken binding to a coupling apparatus protein.
- reference: PMID:41855266
reference_title: "SUN5 forms a regular protein lattice reinforcing the sperm head-tail junction."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "By applying in situ cryoelectron tomography, we find an extensive hexagonal lattice in the nuclear envelope in this region."
explanation: >-
Cryo-electron tomography of isolated human, mouse and boar sperm shows a
lattice in the posterior nuclear envelope where SUN5 sits.
- name: Defective Sperm Head-Tail Coupling
description: >-
The head-tail coupling apparatus assembles normally early in
spermiogenesis, but without SUN5 it detaches with the basal plate from the
implantation fossa as the spermatid elongates. The centrosome and coupling
apparatus drift away from the nucleus, and head and tail separate once the
manchette disappears. The break lies between the nucleus and the proximal
centriole, so the headless tails keep both centrioles and the heads lack an
implantation fossa and basal plate.
biological_scale: CELLULAR
cell_types:
- preferred_term: elongating spermatid
term:
id: CL:0000018
label: spermatid
biological_processes:
- preferred_term: spermatid development
modifier: DECREASED
term:
id: GO:0007286
label: spermatid development
cellular_components:
- preferred_term: sperm head-tail coupling apparatus
term:
id: GO:0120212
label: sperm head-tail coupling apparatus
downstream:
- target: Acephalic spermatozoa
causal_link_type: DIRECT
evidence:
- reference: PMID:28945193
reference_title: "Essential role for SUN5 in anchoring sperm head to the tail."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Additional studies revealed that SUN5 was located in the neck of the spermatozoa, anchoring sperm head to the tail, and without functional SUN5 the sperm head to tail coupling apparatus was detached from nucleus during spermatid elongation."
explanation: Detachment of the coupling apparatus is the step that produces headless sperm in Sun5-null mice.
- target: Abnormal sperm neck morphology
causal_link_type: DIRECT
evidence:
- reference: PMID:28945193
reference_title: "Essential role for SUN5 in anchoring sperm head to the tail."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Ultrastructural studies of spermatogenesis in Sun5−/− male mice revealed that the sperm head-tail coupling apparatus could be successfully assembled during the early stage of spermiogenesis, but without functional SUN5, the coupling apparatus together with the basal plate disassociated from the implantation fossa during the elongation of the spermatids."
explanation: Timing and site of the coupling failure in Sun5-null spermatids.
- reference: PMID:34268309
reference_title: "SUN5 Interacting With Nesprin3 Plays an Essential Role in Sperm Head-to-Tail Linkage: Research on Sun5 Gene Knockout Mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Furthermore, ultrastructural imaging revealed that the head-tail coupling apparatus (HTCA) and the centrosome were distant from the nucleus at steps 9-10 during spermatid elongation. With the manchette disappearing at steps 13-14, the head and the tail segregated."
explanation: An independent knockout line shows the same coupling failure and its timing.
- reference: PMID:28541472
reference_title: "Homozygous deletion of SUN5 in three men with decapitated spermatozoa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our results, together with those of the previous study, show that SUN5 is required for the formation of the sperm head-tail junction and male fertility."
explanation: Human genetic conclusion that SUN5 is required for the head-tail junction.
- reference: PMID:32104701
reference_title: "Beyond Acephalic Spermatozoa: The Complexity of Intracytoplasmic Sperm Injection Outcomes."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "The separation in subtype II is located between the nucleus and proximal centriole"
explanation: >-
Review placing SUN5-related acephalic sperm in subtype II, where the
break lies between the nucleus and the proximal centriole.
- name: Impaired Germ Cell Nuclear mRNA Export
description: >-
In Sun5 knockout mice SUN5 also interacts with the mRNA export factor NXF1
and the nucleoporin NUP93, and germ cells retain poly(A) RNA in the nucleus.
The authors link this to lower sperm counts and motility in the mice.
Whether it contributes to the human phenotype has not been studied, and
reported patients are not described as oligozoospermic, so this node has no
phenotype edge.
biological_scale: CELLULAR
cell_types:
- preferred_term: male germ cell
term:
id: CL:0000015
label: male germ cell
biological_processes:
- preferred_term: mRNA export from nucleus
modifier: DECREASED
term:
id: GO:0006406
label: mRNA export from nucleus
evidence:
- reference: PMID:39108207
reference_title: "SUN5, a testis-specific nuclear membrane protein, participates in recruitment and export of nuclear mRNA in spermatogenesis."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In Sun5 -/- mice, the binding of Nxf1 and Nup93 decreases due to loss of Sun5 function, and the process of submitting Nxf1-binding mRNPs to Nup93 is inhibited, resulting in abnormal spermatogenesis."
explanation: Mouse evidence for an mRNA export role of SUN5 in germ cells.
phenotypes:
- category: Reproductive
name: Male infertility
description: Primary male infertility is the presenting complaint in every reported man.
phenotype_term:
preferred_term: Male infertility
term:
id: HP:0003251
label: Male infertility
evidence:
- reference: PMID:27640305
reference_title: "Biallelic SUN5 Mutations Cause Autosomal-Recessive Acephalic Spermatozoa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In summary, these results demonstrate that biallelic SUN5 mutations cause male infertility due to autosomal-recessive acephalic spermatozoa syndrome."
explanation: Infertility is the outcome in the biallelic carriers of the founding cohort.
- reference: PMID:28945193
reference_title: "Essential role for SUN5 in anchoring sperm head to the tail."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Here, we generated Sun5-/- mice and found that male mice were infertile."
explanation: Male infertility is reproduced in the knockout mouse.
- category: Reproductive
name: Acephalic spermatozoa
description: >-
The defining finding. The ejaculate contains mostly headless flagella and
a minority of tail-less heads; one patient had 98% acephalic spermatozoa.
In the knockout mouse the headless tails carry a retained cytoplasmic
droplet and can be mistaken for round-headed sperm.
phenotype_term:
preferred_term: Acephalic spermatozoa
term:
id: HP:0012869
label: Acephalic spermatozoa
sequelae:
- target: Male infertility
description: Headless tails cannot fertilize an oocyte, so natural conception is not possible.
evidence:
- reference: PMID:33671757
reference_title: "Identification and Characterization of the Most Common Genetic Variant Responsible for Acephalic Spermatozoa Syndrome in Men Originating from North Africa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Acephalic spermatozoa syndrome (ASS) is a rare but extremely severe type of teratozoospermia, defined by the presence of a majority of headless flagella and a minority of tail-less sperm heads in the ejaculate."
explanation: Definition of the semen phenotype in a SUN5 cohort.
- reference: PMID:40740627
reference_title: "Novel SUN5 Mutation Associated with Acephalic Spermatozoa Syndrome: A Cross-sectional Study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "in exon 13 of the SUN5 gene in one patient with 98% acephalic spermatozoa in the total sperm population"
explanation: Proportion of headless sperm in a homozygous missense carrier.
- reference: PMID:28945193
reference_title: "Essential role for SUN5 in anchoring sperm head to the tail."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Most Sun5-null spermatozoa displayed a globozoospermia-like phenotype but they were actually acephalic spermatozoa."
explanation: The knockout mouse reproduces acephalic sperm, which resemble round-headed sperm.
- category: Reproductive
name: Abnormal sperm neck morphology
description: >-
The few spermatozoa whose head remains attached have an abnormal
head-tail junction: the head lacks an implantation fossa and the head and
tail are not aligned on one axis.
phenotype_term:
preferred_term: Abnormal sperm neck morphology
term:
id: HP:0012866
label: Abnormal sperm neck morphology
sequelae:
- target: Male infertility
description: The rare attached sperm are themselves malformed.
evidence:
- reference: PMID:29329387
reference_title: "Patients with acephalic spermatozoa syndrome linked to SUN5 mutations have a favorable pregnancy outcome from ICSI."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "ASS is a rare cause of infertility characterized by the production of a majority of headless spermatozoa, along with a small proportion of intact spermatozoa with an abnormal head-tail junction."
explanation: Background statement of the abnormal junction in the remaining intact sperm.
- reference: PMID:28945193
reference_title: "Essential role for SUN5 in anchoring sperm head to the tail."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Some of the sperm heads in SUN5-mutated human sperm samples are linked to the tail but exhibit abnormal structures; these sperm heads do not have implantation fossa and have lost the linear alignment of the sperm axis."
explanation: Ultrastructure of the attached sperm in SUN5 patients.
genetic:
- name: SUN5
association: Causal
relationship_type: CAUSATIVE
gene_term:
preferred_term: SUN5
term:
id: hgnc:16252
label: SUN5
notes: >-
SUN5 was previously named SPAG4L and TSARG4. Reported alleles include
c.381delA (p.Val128Serfs*7), recurrent in Chinese patients; the founder
splice variant c.211+1_211+2dup in men of North African origin; c.340G>A
(p.Gly114Arg) and c.425+1G>A, which disrupt splicing; nonsense alleles
c.88C>T (p.Arg30*), c.216G>A (p.Trp72*), c.475C>T (p.Arg159*), c.675C>A
(p.Tyr225*), c.829C>T (p.Gln277*) and c.851C>G (p.Ser284*); a 5-kb
deletion-insertion removing exon 8; a whole-gene deletion; and missense
alleles including p.Thr275Met, p.Asn348Ile, p.Arg356Cys, p.Gly259Ser and
p.Arg358Gln. No ClinGen gene-disease validity assertion for SUN5 is in the
cached ClinGen export.
case_fractions:
- population: Chinese acephalic spermatozoa cohort (17 unrelated men)
case_fraction_percent: 47.06
cohort_size: 17
notes: Eight of 17 men carried biallelic SUN5 variants.
evidence:
- reference: PMID:27640305
reference_title: "Biallelic SUN5 Mutations Cause Autosomal-Recessive Acephalic Spermatozoa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These 10 SUN5 variants were found in 8 of 17 unrelated men, explaining the genetic defect in 47.06% of the affected individuals in our cohort."
explanation: SUN5 share of acephalic spermatozoa cases in the founding cohort.
- population: Fujian, China acephalic spermatozoa cohort (15 unrelated men)
case_fraction_percent: 33.33
cohort_size: 15
notes: All five solved cases carried the same homozygous c.381delA allele.
evidence:
- reference: PMID:29331481
reference_title: "Genetic contribution of SUN5 mutations to acephalic spermatozoa in Fujian China."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Five of the 15 (33.33%) subjects were found to carry the same homozygous mutation in the SUN5 gene c.381delA (p.V128Sfs*7)."
explanation: SUN5 share of cases in a second Chinese cohort.
- population: Acephalic spermatozoa cohort of North African origin (France and Tunisia)
case_fraction_percent: 78
cohort_size: 9
notes: Seven of nine men were homozygous for the c.211+1_211+2dup founder variant.
evidence:
- reference: PMID:33671757
reference_title: "Identification and Characterization of the Most Common Genetic Variant Responsible for Acephalic Spermatozoa Syndrome in Men Originating from North Africa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Variant filtering permitted us to identify the same SUN5 homozygous frameshift variant (c.211+1_211+2dup) in 7/9 individuals (78%)."
explanation: SUN5 share of cases in men of North African origin.
evidence:
- reference: PMID:27640305
reference_title: "Biallelic SUN5 Mutations Cause Autosomal-Recessive Acephalic Spermatozoa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We performed whole-exome sequencing in two unrelated infertile men and subsequent variant filtering identified one homozygous ... SUN5 (also named TSARG4) variants."
explanation: First gene-disease report.
- reference: PMID:28541472
reference_title: "Homozygous deletion of SUN5 in three men with decapitated spermatozoa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We therefore present the second case where the acephalic spermatozoa syndrome is associated with two LOF alleles of SUN5."
explanation: Independent replication in a North African family.
- reference: PMID:33848337
reference_title: "Pathogenesis of acephalic spermatozoa syndrome caused by SUN5 variant."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we performed whole-exome sequencing in 10 unrelated ASS and identified 2 homozygous variants ... in SUN5 in 4 patients."
explanation: Further nonsense and frameshift alleles in an unrelated cohort.
- reference: PMID:33452591
reference_title: "Genetic basis of acephalic spermatozoa syndrome, and intracytoplasmic sperm injection outcomes in infertile men: a systematic scoping review."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Notably, only SUN5 and PMFBP1 mutations are well-known to be implicated in ASS."
explanation: Systematic review ranking SUN5 among the two best-established acephalic spermatozoa genes.
animal_models:
- name: Sun5 knockout mouse
species: Mouse
genotype: Sun5 -/-
publication: PMID:28945193
description: >-
Male Sun5-null mice are infertile and produce mostly headless sperm, with
the coupling apparatus detaching from the nucleus during spermatid
elongation. Healthy offspring were obtained by injecting the tail-less
heads into oocytes. Independent knockout lines reproduce the phenotype.
modeled_mechanisms:
- target: Defective Sperm Head-Tail Coupling
relationship: RECAPITULATES
fidelity: HIGH
model_scale: CELLULAR
description: The knockout reproduces the human acephalic phenotype and shows when and where the junction fails.
limitations: >-
Most mouse acephalic sperm retain a large cytoplasmic droplet and look
round-headed, a feature not emphasized in patient reports, and the mouse
lines are complete nulls whereas some human alleles are missense.
evidence:
- reference: PMID:34268309
reference_title: "SUN5 Interacting With Nesprin3 Plays an Essential Role in Sperm Head-to-Tail Linkage: Research on Sun5 Gene Knockout Mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In this study, we generated Sun5 knockout mice and found that the head-to-tail linkage was broken in Sun5-/- mice, which was similar to human acephalic spermatozoa syndrome."
explanation: An independent knockout line reproduces the human phenotype.
- target: Disrupted SUN5 Nuclear Envelope Anchoring Complex
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: MOLECULAR
description: Knockout testis was used to identify the LaminB1, Septin12 and Nesprin3 partners of SUN5.
limitations: >-
Partner interactions were mapped in mouse testis and transfected cells;
only Nesprin3 and ODF1 mislocalization has been checked in patient sperm.
evidence:
- reference: PMID:38870534
reference_title: "SUN5 interacts with nuclear membrane LaminB1 and cytoskeletal GTPase Septin12 mediating the sperm head-and-tail junction."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In the present study, we generated Sun5 knockout mice, which presented the phenotype of ASS."
explanation: A third knockout line reproduces the phenotype and was used to map partners.
diagnosis:
- name: Semen analysis and sperm electron microscopy
description: >-
Semen analysis shows mostly headless flagella with a few tail-less heads.
Transmission electron microscopy locates the break between the nucleus and
the proximal centriole, and in North African patients showed a conserved
flagellar structure and slightly decondensed chromatin.
diagnosis_term:
preferred_term: transmission electron microscopy of spermatozoa
term:
id: NCIT:C18216
label: Transmission Electron Microscopy
evidence:
- reference: PMID:33671757
reference_title: "Identification and Characterization of the Most Common Genetic Variant Responsible for Acephalic Spermatozoa Syndrome in Men Originating from North Africa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Transmission electron microscopy showed a conserved flagellar structure and a slightly decondensed chromatin."
explanation: Ultrastructural findings in SUN5 patient sperm.
- name: Whole-exome sequencing
description: >-
Most SUN5 cases were found by exome sequencing confirmed by Sanger
sequencing. For men of North African origin, targeted genotyping of the
c.211+1_211+2dup founder variant is a cheap first test.
diagnosis_term:
preferred_term: whole-exome sequencing
term:
id: NCIT:C101295
label: Whole Exome Sequencing
evidence:
- reference: PMID:27640305
reference_title: "Biallelic SUN5 Mutations Cause Autosomal-Recessive Acephalic Spermatozoa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We performed whole-exome sequencing in two unrelated infertile men and subsequent variant filtering identified one homozygous"
explanation: Exome sequencing found the first SUN5 variants.
- reference: PMID:33671757
reference_title: "Identification and Characterization of the Most Common Genetic Variant Responsible for Acephalic Spermatozoa Syndrome in Men Originating from North Africa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Consequently, a simple and inexpensive genotyping of the 211+1_211+2dup variant could be beneficial for affected men of North African origin before resorting to more exhaustive genetic analyses."
explanation: Recommends founder-variant genotyping before broader sequencing.
- name: Screening for SUN5 genomic deletion
description: >-
A single heterozygous SUN5 variant calls for copy-number analysis of the
other allele, because a whole-gene deletion can be in trans.
diagnosis_term:
preferred_term: whole-genome sequencing for copy-number analysis
term:
id: NCIT:C101294
label: Whole Genome Sequencing
evidence:
- reference: PMID:34159570
reference_title: "Novel Mutation and Deletion in SUN5 Cause Male Infertility with Acephalic Spermatozoa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We recommended a clinical diagnostic strategy for SUN5 genomic deletion to screen heterozygous deletions and indicated that the diagnostic value of screening for SUN5 mutations and deletions in infertile men with ASS."
explanation: Authors recommend deletion screening in acephalic spermatozoa.
- reference: PMID:34159570
reference_title: "Novel Mutation and Deletion in SUN5 Cause Male Infertility with Acephalic Spermatozoa Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Whole genome sequencing (WGS) was performed to detect heterozygous deletion."
explanation: Whole-genome sequencing detected the deleted allele.
differential_diagnoses:
- name: TSGA10-related acephalic spermatozoa (SPGF26)
disease_term:
preferred_term: spermatogenic failure 26
term:
id: MONDO:0054730
label: spermatogenic failure 26
distinguishing_features:
- >-
The same semen phenotype, but the break lies between the distal centriole
and the midpiece rather than between the nucleus and the proximal
centriole, and the tails show a disorganized mitochondrial sheath.
- >-
Break site matters for ICSI: sperm from the SUN5 break subtype gave better
ICSI outcomes than other subtypes.
evidence:
- reference: PMID:32104701
reference_title: "Beyond Acephalic Spermatozoa: The Complexity of Intracytoplasmic Sperm Injection Outcomes."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "the breakage of TSGA10 associated with AS sperms is located between the distal centriole and the midpiece"
explanation: Review placing the TSGA10 break at a different site from SUN5.
- reference: PMID:32104701
reference_title: "Beyond Acephalic Spermatozoa: The Complexity of Intracytoplasmic Sperm Injection Outcomes."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Interestingly, all AS sperm of subtype II achieved better ICSI outcomes than other subtypes, resulting in clinical pregnancies and live births."
explanation: The SUN5 subtype has the better ICSI outcomes.
- name: PMFBP1-related acephalic spermatozoa (SPGF31)
disease_term:
preferred_term: spermatogenic failure 31
term:
id: MONDO:0020852
label: spermatogenic failure 31
distinguishing_features:
- >-
Clinically indistinguishable from SPGF16 and in the same ultrastructural
subtype; genetic testing separates them. In knockout mice the two proteins
end up on opposite fragments: without SUN5 the tail-side partners stay on
the decapitated tail, while without PMFBP1 SUN5 stays on the detached head.
evidence:
- reference: PMID:34389728
reference_title: "The missing linker between SUN5 and PMFBP1 in sperm head-tail coupling apparatus."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We show that lack of Sun5 results in CENTLEIN and PMFBP1 left in the decapitated tail, while disruption of Pmfbp1 results in SUN5 and CENTLEIN left on the detached sperm head."
explanation: SUN5 and PMFBP1 act on opposite sides of the coupling apparatus.
- reference: PMID:32104701
reference_title: "Beyond Acephalic Spermatozoa: The Complexity of Intracytoplasmic Sperm Injection Outcomes."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Based on electron microscopic observations, broken points of the sperm neck are AS defects that are based on various genes that can be classified into three subtypes: HOOK1, SUN5, and PMFBP1 genes of subtype II"
explanation: SUN5 and PMFBP1 share an ultrastructural subtype.
treatments:
- name: Intracytoplasmic Sperm Injection
description: >-
ICSI with the detached heads or the rare intact sperm is the only route to
biological paternity. A retrospective cohort reported high fertilization,
good embryo quality and pregnancy in all five treated SUN5 patients, and
healthy children have been born; one later family had two failed cycles.
therapeutic_modality: OTHER
treatment_term:
preferred_term: intracytoplasmic sperm injection
term:
id: NCIT:C185482
label: Intracytoplasmic Sperm Injection
target_mechanisms:
- target: Acephalic spermatozoa
description: Injecting a detached head into the oocyte bypasses the need for an intact sperm.
evidence:
- reference: PMID:29329387
reference_title: "Patients with acephalic spermatozoa syndrome linked to SUN5 mutations have a favorable pregnancy outcome from ICSI."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The rates of fertilization, good-quality embryos and pregnancy for five patients with SUN5 mutations following ICSI were 81.5%, 81.8% and 100%, respectively."
explanation: Good ICSI outcomes in a SUN5 cohort.
- reference: PMID:28945193
reference_title: "Essential role for SUN5 in anchoring sperm head to the tail."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Finally, we found that healthy heterozygous offspring could be obtained via intracytoplasmic injection of Sun5-mutated sperm heads for both male mice and patients."
explanation: Healthy offspring from ICSI with SUN5-mutant sperm heads in patients.
- reference: PMID:33671757
reference_title: "Identification and Characterization of the Most Common Genetic Variant Responsible for Acephalic Spermatozoa Syndrome in Men Originating from North Africa."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "FISH did not highlight a higher rate of chromosome aneuploidy in spermatozoa from SUN5 patients compared to controls, indicating that intra-cytoplasmic sperm injection (ICSI) can be proposed for patients carrying the c.211+1_211+2dup variant."
explanation: No excess sperm aneuploidy, supporting ICSI.
- reference: PMID:40977202
reference_title: "Whole-exome sequencing reveals a novel mutation in the SUN5 gene causing acephalic spermatozoa syndrome."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "We conducted two intracytoplasmic sperm injections (ICSI) cycles for the proband, however, the treatment did not result in his partner achieving pregnancy."
explanation: ICSI did not succeed for one SUN5 patient.
- name: Genetic Counseling
description: >-
Counseling on autosomal recessive inheritance and on the share of
acephalic spermatozoa explained by SUN5, which differs between
populations.
therapeutic_modality: OTHER
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:29331481
reference_title: "Genetic contribution of SUN5 mutations to acephalic spermatozoa in Fujian China."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These results will help in the genetic counseling of patients with acephalic spermatozoa."
explanation: Authors note the relevance of SUN5 frequency estimates for counseling.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Create: Spermatogenic_Failure_16 · 2026-10-31T04:30:53Z · View source
New entry for spermatogenic failure 16 (MONDO:0014961, OMIM 617187), curated from stub Spermatogenic_Failure_16 as a DISEASE: a single-gene Mendelian disorder with its own MONDO and OMIM records. Gene identity: MONDO's causal-gene restriction, its OMIM xref and every primary report name SUN5 (hgnc:16252, looked up in HGNC REST). The disease is SUN5-related acephalic spermatozoa syndrome, not SPATA16 globozoospermia, which is a different spermatogenic failure number. The name was kept as the MONDO label because no gene-related name is established (entry-naming procedure step 7). Deep research: one openscientist report (research/Spermatogenic_Failure_16-deep-research-openscientist.md) completed on the first run. Its 16 references all resolved; 4 of 13 quotes did not match their cited abstracts and several suggested NCIT and HP CURIEs were mislabelled, so no quote or CURIE was copied from it. just preflight-dr returned PASS (SUN5 named 100 times, OMIM 617187 matches). The report was used as a cross-check; the entry was built from PubMed abstracts and PMC full texts fetched with just fetch-reference. Content: four pathophysiology nodes (Loss of SUN5 Protein, Disrupted SUN5 Nuclear Envelope Anchoring Complex, Defective Sperm Head-Tail Coupling, Impaired Germ Cell Nuclear mRNA Export) with edge-level evidence; three phenotypes (male infertility, acephalic spermatozoa, abnormal sperm neck morphology); SUN5 genetics with case fractions from three cohorts; the Sun5 knockout mouse; diagnosis, differential diagnosis against SPGF26 (TSGA10) and SPGF31 (PMFBP1); ICSI and genetic counseling. The node name Defective Sperm Head-Tail Coupling matches Spermatogenic_Failure_26. No mechanism module covers the head-tail coupling apparatus, so no conforms_to was declared. The mRNA export node is mouse-only and has no phenotype edge. MONDO's text definition calls this disease an azoospermia; patients make spermatozoa, so this is recorded in notes as a candidate upstream correction. No GeneReviews chapter (just check-genereviews --online: NO_CHAPTER) and no ClinGen assertion for SUN5. Validation: just validate, just validate-terms, just count-verified-snippets (54/54) and just validate-disorders all passed, as did the offline whole-repo gates and just check-snippet-grading.
Disease: Spermatogenic Failure 16 (SPGF16) · Causal gene: SUN5 (SPAG4L / TSARG4) OMIM: 617187 · MONDO: MONDO:0014961 · HGNC: HGNC:16252 · Category: Mendelian (autosomal recessive)
Spermatogenic Failure 16 (SPGF16) is a non-syndromic, autosomal-recessive form of male infertility caused by biallelic loss-of-function variants in SUN5 (also named SPAG4L or TSARG4), a testis-specific inner-nuclear-membrane LINC-complex protein. SPGF16 is the molecular-genetic designation for the most common genetic subtype of acephalic spermatozoa syndrome (ASS) — a severe teratozoospermia in which the ejaculate is dominated by headless ("decapitated") sperm tails, detached heads, and sperm whose heads and tails are joined by a fragile, abnormal junction. SUN5 mutations are reported in roughly 33–47% of ASS cases, making it the single most frequently identified cause of the syndrome.
Mechanistically, SUN5 is a SUN-domain protein that localizes to the base of the sperm head (the head–tail coupling apparatus, HTCA). It physically bridges the sperm nucleus to the proximal centriole/flagellum: its nucleoplasmic side binds the nuclear-membrane protein LaminB1, while its other side binds the cytoskeletal GTPase Septin12 and cooperates with CENTLEIN and PMFBP1. In situ cryo-electron tomography shows SUN5 forms an extensive hexagonal protein lattice in the nuclear envelope at this junction. When SUN5 is absent, the Septin12-associated proximal centriole separates from the nucleus, the head–tail junction fails, and sperm heads detach from their tails during spermiogenesis or ejaculation — producing the acephalic phenotype. Sun5-knockout mice recapitulate the human disease, confirming a conserved, autosomal-recessive mechanism.
Clinically, SPGF16 presents as isolated primary male infertility. Affected men have normal virilization, normal testicular volume, and normal endocrine function; there are no systemic or syndromic features. Diagnosis rests on semen analysis and sperm morphology (H&E staining, transmission electron microscopy showing head–tail junction defects) confirmed by SUN5 sequencing (WES/Sanger) and absent SUN5 protein on immunofluorescence/Western blot. Because the defect is purely structural and the detached heads frequently contain intact genetic material, intracytoplasmic sperm injection (ICSI) is an effective treatment, with reported fertilization, embryo, and pregnancy rates that are favorable (one cohort: 81.5% fertilization, 81.8% good-quality embryos, 100% pregnancy among SUN5 patients). This report synthesizes 8 confirmed findings across 26 reviewed papers into a complete, section-by-section knowledge-base entry.
Overview. SPGF16 is a Mendelian, autosomal-recessive male infertility disorder. It is the genetic-nomenclature label (OMIM phenotype series "Spermatogenic failure") for SUN5-related acephalic spermatozoa syndrome (ASS), a rare and severe teratozoospermia defined by a predominance of headless spermatozoa in the ejaculate. ASS is described as "a severe teratospermia with decaudated, decapitated, and malformed sperm, resulting in male infertility" (PMID: 38870534).
Key identifiers.
| Resource | Identifier |
|---|---|
| OMIM (phenotype) | 617187 (Spermatogenic failure 16) |
| MONDO | MONDO:0014961 |
| Causal gene | SUN5 (HGNC:16252; NCBI Gene 140732; Ensembl ENSG00000167098; UniProt Q8TC36) |
| Gene OMIM | SUN5 613942 |
| ICD-10 | N46 (male infertility) — no SPGF16-specific code |
| ICD-11 | GB04 (male infertility) — no specific code |
| MeSH | Closest: "Infertility, Male"; "Teratozoospermia" |
Synonyms: spermatogenic failure 16; SPGF16; spermatogenic failure type 16; SUN5 azoospermia; azoospermia caused by mutation in SUN5; SUN5-related acephalic spermatozoa syndrome; acephalic spermatozoa syndrome (ASS, when SUN5-caused); headless spermatozoa.
Information source. The knowledge base here is derived from aggregated disease-level resources (OMIM, MONDO, gnomAD) plus individual-patient case reports and small cohort studies (WES-based gene discovery and ICSI outcome cohorts, predominantly from China). There is no large EHR-derived dataset; the evidence is primarily case-level clinical/genetic literature plus mouse models.
Primary cause — genetic. SPGF16 is caused by biallelic (homozygous or compound-heterozygous) loss-of-function variants in SUN5. The landmark discovery study performed "whole-exome sequencing in two unrelated infertile men and subsequent variant filtering identified one homozygous (c.824C>T [p.Thr275Met]) and one compound heterozygous (c.1006C>T [p.Arg356Cys] and c.485T>A [p.Met162Lys]) SUN5 (also named TSARG4) variants" (PMID: 27640305). SUN5 is the most frequently identified ASS cause: "Mutations in the SUN5 gene have been identified most frequently (33-47%) in ASS cases" (PMID: 38870534).
Genetic risk factors. The only established risk factor is inheritance of two pathogenic SUN5 alleles. Consanguinity increases the risk of homozygosity — multiple reported cases arise from consanguineous or first-cousin unions (e.g., two infertile brothers of first-cousin parents, PMID: 40977202). No susceptibility loci or validated modifier genes have been established for SPGF16 specifically.
Environmental risk factors. None established. SPGF16 is a monogenic structural sperm defect; it is not attributable to toxins, lifestyle, occupational exposure, age, or infection. These classic male-infertility risk factors are not implicated in this Mendelian subtype.
Protective factors. None identified. Heterozygous carriers are fertile (recessive inheritance); a single wild-type allele is "protective" in the Mendelian sense, but there are no described protective variants or environmental protective factors.
Gene–environment interactions. No gene–environment interaction has been documented for SPGF16. The phenotype is driven by the genotype essentially deterministically (high penetrance in biallelic LoF).
SPGF16 is non-syndromic: the phenotype is confined to the reproductive system. Affected men present with primary infertility and otherwise normal health.
| Phenotype | Type | HPO term (suggested) | Characteristics |
|---|---|---|---|
| Male infertility | Clinical sign | HP:0003251 (Male infertility) | Post-pubertal/congenital onset; severe; stable; ~100% of affected men |
| Acephalic/headless spermatozoa | Laboratory (semen) abnormality | HP:0012874 (Abnormal sperm morphology) / teratozoospermia | Predominant finding; severe |
| Abnormal sperm head–tail junction | Laboratory abnormality | HP:0012874 | Fragile junction in the minority of "intact" sperm |
| Asthenozoospermia / abnormal motility | Laboratory abnormality | HP:0008669 (Abnormal spermatogenesis) | Detached tails may retain motility; whole-sperm motility impaired |
| Normal external genitalia / testicular volume | Normal finding (exclusionary) | — | Documented normal exam |
| Normal endocrine/hormonal profile | Normal finding | — | FSH/LH/testosterone typically normal |
Clinical documentation: "Male external genitalia developed normally, bilateral testicles were normal in volume, and bilateral epididymis and spermatic vein were palpated without nodules, cysts, and tenderness. Repeated semen analysis showed that a large number of immature sperm could be seen, and they had the ability to move" (PMID: 34393249). The core teratozoospermia is "decaudated, decapitated, and malformed sperm" (PMID: 38870534).
Onset / severity / progression / frequency. Onset is effectively congenital at the cellular level but manifests post-pubertally as infertility when reproduction is attempted. Severity is high (near-absolute natural infertility). The condition is stable and non-progressive — it does not worsen over time nor cause systemic morbidity. Frequency of the acephalic phenotype among affected men approaches 100% of sperm being abnormal.
Quality-of-life impact. The impact is confined to reproductive function and its psychosocial consequences (infertility-related distress, family planning burden). There is no physical disability, pain, or reduced life expectancy. No disease-specific QoL instrument (EQ-5D/SF-36) data exist for SPGF16; impact is inferred from the general infertility literature.
Causal gene. SUN5 (Sad1 and UNC84 domain containing 5), aliases SPAG4L and TSARG4. HGNC:16252; NCBI Gene 140732; Ensembl ENSG00000167098; chromosome 20q11.21 (GRCh38 chr20:32,983,773–33,004,433); 13 exons; 377-amino-acid protein (UniProt Q8TC36); reference transcript NM_080675. SUN5 encodes a testis-specific SUN-domain nuclear-envelope protein and a member of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex.
Pathogenic variant spectrum. Variants span missense, frameshift, nonsense, splice-site, and large structural deletions. Representative pathogenic alleles and their gnomAD v4 exome allele frequencies:
| Variant (cDNA) | Protein | Class | gnomAD v4 AF |
|---|---|---|---|
| c.381del | p.Val128SerfsTer7 | Frameshift (recurrent, most common) | 3.97×10⁻⁵ (AC 58) |
| c.824C>T | p.Thr275Met | Missense | 1.78×10⁻⁵ |
| c.1066C>T | p.Arg356Cys | Missense | 1.73×10⁻⁵ |
| c.1067G>A | p.Arg356His | Missense | 8.3×10⁻⁶ |
| c.1043A>T | p.Asn348Ile | Missense | 1.87×10⁻⁵ |
| c.775G>A | p.Gly259Ser | Missense | 5.5×10⁻⁶ |
| c.340G>A | p.Gly114Arg | Missense | 2.7×10⁻⁶ |
| c.1072C>T | p.Arg358Ter | Nonsense | 6.9×10⁻⁶ |
| c.485T>A | p.Met162Lys | Missense | — |
| c.1006C>T | p.Arg356Cys | Missense | — |
| c.829C>T | p.Gln277* | Nonsense | — |
| c.211+1insGT | splice | Splice-site | — |
| c.879dupC | p.(fs) | Frameshift | — |
| c.1073G>A | p.Arg358Gln | Missense | — |
| Large deletion (partial EFCAB8/BPIFB2 + complete SUN5) | — | Structural (CNV) | — |
The structural deletion was reported alongside a novel missense allele: "one novel homozygous missense mutation (c.775G>A; p.G259S) and one compound heterozygous including one reported missense mutation (c.1043A>T; p.N348I) and a large deletion that contains partial EFCAB8 … and BPIFB2 … and complete SUN5 (NM_080675)" (PMID: 34159570). Additional alleles include the homozygous c.879dupC frameshift (PMID: 40977202) and homozygous c.1073G>A (p.Arg358Gln) (PMID: 40740627).
Variant classification (ACMG/AMP). Pathogenic/likely pathogenic for biallelic LoF and recurrent hotspot missense alleles (notably codon 356/358). Classification criteria typically invoked: PVS1 (null variants), PM2_Supporting (rare in gnomAD), PP4 (phenotype match), PM3 (recessive, in trans), and functional evidence (absent sperm SUN5).
Allele frequency / origin. All pathogenic alleles are rare germline variants at carrier-level frequencies (AF ≤ ~4×10⁻⁵). None are somatic. The recurrent frameshift c.381del is the most common.
Functional consequence. Loss of function — mutations abolish or destabilize SUN5 protein, eliminating the nucleus-to-flagellum anchor. Patient sperm show absent SUN5 on immunostaining/Western blot.
Constraint. gnomAD v4 shows SUN5 is LoF-tolerant (pLI ≈ 0; observed/expected LoF = 0.82; LOEUF = 1.05; mis_z = 0.98; lof_z = 1.13). There is no depletion of heterozygous LoF alleles — exactly as expected for a gene whose only essential function is in recessive male fertility (gnomAD v4; context in PMID: 34159570).
Modifier genes / epigenetics / chromosomal abnormalities. No validated modifier genes. No disease-specific epigenetic mechanism described (SUN5 participates in nuclear mRNA recruitment/export in spermatogenesis, PMID: 39108207, but this is a normal function, not an epigenetic disease mechanism). The only "chromosomal abnormality" relevant is the large CNV deletion encompassing SUN5 noted above.
Environmental factors: None established. SPGF16 is a monogenic disorder; toxins, radiation, and pollution are not applicable. Lifestyle factors: None established (smoking, diet, alcohol are not causal for this Mendelian subtype). Infectious agents: Not applicable — no infectious trigger.
This section is essentially negative: SPGF16 is a purely genetic, structural sperm defect.
Branch (downstream network): SUN5 acts within a multi-protein HTCA scaffold. The adaptor CENTLEIN links SUN5 to PMFBP1; in its absence "the absence of Centlein sets SUN5 and PMFBP1 apart, the former close to the sperm head and the latter in the decapitated tail" (PMID: 34389728). Other HTCA partners — CCDC113, CCDC188, CEP250, TSGA10, SPATA20, SPATC1L, BRDT, and ZMYND15 (which interacts directly with SUN5) — cause overlapping ASS phenotypes when mutated, placing SUN5 at the hub of head–tail anchoring.
Clinical / laboratory workup: - Semen analysis + sperm morphology (H&E staining): predominance of headless tails, detached heads, and malformed sperm; "a large number of immature sperm… they had the ability to move" (PMID: 34393249). - Transmission electron microscopy (TEM): demonstrates head–tail junction/HTCA defects and abnormal neck structures. - Hormonal panel: FSH, LH, testosterone — typically normal, distinguishing from hypogonadotropic/primary testicular failure. - Physical exam / scrotal ultrasound: normal testicular volume, no varicocele/obstruction. - Immunofluorescence / Western blot: absent SUN5 in spermatozoa confirms the molecular defect.
Genetic testing: - Single-gene / panel testing of SUN5 is first-line given its dominant contribution; targeted Sanger confirmation of candidate variants. - Whole-exome sequencing (WES) is the workhorse for discovery and for cases negative on SUN5 (to assess PMFBP1, TSGA10, CEP250, CCDC188, CCDC113, SPATA20, SPATC1L, BRDT, ZMYND15). - CMA / CNV analysis is warranted because large deletions encompassing SUN5 occur (PMID: 34159570). - Karyotyping/FISH/mtDNA/repeat-expansion testing: not specifically indicated for SPGF16 (karyotype normal in typical cases; useful to exclude other azoospermia causes).
Clinical criteria / differential diagnosis: Diagnosis = morphological ASS + biallelic SUN5. Differential includes other ASS genes (PMFBP1, TSGA10, CEP250, CCDC188, CCDC113, etc.), globozoospermia (DPY19L2 — round-headed, acrosome defect), MMAF, and obstructive/non-obstructive azoospermia. SUN5 is distinguished by its specific role at the head–tail junction (not the acrosome; PMID: 25775128) and its favorable ICSI prognosis.
Screening: No population newborn/carrier screening exists. Cascade carrier testing of relatives and partner carrier testing are reasonable once a proband's variants are known.
There is no pharmacological cure; management is reproductive, centered on ICSI.
| Intervention | Role in SPGF16 | NCIT (suggested) | Evidence |
|---|---|---|---|
| Intracytoplasmic sperm injection (ICSI) | First-line; bypasses the structural defect by injecting a sperm head (or intact sperm) directly into the oocyte | NCIT:C92531 (Intracytoplasmic Sperm Injection) | Favorable outcomes (PMID: 29329387) |
| IVF with ICSI (ART) | Framework for ICSI | NCIT:C19829 (In Vitro Fertilization) | — |
| Genetic counseling | Inform recurrence risk, carrier/partner testing | NCIT:C15417 (Genetic Counseling) | — |
| Preimplantation genetic testing (optional) | Consider when both partners carry risk alleles | — | — |
Pharmacotherapy / pharmacogenomics: Not applicable. Gene/cell/RNA therapies: None clinical; purely conceptual (the defect is germ-cell structural and not currently a gene-therapy target). Surgical: Sperm retrieval is generally unnecessary because sperm are present in the ejaculate (the problem is morphology, not count/azoospermia); standard ejaculate sperm are used for ICSI. Experimental: No SPGF16-specific registered trials identified.
Treatment outcome nuance: Because the detached head usually retains an intact nucleus, injecting it supports fertilization; however, selecting a sperm/head with an intact centriolar/genetic complement matters — mis-injection of a head plus detached tail produced fertilization failure in a related CCDC188 case (PMID: 41004021), underscoring the importance of gene-specific prognosis.
Biallelic LoF in SUN5 (missense/frameshift/nonsense/splice/CNV)
│ (loss of testis-specific SUN-domain protein)
▼
No SUN5 at sperm-head base ──► Hexagonal NE lattice & HTCA fail to assemble
│ (cryo-ET; PMID 41855266)
▼
LaminB1 — SUN5 — Septin12 bridge disrupted
│ ├── CENTLEIN/PMFBP1 mis-sorted (PMID 34389728)
▼ └── CCDC113/CCDC188/CEP250/ZMYND15 network destabilized
Septin12–proximal centriole separates from nucleus (PMID 38870534)
▼
Head-to-tail junction breaks
▼
Acephalic (headless) spermatozoa + detached heads in ejaculate
▼
Primary male infertility ──► rescued by ICSI (favorable outcomes; PMID 29329387)
Upstream vs downstream: The initiating lesion (upstream) is the SUN5 mutation; the most proximal molecular consequence is failure of the nuclear-envelope LINC bridge; downstream are the structural head–tail breakage and the clinical infertility. SUN5 is a hub — many ASS genes converge on the same HTCA, so SUN5 loss both directly breaks the bridge and indirectly mislocalizes partner proteins.
| PMID | Title (abbrev.) | Role |
|---|---|---|
| 27640305 | Biallelic SUN5 Mutations Cause Autosomal-Recessive Acephalic Spermatozoa Syndrome | Landmark — establishes SUN5 causality; original variants |
| 38870534 | SUN5 interacts with LaminB1 and Septin12… | Core mechanism; 33–47% ASS; KO mouse ASS |
| 41855266 | SUN5 forms a regular protein lattice… | Cryo-ET hexagonal lattice; cross-species localization |
| 34389728 | The missing linker between SUN5 and PMFBP1… | Places SUN5 in HTCA (CENTLEIN/PMFBP1) |
| 25775128 | Dynamics of Sun5 localization… | Dynamic relocalization; excluded from acrosome |
| 28945193 | Essential role for SUN5 in anchoring sperm head to the tail | Foundational KO mouse |
| 29329387 | …SUN5 mutations have a favorable pregnancy outcome from ICSI | Treatment outcome data |
| 34159570 | Novel Mutation and Deletion in SUN5… | Structural deletion; LoF-tolerant constraint |
| 34393249 | Genetic analysis of three ASS cases… | Clinical exam/semen findings |
| 39108207 | SUN5… recruitment/export of nuclear mRNA | Additional SUN5 function |
| 40977202, 40740627 | Novel SUN5 variants (c.879dupC; c.1073G>A) | Expand variant spectrum; variable ICSI outcome |
| 42522282, 39671309, 41004021, 39726222 | ZMYND15/CCDC113/CCDC188/CEP250 ASS genes | Context: SUN5 as HTCA hub; differential genes |
Consistency: All primary sources converge — SUN5 is the most common ASS gene, acts at the head–tail junction, is conserved in mouse models, and is ICSI-amenable. The principal nuance is variable ICSI success (most cohorts favorable; occasional failures), suggesting additional factors (e.g., centriole/genetic integrity of the injected head) modulate outcome.
Report compiled from 8 confirmed findings across 26 reviewed primary and secondary sources. Evidence types: human clinical/genetic (case reports, WES cohorts, ICSI outcome studies), model organism (Sun5-KO mouse), in vitro (co-IP/IF/WB), and structural/computational (cryo-ET, gnomAD constraint).
Checked with linkml-reference-validator 0.4.0.
| Outcome | Count |
|---|---|
| References checked | 16 |
| Resolved | 16 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 13 |
| Quoted claims found in source | 9 |
| Quoted claims not found in source | 4 |
| References weighed for topical relevance | 16 |
| On topic | 16 |
| Off topic | 0 |
Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:
Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.
PMID:27640305 (abstract only): "whole-exome sequencing in two unrelated infertile men and subsequent variant filtering identified one homozygous (c.824C>T [p.Thr275Met]) and one compound heterozygous (c.1006C>T [p.Arg356Cys] and c.485T>A [p.Met162Lys]) SUN5 (also named TSARG4) variants"PMID:34159570 (abstract only): "one novel homozygous missense mutation (c.775G>A; p.G259S) and one compound heterozygous including one reported missense mutation (c.1043A>T; p.N348I) and a large deletion that contains partial EFCAB8 … and BPIFB2 … and complete SUN5 (NM_080675)"PMID:25775128 (abstract only): "In pachytene spermatocytes, it is located in a membranous compartment… In round spermatids, it progresses to the Golgi and the NE before to be located to the tail/head junction in epididymal sperm… Sun5 is not, as initially reported, facing the acrosome but is in fact excluded from this zone"PMID:34393249 (abstract only): "a large number of immature sperm… they had the ability to move"Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 24 |
| Resolved | 22 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 2 |
| Terms whose name was checked | 9 |
| Terms named correctly | 2 |
| Terms named as a different term | 4 |
| Terms whose name is worth a second look | 3 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0014961 (2 mentions) - the report calls it "MONDO"; MONDO calls it spermatogenic failure 16HP:0012874 (2 mentions) - the report calls it "Abnormal sperm morphology", "Laboratory abnormality"; HP calls it Abnormal male reproductive system physiologyNCIT:C92531 (1 mention) - the report calls it "Intracytoplasmic Sperm Injection"; NCIT calls it ARID1A wt AlleleNCIT:C15417 (2 mentions) - the report calls it "Genetic Counseling"; NCIT calls it Randomized Clinical TrialThe report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
GO:0005637 (3 mentions) - the report calls it "nuclear envelope / inner nuclear membrane"; GO calls it nuclear inner membraneGO:0034993 (1 mention) - the report calls it "SUN–KASH / LINC"; GO calls it meiotic nuclear membrane microtubule tethering complex, and lists "SUN-KASH complex" among its other namesUBERON:0000079 (1 mention) - the report calls it "Body system: Male reproductive system"; UBERON calls it male reproductive system**The report gives these identifiers more than one name of its own:
HP:0012874 - called "Abnormal sperm morphology", "Laboratory abnormality"Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: MGI.