Spermatogenic Failure 95

👪

Inheritance

1

Autosomal recessive HP:0000007

Homozygous truncating variants segregate with infertility in consanguineous families, and a compound heterozygous proband inherited one missense variant from each parent.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:36752199 SUPPORT Human clinical

"Subsequent Sanger sequencing of all the available family members demonstrated that CFAP57 mutations were recessively segregated with the MMAF phenotype in all the family members"

Recessive segregation in three families.

PMID:41466333 SUPPORT Human clinical

"A second patient (P2) harbored a rare compound heterozygous mutation in CFAP57, with c.1340T > C (p.V447A) inherited from the father and c.1856G > A (p.R619H) from the mother"

Compound heterozygous proband with one variant from each parent.

◈

Mechanistic Hypotheses

1

Truncations confined to the long CFAP57 isoform cause isolated MMAF, while variants affecting both isoforms can cause primary ciliary dyskinesia

cfap57_isoform_specificity EMERGING

Evidence balance 5 support 2 refute

The long isoform (1,250 aa) is required in sperm; the short isoform (698 aa), which retains most WD repeats, is expressed in testis and nasal epithelium and is proposed to sustain respiratory cilia. All reported MMAF nonsense variants lie in the long-isoform-specific region, and the men carrying them have had no PCD. The one CFAP57 PCD patient carries a variant in exon 11, shared by both isoforms, and his fertility was not reported. Two points do not fit cleanly. A compound heterozygous MMAF proband carries missense variants (p.V447A, p.R619H) in the region shared with the short isoform, yet clinical evaluation found no evidence of PCD; the authors read this as selective impairment of the long isoform, which would mean that a variant's position in the shared region does not by itself predict loss of short-isoform function, and that missense changes may spare the short isoform where the exon 11 skip in the PCD patient does not. Separately, one Pakistani proband reported occasional breathing difficulty but was not examined.

Show evidence (7 references)

PMID:36752199 SUPPORT Human clinical

"In this study, we recruited 3 unrelated consanguineous Pakistani families with multiple MMAF-affected individuals, who had no overt ciliary symptoms."

Long-isoform truncations without ciliary disease.

PMID:41793497 SUPPORT Human clinical

"Notably, the patient exhibited no signs of primary ciliary dyskinesia (PCD), suggesting that the mutation selectively affects the sperm-specific isoform of CFAP57."

A further long-isoform nonsense proband without PCD.

PMID:32764743 SUPPORT Human clinical

"Interestingly, the variant results in the skipping of exon 11 (58 amino acids), which may be due to disruption of an exonic splicing enhancer."

The PCD allele lies in exon 11, within the region shared by both isoforms, consistent with respiratory disease requiring loss of the short isoform as well.

+ 4 more references

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Pathophysiology

4

Loss of Long-Isoform CFAP57 from the Sperm Flagellum

Nonsense variants in the long-isoform-specific region (p.R913*, p.R958*, p.R1075*, p.R1084X) abolish CFAP57 from patient sperm while leaving the short isoform intact. CFAP57 binds the double-headed IDA heavy chain DNAH10 and acts as a docking factor for IDAs.

CFAP57 hgnc:26485

dynein heavy chain binding (inner dynein arm docking) GO:0045504 ↓ DECREASED

Downstream

Inner Dynein Arm Assembly Failure in the Sperm Axoneme IDA proteins are synthesized normally in mutant testes but are not assembled onto sperm flagella.

Mislocalization of MYH10 and IFT88 in the Sperm Flagellum CFAP57 binds MYH10 and is needed for its distribution along the flagellum.

Show evidence (3 references)

PMID:36752199 SUPPORT Human clinical

"Thus, the CFAP57 mutation M2 caused a total loss of CFAP57 in sperm flagella from P7."

Protein loss in patient sperm.

PMID:36752199 SUPPORT Human clinical

"The M1 and M2 we identified only affect the long isoform of CFAP57 (NM_001195831.2) (Supplemental Figure 3A)."

The MMAF alleles are confined to the long isoform.

PMID:40898283 SUPPORT In vitro / ex vivo

"Co-IP experiment confirmed that DNAH10 can interact with CFAP57, DYNLL1, and CCDC73."

Co-immunoprecipitation from mouse lung tissue shows CFAP57 binds the IDA heavy chain DNAH10, grounding the dynein heavy chain binding function.

Inner Dynein Arm Assembly Failure in the Sperm Axoneme

Patient sperm lack IDAs while outer dynein arms remain. In mutant mice the single-headed IDA markers DNAH6 and DNALI1 are lost or reduced to a few foci, while the double-headed IDA heavy chain DNAH10 and ODA proteins are still present in a discontinuous pattern.

Inner dynein arm assembly GO:0036159 ↓ DECREASED

Inner dynein arm GO:0036156

Animal models

Cfap57 p.R958* equivalent mouse Mouse recapitulates Reproduces the IDA assembly defect seen in patient sperm.

Downstream

Multiple Morphological Abnormalities of the Sperm Flagella Loss of IDAs removes motility; how it also produces the flagellar malformations is not established, and patients can keep an intact 9+2 axoneme.

Abnormal sperm axoneme morphology

Show evidence (2 references)

PMID:36752199 SUPPORT Human clinical

"Detailed analysis of dynein arms revealed that the IDAs were absent, while ODAs were identifiable in the patient (Figure 4A)."

IDA loss by TEM in patient sperm.

PMID:36752199 SUPPORT Model organism

"Overall, our results suggested that CFAP57 played an essential role particularly in single-headed IDA assembly (Supplemental Figure 7)."

In mutant mice, single-headed IDAs are the most affected.

Mislocalization of MYH10 and IFT88 in the Sperm Flagellum

CFAP57 interacts with the non-muscle myosin MYH10. In patient sperm MYH10 is confined to the midpiece and missing from the principal and end pieces, and the intraflagellar transport protein IFT88 is also affected, suggesting impaired intraflagellar transport during flagellogenesis.

Sperm CL:0000019

Downstream

Multiple Morphological Abnormalities of the Sperm Flagella Proposed to impair flagellar assembly through disrupted intraflagellar transport.

Show evidence (1 reference)

PMID:41466333 SUPPORT Human clinical

"This mislocalization affected the expression of IFT88, a key component of the intraflagellar transport (IFT) system that plays a critical role in mammalian flagellar assembly."

IFT88 is affected secondarily to MYH10 mislocalization.

Multiple Morphological Abnormalities of the Sperm Flagella

Short, absent, coiled, bent and irregular-caliber flagella with reduced progressive motility. Ultrastructure varies between reports: an intact 9+2 axoneme lacking IDAs in one Pakistani proband, but loss of the central pair and radial spokes with displaced doublets and disorganized mitochondria in a Chinese proband.

Sperm CL:0000019

Sperm flagellum assembly GO:0120316 ↓ DECREASED

Animal models

Cfap57 p.R958* equivalent mouse Mouse partially recapitulates MMAF is reproduced, with a more severe axonemal and sperm-count defect than in patients.

Downstream

Reduced sperm motility

Male infertility Malformed, poorly motile sperm cannot reach or fertilize the oocyte in vivo.

Short sperm flagella

Absent sperm flagella

Coiled sperm flagella

Bent sperm flagella

Irregularly shaped sperm tail

Show evidence (2 references)

PMID:36752199 SUPPORT Human clinical

"the results revealed that most spermatozoa from the 2 individuals had malformed flagella, including absent, short, coiled, bent, and irregular caliber, which are typical characteristics of MMAF"

MMAF in two Pakistani probands.

PMID:41466333 SUPPORT Human clinical

"The tail exhibited characteristic MMAF phenotypes, including coiled, bent, irregular, short or/and absent flagella (Fig. 2A)."

MMAF in a Chinese proband.

⬡

Pathograph

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Phenotypes

9

Male infertility Reproductive HP:0003251

Show evidence (1 reference)

PMID:36752199 SUPPORT Human clinical

"Despite having regular unprotected sexual intercourse for at least 8 years, all of these individuals experienced infertility."

Infertility in seven affected brothers.

Reduced sperm motility Reproductive HP:0012207

Show evidence (2 references)

PMID:41466333 SUPPORT Human clinical

"The semen characteristics from P1 and P2 was analyzed by routine clinical tests, and the results revealed that the sperm motility was significantly reduced, and most sperm were classified as immobile sperm (64.1%-79.3%) (Table 1)."

Reduced motility in two probands.

PMID:41793497 SUPPORT Human clinical

"Semen analysis showed that 63% of sperm were immotile and only 4% had normal morphology, consistent with an MMAF phenotype."

Reduced motility in the Emirati proband.

Short sperm flagella Reproductive HP:0032559

Show evidence (1 reference)

PMID:36752199 SUPPORT Human clinical

"the results revealed that most spermatozoa from the 2 individuals had malformed flagella, including absent, short, coiled, bent, and irregular caliber, which are typical characteristics of MMAF"

Short flagella in patient sperm.

Absent sperm flagella Reproductive HP:0032558

Show evidence (1 reference)

PMID:41466333 SUPPORT Human clinical

"The tail exhibited characteristic MMAF phenotypes, including coiled, bent, irregular, short or/and absent flagella (Fig. 2A)."

Absent flagella in patient sperm.

Coiled sperm flagella Reproductive HP:0032560

Show evidence (1 reference)

PMID:41466333 SUPPORT Human clinical

"The tail exhibited characteristic MMAF phenotypes, including coiled, bent, irregular, short or/and absent flagella (Fig. 2A)."

Coiled flagella in patient sperm.

Bent sperm flagella Reproductive HP:0034811

Show evidence (1 reference)

PMID:36752199 SUPPORT Human clinical

"the results revealed that most spermatozoa from the 2 individuals had malformed flagella, including absent, short, coiled, bent, and irregular caliber, which are typical characteristics of MMAF"

Bent flagella in patient sperm.

Irregularly shaped sperm tail Reproductive HP:0033393

Show evidence (1 reference)

PMID:36752199 SUPPORT Human clinical

"the results revealed that most spermatozoa from the 2 individuals had malformed flagella, including absent, short, coiled, bent, and irregular caliber, which are typical characteristics of MMAF"

Irregular-caliber flagella in patient sperm.

Abnormal sperm axoneme morphology Reproductive HP:0033524

Show evidence (2 references)

PMID:36752199 SUPPORT Human clinical

"Detailed analysis of dynein arms revealed that the IDAs were absent, while ODAs were identifiable in the patient (Figure 4A)."

IDA loss in a Pakistani proband.

PMID:41466333 SUPPORT Human clinical

"the sperm with the CFAP57 mutation displayed disorganization in mitochondrial assembly and haphazard “9 + 2” microtubules arrangement, for example, the CP and RS are absent, the doublet microtubule (DMT) was displacement (Fig. 2B)."

Central pair and radial spoke loss in a Chinese proband.

Abnormal sperm head morphology Reproductive HP:0012865

Show evidence (1 reference)

PMID:41466333 SUPPORT Human clinical

"In contrast, the sperm from P1 exhibited various morphological abnormalities, including irregular shapes such as indentation and conical forms in the heads."

Head defects in one proband.

🧬

Genetic Associations

1

CFAP57 (Causal)

Gene: CFAP57 hgnc:26485 gene page

Show evidence (3 references)

PMID:36752199 SUPPORT Human clinical

"Whole-exome sequencing and Sanger sequencing identified 2 cilia and flagella associated protein 57 (CFAP57) loss-of-function mutations (c.2872C>T, p. R958*; and c.2737C>T, p. R913*) recessively segregating with male infertility."

First families.

PMID:41466333 SUPPORT Human clinical

"Here, we report novel biallelic mutations in the CFAP57 gene identified in two infertile males from two unrelated families."

Two further probands.

PMID:41793497 SUPPORT Human clinical

"Sanger sequencing confirmed the segregation of the variant within the family; the proband was homozygous for the mutation, while both parents were heterozygous carriers."

A further homozygous proband with carrier parents.

💊

Medical Actions

2

Intracytoplasmic Sperm Injection

Action: Intracytoplasmic Sperm Injection NCIT:C185482

Platform: Other

ICSI bypasses the motility defect. One proband achieved a clinical pregnancy and delivery from a single cycle (11 of 14 oocytes fertilized, five blastocysts).

Mechanism Target:

Multiple Morphological Abnormalities of the Sperm Flagella — Direct injection makes flagellar propulsion irrelevant to fertilization.

Show evidence (1 reference)

PMID:41466333 SUPPORT Human clinical

"These results suggest that patients with MMAF resulting from CFAP57 variants can be effectively treated with ICSI."

ICSI circumvents the flagellar defect.

Show evidence (1 reference)

PMID:41466333 SUPPORT Human clinical

"After frozen-thawed embryo transfer (FET) of one high-quality blastocyst, a clinical pregnancy was achieved (Table 2)."

Clinical pregnancy after ICSI in one proband; the only reported outcome.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Counselling for autosomal recessive recurrence and carrier testing of relatives once the familial CFAP57 variants are known; the isoform location of the variant bears on whether respiratory involvement should be considered.

Show evidence (1 reference)

PMID:41793497 SUPPORT INDIRECT Human clinical

"Sanger sequencing confirmed the segregation of the variant within the family; the proband was homozygous for the mutation, while both parents were heterozygous carriers."

Carrier parents in a consanguineous family illustrate the recurrence and carrier-testing questions that counselling addresses.

🔬

Diagnosis

3

Molecular Genetic Testing

Establishes the diagnosis; probands were identified by whole-exome sequencing with Sanger confirmation. MMAF is genetically heterogeneous.

Genetic Testing NCIT:C15709

Show evidence (1 reference)

PMID:41793497 SUPPORT Human clinical

"WES revealed a novel homozygous nonsense mutation in CFAP57 (c.3223 C > T; p.Arg1075Ter), located within a large homozygous region on chromosome 1."

Exome sequencing identified the causal variant.

Semen Analysis

Shows asthenozoospermia with MMAF and usually normal sperm concentration.

Show evidence (1 reference)

PMID:41793497 SUPPORT Human clinical

"Semen analysis showed that 63% of sperm were immotile and only 4% had normal morphology, consistent with an MMAF phenotype."

Semen analysis findings.

Transmission Electron Microscopy of Sperm Flagella

Shows absent IDAs, sometimes with loss of the central pair and radial spokes.

Transmission Electron Microscopy NCIT:C18216

Show evidence (1 reference)

PMID:36752199 SUPPORT Human clinical

"Detailed analysis of dynein arms revealed that the IDAs were absent, while ODAs were identifiable in the patient (Figure 4A)."

TEM finding in patient sperm.

🐁

Animal Models

1

Cfap57 p.R958* equivalent mouse

Mice carrying a frameshift equivalent to the human p.R958* allele lose the long isoform and are infertile with immotile MMAF sperm and loss of single-headed IDAs; sperm number falls to about 5% of controls and the axoneme is disorganized in all sections.

Species

Mouse

Genotype

Cfap57 c.2865-2871del (p.Lys956Phefs*4), homozygous (Cfap57 M/M)

Publication

PMID:36752199

Pathograph links

Inner Dynein Arm Assembly Failure in the Sperm Axoneme recapitulates fidelity: high Reproduces the IDA assembly defect seen in patient sperm.

Show evidence (1 reference)

PMID:36752199 SUPPORT Model organism

"Subsequent examinations of the spermatozoa from Cfap57-mutant mice revealed that CFAP57 deficiency disrupted the inner dynein arm (IDA) assembly in sperm flagella and that single-headed IDAs were more likely to be affected."

IDA assembly failure in mutant mice.

Multiple Morphological Abnormalities of the Sperm Flagella partially recapitulates fidelity: moderate MMAF is reproduced, with a more severe axonemal and sperm-count defect than in patients.

Limitations: Mutant mice have severe oligozoospermia and fully disorganized axonemes, whereas patients usually have normal sperm counts and can keep an intact 9+2 axoneme.

Divergences from the human mechanism

species mismatch qualifying

The mouse sperm axoneme disintegrates after IDA loss and sperm output falls to about 5%, while in human sperm the 9+2 structure can survive without IDAs and concentration is usually normal; the mouse overstates the structural and count phenotype.

Show evidence (2 references)

PMID:36752199 SUPPORT Model organism

"Therefore, it is supposed that the integrity of the axoneme structure in mutant mouse sperm is more susceptible to IDA assembly failure than in humans."

Authors' statement of the species difference.

+ 1 more reference

{ }

Source YAML

click to show

name: Spermatogenic Failure 95
creation_date: "2026-10-16T00:00:00Z"
category: Mendelian
synonyms:
- SPGF95
- spermatogenic failure 95
- CFAP57-related multiple morphological abnormalities of the sperm flagella
description: >-
  Spermatogenic failure 95 (SPGF95) is autosomal recessive male infertility
  caused by biallelic variants in CFAP57, a WD-repeat axonemal protein that
  docks a subset of inner dynein arms (IDAs) onto the microtubule doublets.
  CFAP57 has a long and a short isoform; the truncating variants reported in
  infertile men lie in the region unique to the long isoform, which is the
  form required in sperm, and spare the short isoform that is thought to
  serve respiratory cilia. Loss of long-isoform CFAP57 prevents assembly of
  IDAs, especially the single-headed IDAs, in the sperm flagellum.

  Affected men have asthenozoospermia with multiple morphological
  abnormalities of the sperm flagella (MMAF): short, absent, coiled, bent and
  irregular-caliber flagella, with sperm concentration usually normal. Sperm
  ultrastructure ranges from an intact 9+2 axoneme lacking only the IDAs to
  loss of the central pair and radial spokes. Affected men have generally had
  no respiratory disease, unlike the single reported man with primary
  ciliary dyskinesia from a CFAP57 variant in a region shared by both
  isoforms. Intracytoplasmic sperm injection (ICSI) has produced a live birth.
disease_term:
  preferred_term: spermatogenic failure 95
  term:
    id: MONDO:0975747
    label: spermatogenic failure 95
parents:
- Spermatogenic Failure
- Genetic Disease
notes: >-
  MONDO cross-references the phenotype as OMIM 620917. ClinGen has not
  curated CFAP57 for this disease; its only CFAP57 curation is Limited
  (autosomal recessive) for primary ciliary dyskinesia, based on one proband
  (PMID:32764743), so no validity tier is recorded here. In the first
  families (PMID:36752199), seven infertile brothers in three consanguineous
  Pakistani families carried homozygous truncating variants; four had
  asthenozoospermia and one had azoospermia, and only two were examined for
  sperm morphology. Further probands are a Chinese homozygous nonsense case
  and a compound heterozygous missense case (PMID:41466333) and an Emirati
  homozygous nonsense case (PMID:41793497).
  No GeneReviews or StatPearls chapter covers this disorder.
inheritance:
- name: Autosomal recessive
  description: >-
    Homozygous truncating variants segregate with infertility in
    consanguineous families, and a compound heterozygous proband inherited
    one missense variant from each parent.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:36752199
    reference_title: "Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subsequent Sanger sequencing of all the available family members demonstrated that CFAP57 mutations were recessively segregated with the MMAF phenotype in all the family members"
    explanation: Recessive segregation in three families.
  - reference: PMID:41466333
    reference_title: "Mutations in CFAP57 disrupt the localization of MYH10 and IFT88, leading to flagellogenesis failure in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A second patient (P2) harbored a rare compound heterozygous mutation in CFAP57, with c.1340T > C (p.V447A) inherited from the father and c.1856G > A (p.R619H) from the mother"
    explanation: Compound heterozygous proband with one variant from each parent.
pathophysiology:
- name: Loss of Long-Isoform CFAP57 from the Sperm Flagellum
  description: >-
    Nonsense variants in the long-isoform-specific region (p.R913*, p.R958*,
    p.R1075*, p.R1084X) abolish CFAP57 from patient sperm while leaving the
    short isoform intact. CFAP57 binds the double-headed IDA heavy chain
    DNAH10 and acts as a docking factor for IDAs.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CFAP57
    term:
      id: hgnc:26485
      label: CFAP57
  molecular_functions:
  - preferred_term: dynein heavy chain binding (inner dynein arm docking)
    modifier: DECREASED
    term:
      id: GO:0045504
      label: dynein heavy chain binding
  downstream:
  - target: Inner Dynein Arm Assembly Failure in the Sperm Axoneme
    causal_link_type: DIRECT
    description: >-
      IDA proteins are synthesized normally in mutant testes but are not
      assembled onto sperm flagella.
    evidence:
    - reference: PMID:36752199
      reference_title: "Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Thus, we think that loss of long transcript-encoded CFAP57 protein interfered with the normal assembly of IDAs, resulting in the loss of IDAs in human and mouse sperm flagella."
      explanation: >-
        IDA proteins are made but not assembled when long-isoform CFAP57 is
        absent. The sentence covers human and mouse sperm, but the
        MODEL_ORGANISM grade rests on the mouse testis data showing IDA
        proteins synthesized normally yet absent from Cfap57 mutant flagella.
  - target: Mislocalization of MYH10 and IFT88 in the Sperm Flagellum
    causal_link_type: DIRECT
    description: CFAP57 binds MYH10 and is needed for its distribution along the flagellum.
    evidence:
    - reference: PMID:41466333
      reference_title: "Mutations in CFAP57 disrupt the localization of MYH10 and IFT88, leading to flagellogenesis failure in humans and mice."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In sperm with CFAP57 mutations, MYH10 was mislocalized to the mid-piece region while being notably absent from the principal and end pieces."
      explanation: MYH10 mislocalization in patient sperm.
  evidence:
  - reference: PMID:36752199
    reference_title: "Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus, the CFAP57 mutation M2 caused a total loss of CFAP57 in sperm flagella from P7."
    explanation: Protein loss in patient sperm.
  - reference: PMID:36752199
    reference_title: "Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The M1 and M2 we identified only affect the long isoform of CFAP57 (NM_001195831.2) (Supplemental Figure 3A)."
    explanation: The MMAF alleles are confined to the long isoform.
  - reference: PMID:40898283
    reference_title: "DNAH10 mutation cause primary ciliary dyskinesia with defects of IDAf complex assembly and lung fibrosis manifestation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Co-IP experiment confirmed that DNAH10 can interact with CFAP57, DYNLL1, and CCDC73."
    explanation: >-
      Co-immunoprecipitation from mouse lung tissue shows CFAP57 binds the
      IDA heavy chain DNAH10, grounding the dynein heavy chain binding
      function.
- name: Inner Dynein Arm Assembly Failure in the Sperm Axoneme
  description: >-
    Patient sperm lack IDAs while outer dynein arms remain. In mutant mice the
    single-headed IDA markers DNAH6 and DNALI1 are lost or reduced to a few
    foci, while the double-headed IDA heavy chain DNAH10 and ODA proteins
    are still present in a discontinuous pattern.
  biological_scale: MOLECULAR
  cellular_components:
  - preferred_term: Inner dynein arm
    term:
      id: GO:0036156
      label: inner dynein arm
  biological_processes:
  - preferred_term: Inner dynein arm assembly
    modifier: DECREASED
    term:
      id: GO:0036159
      label: inner dynein arm assembly
  downstream:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Loss of IDAs removes motility; how it also produces the flagellar
      malformations is not established, and patients can keep an intact 9+2
      axoneme.
  - target: Abnormal sperm axoneme morphology
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:36752199
    reference_title: "Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Detailed analysis of dynein arms revealed that the IDAs were absent, while ODAs were identifiable in the patient (Figure 4A)."
    explanation: IDA loss by TEM in patient sperm.
  - reference: PMID:36752199
    reference_title: "Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Overall, our results suggested that CFAP57 played an essential role particularly in single-headed IDA assembly (Supplemental Figure 7)."
    explanation: In mutant mice, single-headed IDAs are the most affected.
- name: Mislocalization of MYH10 and IFT88 in the Sperm Flagellum
  description: >-
    CFAP57 interacts with the non-muscle myosin MYH10. In patient sperm MYH10
    is confined to the midpiece and missing from the principal and end
    pieces, and the intraflagellar transport protein IFT88 is also affected,
    suggesting impaired intraflagellar transport during flagellogenesis.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  downstream:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Proposed to impair flagellar assembly through disrupted intraflagellar transport.
  evidence:
  - reference: PMID:41466333
    reference_title: "Mutations in CFAP57 disrupt the localization of MYH10 and IFT88, leading to flagellogenesis failure in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This mislocalization affected the expression of IFT88, a key component of the intraflagellar transport (IFT) system that plays a critical role in mammalian flagellar assembly."
    explanation: IFT88 is affected secondarily to MYH10 mislocalization.
- name: Multiple Morphological Abnormalities of the Sperm Flagella
  description: >-
    Short, absent, coiled, bent and irregular-caliber flagella with reduced
    progressive motility. Ultrastructure varies between reports: an intact
    9+2 axoneme lacking IDAs in one Pakistani proband, but loss of the
    central pair and radial spokes with displaced doublets and disorganized
    mitochondria in a Chinese proband.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  biological_processes:
  - preferred_term: Sperm flagellum assembly
    modifier: DECREASED
    term:
      id: GO:0120316
      label: sperm flagellum assembly
  downstream:
  - target: Reduced sperm motility
    causal_link_type: DIRECT
  - target: Male infertility
    causal_link_type: DIRECT
    description: Malformed, poorly motile sperm cannot reach or fertilize the oocyte in vivo.
  - target: Short sperm flagella
    causal_link_type: DIRECT
  - target: Absent sperm flagella
    causal_link_type: DIRECT
  - target: Coiled sperm flagella
    causal_link_type: DIRECT
  - target: Bent sperm flagella
    causal_link_type: DIRECT
  - target: Irregularly shaped sperm tail
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:36752199
    reference_title: "Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the results revealed that most spermatozoa from the 2 individuals had malformed flagella, including absent, short, coiled, bent, and irregular caliber, which are typical characteristics of MMAF"
    explanation: MMAF in two Pakistani probands.
  - reference: PMID:41466333
    reference_title: "Mutations in CFAP57 disrupt the localization of MYH10 and IFT88, leading to flagellogenesis failure in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The tail exhibited characteristic MMAF phenotypes, including coiled, bent, irregular, short or/and absent flagella (Fig. 2A)."
    explanation: MMAF in a Chinese proband.
mechanistic_hypotheses:
- hypothesis_group_id: cfap57_isoform_specificity
  hypothesis_label: Truncations confined to the long CFAP57 isoform cause isolated MMAF, while variants affecting both isoforms can cause primary ciliary dyskinesia
  status: EMERGING
  description: >-
    The long isoform (1,250 aa) is required in sperm; the short isoform
    (698 aa), which retains most WD repeats, is expressed in testis and nasal
    epithelium and is proposed to sustain respiratory cilia. All reported
    MMAF nonsense variants lie in the long-isoform-specific region, and the
    men carrying them have had no PCD. The one CFAP57 PCD patient carries a
    variant in exon 11, shared by both isoforms, and his fertility was not
    reported. Two points do not fit cleanly. A compound heterozygous MMAF
    proband carries missense variants (p.V447A, p.R619H) in the region shared
    with the short isoform, yet clinical evaluation found no evidence of PCD;
    the authors read this as selective impairment of the long isoform, which
    would mean that a variant's position in the shared region does not by
    itself predict loss of short-isoform function, and that missense changes
    may spare the short isoform where the exon 11 skip in the PCD patient does
    not. Separately, one Pakistani proband reported occasional breathing
    difficulty but was not examined.
  evidence:
  - reference: PMID:36752199
    reference_title: "Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, we recruited 3 unrelated consanguineous Pakistani families with multiple MMAF-affected individuals, who had no overt ciliary symptoms."
    explanation: Long-isoform truncations without ciliary disease.
  - reference: PMID:41793497
    reference_title: "A novel CFAP57 nonsense mutation causes asthenozoospermia in a consanguineous Emirati family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, the patient exhibited no signs of primary ciliary dyskinesia (PCD), suggesting that the mutation selectively affects the sperm-specific isoform of CFAP57."
    explanation: A further long-isoform nonsense proband without PCD.
  - reference: PMID:32764743
    reference_title: "Mutation of CFAP57, a protein required for the asymmetric targeting of a subset of inner dynein arms in Chlamydomonas, causes primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, the variant results in the skipping of exon 11 (58 amino acids), which may be due to disruption of an exonic splicing enhancer."
    explanation: >-
      The PCD allele lies in exon 11, within the region shared by both
      isoforms, consistent with respiratory disease requiring loss of the
      short isoform as well.
  - reference: CGGV:assertion_50ed292f-0044-4c82-9419-a040cbcaf205-2022-06-23T160000.000Z
    reference_title: "CFAP57 / primary ciliary dyskinesia (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "A homozygous nonsense variant, c.1762C>T (p.Arg588*), was identified in a proband with a classic PCD phenotype including neonatal respiratory distress, otitis media, sinusitis, bronchiectasis, and low nasal nitric oxide."
    explanation: ClinGen's PCD curation (Limited) rests on this single shared-region allele.
  - reference: PMID:36752199
    reference_title: "Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, P6 had orally told that he had typhoid, headache, and difficulty in breathing sometimes but refused to participate in any further examinations."
    explanation: >-
      A self-reported, unexamined respiratory complaint in one MMAF proband;
      weak evidence that long-isoform alleles may affect airway cilia.
  - reference: PMID:41466333
    reference_title: "Mutations in CFAP57 disrupt the localization of MYH10 and IFT88, leading to flagellogenesis failure in humans and mice."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, clinical evaluation revealed no evidence of primary ciliary dyskinesia (PCD) in either patient."
    explanation: >-
      Patient P2 carries compound heterozygous missense variants (p.V447A,
      p.R619H) in exons shared by the long and short isoforms, yet had no
      PCD on clinical evaluation. This contradicts the hypothesis's second
      half as a positional rule: a variant in the shared region did not
      produce respiratory disease.
  - reference: PMID:41466333
    reference_title: "Mutations in CFAP57 disrupt the localization of MYH10 and IFT88, leading to flagellogenesis failure in humans and mice."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, P2 mutations cause spermatogenesis defects without PCD, suggesting selective impairment of the long transcript isoform."
    explanation: >-
      The authors reconcile P2 with the isoform model by proposing that his
      missense variants impair the long isoform selectively. That keeps the
      isoform-specific framing, by an inference step: missense substitutions
      may leave the short isoform functional, whereas the exon 11 skip in the
      PCD patient removes 58 residues from both isoforms. No assay of
      short-isoform function in P2 is reported.
phenotypes:
- category: Reproductive
  name: Male infertility
  description: Primary infertility, the presenting complaint.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:36752199
    reference_title: "Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite having regular unprotected sexual intercourse for at least 8 years, all of these individuals experienced infertility."
    explanation: Infertility in seven affected brothers.
- category: Reproductive
  name: Reduced sperm motility
  description: >-
    Asthenozoospermia with 64-79% immotile sperm; sperm concentration is
    normal in the two Chinese probands.
  phenotype_term:
    preferred_term: Asthenozoospermia
    term:
      id: HP:0012207
      label: Reduced sperm motility
  evidence:
  - reference: PMID:41466333
    reference_title: "Mutations in CFAP57 disrupt the localization of MYH10 and IFT88, leading to flagellogenesis failure in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The semen characteristics from P1 and P2 was analyzed by routine clinical tests, and the results revealed that the sperm motility was significantly reduced, and most sperm were classified as immobile sperm (64.1%-79.3%) (Table 1)."
    explanation: Reduced motility in two probands.
  - reference: PMID:41793497
    reference_title: "A novel CFAP57 nonsense mutation causes asthenozoospermia in a consanguineous Emirati family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Semen analysis showed that 63% of sperm were immotile and only 4% had normal morphology, consistent with an MMAF phenotype."
    explanation: Reduced motility in the Emirati proband.
- category: Reproductive
  name: Short sperm flagella
  description: The commonest anomaly in the Chinese probands (about 46-49% of sperm).
  phenotype_term:
    preferred_term: Short sperm flagella
    term:
      id: HP:0032559
      label: Short sperm flagella
  evidence:
  - reference: PMID:36752199
    reference_title: "Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the results revealed that most spermatozoa from the 2 individuals had malformed flagella, including absent, short, coiled, bent, and irregular caliber, which are typical characteristics of MMAF"
    explanation: Short flagella in patient sperm.
- category: Reproductive
  name: Absent sperm flagella
  description: Part of the MMAF mosaic.
  phenotype_term:
    preferred_term: Absent sperm flagella
    term:
      id: HP:0032558
      label: Absent sperm flagella
  evidence:
  - reference: PMID:41466333
    reference_title: "Mutations in CFAP57 disrupt the localization of MYH10 and IFT88, leading to flagellogenesis failure in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The tail exhibited characteristic MMAF phenotypes, including coiled, bent, irregular, short or/and absent flagella (Fig. 2A)."
    explanation: Absent flagella in patient sperm.
- category: Reproductive
  name: Coiled sperm flagella
  description: Part of the MMAF mosaic.
  phenotype_term:
    preferred_term: Coiled sperm flagella
    term:
      id: HP:0032560
      label: Coiled sperm flagella
  evidence:
  - reference: PMID:41466333
    reference_title: "Mutations in CFAP57 disrupt the localization of MYH10 and IFT88, leading to flagellogenesis failure in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The tail exhibited characteristic MMAF phenotypes, including coiled, bent, irregular, short or/and absent flagella (Fig. 2A)."
    explanation: Coiled flagella in patient sperm.
- category: Reproductive
  name: Bent sperm flagella
  description: Part of the MMAF mosaic.
  phenotype_term:
    preferred_term: Bent sperm flagella
    term:
      id: HP:0034811
      label: Bent sperm flagella
  evidence:
  - reference: PMID:36752199
    reference_title: "Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the results revealed that most spermatozoa from the 2 individuals had malformed flagella, including absent, short, coiled, bent, and irregular caliber, which are typical characteristics of MMAF"
    explanation: Bent flagella in patient sperm.
- category: Reproductive
  name: Irregularly shaped sperm tail
  description: Irregular-caliber flagella are part of the MMAF mosaic.
  phenotype_term:
    preferred_term: Irregular-caliber sperm flagella
    term:
      id: HP:0033393
      label: Irregularly shaped sperm tail
  evidence:
  - reference: PMID:36752199
    reference_title: "Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the results revealed that most spermatozoa from the 2 individuals had malformed flagella, including absent, short, coiled, bent, and irregular caliber, which are typical characteristics of MMAF"
    explanation: Irregular-caliber flagella in patient sperm.
- category: Reproductive
  name: Abnormal sperm axoneme morphology
  description: >-
    Electron microscopy shows absent IDAs with an otherwise intact 9+2
    axoneme in one proband, and loss of the central pair and radial spokes
    with displaced doublets in another.
  phenotype_term:
    preferred_term: Abnormal sperm axoneme morphology
    term:
      id: HP:0033524
      label: Abnormal sperm axoneme morphology
  evidence:
  - reference: PMID:36752199
    reference_title: "Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Detailed analysis of dynein arms revealed that the IDAs were absent, while ODAs were identifiable in the patient (Figure 4A)."
    explanation: IDA loss in a Pakistani proband.
  - reference: PMID:41466333
    reference_title: "Mutations in CFAP57 disrupt the localization of MYH10 and IFT88, leading to flagellogenesis failure in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the sperm with the CFAP57 mutation displayed disorganization in mitochondrial assembly and haphazard “9 + 2” microtubules arrangement, for example, the CP and RS are absent, the doublet microtubule (DMT) was displacement (Fig. 2B)."
    explanation: Central pair and radial spoke loss in a Chinese proband.
- category: Reproductive
  name: Abnormal sperm head morphology
  description: >-
    Indented and conical sperm heads were seen in one proband. No mechanism
    links CFAP57 to head shaping, so this phenotype is not linked to the
    causal chain.
  phenotype_term:
    preferred_term: Abnormal sperm head morphology
    term:
      id: HP:0012865
      label: Abnormal sperm head morphology
  evidence:
  - reference: PMID:41466333
    reference_title: "Mutations in CFAP57 disrupt the localization of MYH10 and IFT88, leading to flagellogenesis failure in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, the sperm from P1 exhibited various morphological abnormalities, including irregular shapes such as indentation and conical forms in the heads."
    explanation: Head defects in one proband.
genetic:
- name: CFAP57
  association: Causal
  gene_term:
    preferred_term: CFAP57
    term:
      id: hgnc:26485
      label: CFAP57
  notes: >-
    Reported alleles: homozygous nonsense p.R913* and p.R958* (Pakistani
    families), p.R1084X (Chinese) and p.R1075* (Emirati), all in the
    long-isoform-specific region, and compound heterozygous missense p.V447A
    with p.R619H (Chinese), which lie in the region shared with the short
    isoform; that proband had no evidence of PCD on clinical evaluation, so
    the shared-region location of a variant does not on its own predict
    respiratory disease. ClinGen classifies CFAP57 only for primary ciliary dyskinesia
    (Limited, AR), a different disease, so no validity tier is recorded for
    this entry.
  evidence:
  - reference: PMID:36752199
    reference_title: "Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing and Sanger sequencing identified 2 cilia and flagella associated protein 57 (CFAP57) loss-of-function mutations (c.2872C>T, p. R958*; and c.2737C>T, p. R913*) recessively segregating with male infertility."
    explanation: First families.
  - reference: PMID:41466333
    reference_title: "Mutations in CFAP57 disrupt the localization of MYH10 and IFT88, leading to flagellogenesis failure in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report novel biallelic mutations in the CFAP57 gene identified in two infertile males from two unrelated families."
    explanation: Two further probands.
  - reference: PMID:41793497
    reference_title: "A novel CFAP57 nonsense mutation causes asthenozoospermia in a consanguineous Emirati family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sanger sequencing confirmed the segregation of the variant within the family; the proband was homozygous for the mutation, while both parents were heterozygous carriers."
    explanation: A further homozygous proband with carrier parents.
animal_models:
- name: Cfap57 p.R958* equivalent mouse
  species: Mouse
  genotype: Cfap57 c.2865-2871del (p.Lys956Phefs*4), homozygous (Cfap57 M/M)
  publication: PMID:36752199
  description: >-
    Mice carrying a frameshift equivalent to the human p.R958* allele lose
    the long isoform and are infertile with immotile MMAF sperm and loss of
    single-headed IDAs; sperm number falls to about 5% of controls and the
    axoneme is disorganized in all sections.
  modeled_mechanisms:
  - target: Inner Dynein Arm Assembly Failure in the Sperm Axoneme
    relationship: RECAPITULATES
    fidelity: HIGH
    description: Reproduces the IDA assembly defect seen in patient sperm.
    evidence:
    - reference: PMID:36752199
      reference_title: "Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Subsequent examinations of the spermatozoa from Cfap57-mutant mice revealed that CFAP57 deficiency disrupted the inner dynein arm (IDA) assembly in sperm flagella and that single-headed IDAs were more likely to be affected."
      explanation: IDA assembly failure in mutant mice.
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: MMAF is reproduced, with a more severe axonemal and sperm-count defect than in patients.
    limitations: >-
      Mutant mice have severe oligozoospermia and fully disorganized axonemes,
      whereas patients usually have normal sperm counts and can keep an
      intact 9+2 axoneme.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The mouse sperm axoneme disintegrates after IDA loss and sperm output
        falls to about 5%, while in human sperm the 9+2 structure can survive
        without IDAs and concentration is usually normal; the mouse
        overstates the structural and count phenotype.
    evidence:
    - reference: PMID:36752199
      reference_title: "Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Therefore, it is supposed that the integrity of the axoneme structure in mutant mouse sperm is more susceptible to IDA assembly failure than in humans."
      explanation: Authors' statement of the species difference.
    - reference: PMID:36752199
      reference_title: "Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Hence, Cfap57M/M mice recapitulated the MMAF phenotype found in the affected individuals carrying homozygous M1 mutations, showing that the CFAP57 mutation is indeed pathogenic for MMAF in both infertile cases and mutant mice."
      explanation: The mouse reproduces MMAF.
treatments:
- name: Intracytoplasmic Sperm Injection
  description: >-
    ICSI bypasses the motility defect. One proband achieved a clinical
    pregnancy and delivery from a single cycle (11 of 14 oocytes fertilized,
    five blastocysts).
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Intracytoplasmic Sperm Injection
    term:
      id: NCIT:C185482
      label: Intracytoplasmic Sperm Injection
  target_mechanisms:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    description: Direct injection makes flagellar propulsion irrelevant to fertilization.
    evidence:
    - reference: PMID:41466333
      reference_title: "Mutations in CFAP57 disrupt the localization of MYH10 and IFT88, leading to flagellogenesis failure in humans and mice."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These results suggest that patients with MMAF resulting from CFAP57 variants can be effectively treated with ICSI."
      explanation: ICSI circumvents the flagellar defect.
  evidence:
  - reference: PMID:41466333
    reference_title: "Mutations in CFAP57 disrupt the localization of MYH10 and IFT88, leading to flagellogenesis failure in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After frozen-thawed embryo transfer (FET) of one high-quality blastocyst, a clinical pregnancy was achieved (Table 2)."
    explanation: Clinical pregnancy after ICSI in one proband; the only reported outcome.
- name: Genetic Counseling
  description: >-
    Counselling for autosomal recessive recurrence and carrier testing of
    relatives once the familial CFAP57 variants are known; the isoform
    location of the variant bears on whether respiratory involvement should
    be considered.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:41793497
    reference_title: "A novel CFAP57 nonsense mutation causes asthenozoospermia in a consanguineous Emirati family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Sanger sequencing confirmed the segregation of the variant within the family; the proband was homozygous for the mutation, while both parents were heterozygous carriers."
    explanation: >-
      Carrier parents in a consanguineous family illustrate the recurrence
      and carrier-testing questions that counselling addresses.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Establishes the diagnosis; probands were identified by whole-exome
    sequencing with Sanger confirmation. MMAF is genetically heterogeneous.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:41793497
    reference_title: "A novel CFAP57 nonsense mutation causes asthenozoospermia in a consanguineous Emirati family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WES revealed a novel homozygous nonsense mutation in CFAP57 (c.3223 C > T; p.Arg1075Ter), located within a large homozygous region on chromosome 1."
    explanation: Exome sequencing identified the causal variant.
- name: Semen Analysis
  description: Shows asthenozoospermia with MMAF and usually normal sperm concentration.
  evidence:
  - reference: PMID:41793497
    reference_title: "A novel CFAP57 nonsense mutation causes asthenozoospermia in a consanguineous Emirati family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Semen analysis showed that 63% of sperm were immotile and only 4% had normal morphology, consistent with an MMAF phenotype."
    explanation: Semen analysis findings.
- name: Transmission Electron Microscopy of Sperm Flagella
  description: >-
    Shows absent IDAs, sometimes with loss of the central pair and radial
    spokes.
  diagnosis_term:
    preferred_term: Transmission Electron Microscopy
    term:
      id: NCIT:C18216
      label: Transmission Electron Microscopy
  evidence:
  - reference: PMID:36752199
    reference_title: "Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Detailed analysis of dynein arms revealed that the IDAs were absent, while ODAs were identifiable in the patient (Figure 4A)."
    explanation: TEM finding in patient sperm.

📚

References & Deep Research

Deep Research

1

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.

Evaluations and curation notes (1)

Create: Spermatogenic Failure 95 (CFAP57) · 2026-10-16T13:41:55Z · View source

New entry for SPGF95 (MONDO:0975747), autosomal recessive MMAF caused by CFAP57. Deep research with the claude_code provider (research/Spermatogenic_Failure_95-deep-research-claude_code.md; preflight-dr matched CFAP57) was used as leads only; PubMed search added the 2025 Chinese families (PMID:41466333), the 2026 Emirati family (PMID:41793497), the PCD report (PMID:32764743) and the DNAH10-CFAP57 interaction (PMID:40898283). Pathograph: loss of long-isoform CFAP57 (GO:0045504 dynein heavy chain binding, DECREASED) -> inner dynein arm assembly failure and MYH10/IFT88 mislocalization -> MMAF -> phenotypes. Divergent sperm ultrastructure between reports is stated on the MMAF node. Hypothesis on isoform specificity: long-isoform truncations give isolated MMAF, the exon 11 shared-region allele gave PCD (ClinGen Limited for PCD, cited as REVIEW_SYNTHESIS; no tier recorded for SPGF95 because ClinGen has not curated this pair), with a weak REFUTE item for one unexamined breathing complaint. Mouse model with SPECIES_MISMATCH divergence (oligozoospermia and disorganized axoneme in mice). ICSI with one delivery, genetic counselling, exome testing, semen analysis, TEM. No GeneReviews/StatPearls chapter. Stub deleted. Validated with the same gates as the companion entries.

Claude Code ▸

1. Disease Information

claude-haiku-5-5, claude-sonnet-5-5 7 citations 2026-10-16T13:13:43.319470

1. Disease Information

Overview. SPGF95 is an autosomal recessive form of male infertility. It is caused by homozygous loss-of-function variants in CFAP57. Sperm show multiple morphological abnormalities of the flagella (MMAF): absent, short, coiled, bent and irregular-caliber tails. Progressive motility is markedly reduced. Female fertility appears unaffected. - The OMIM phenotype table lists it as 1p34.2, AR, MIM 620917, gene CFAP57 (MIM 614259), per a search-surfaced OMIM table. The same snippet carries the clinical description and the female-fertility note. - This is a single-gene Mendelian disease, a member of the numbered "spermatogenic failure" series. It is not a grouping.

Identifiers

System	Value	Status
OMIM	620917	from search snippets (OMIM page not opened)
Disease Ontology	DOID:0070594	from the Alliance page
Synonym	SPGF95	same
MONDO	not found	The task header gives "MONDO:0975747", but I could not confirm it. Resolve it in OLS or MONDO before use.
Parent MONDO class	spermatogenic failure, MONDO:0004983	from a DrugMAP snippet
Sibling for scale	SPGF93 = MONDO:0971000	from a PomBase snippet

Not found: Orphanet, ICD-10/11 and MeSH identifiers.
The data are disease-level (OMIM, literature), not derived from EHR.

Synonyms. The descriptive label "MMAF due to CFAP57 mutation" is a term in the literature. I did not find other alternative names.

2. Etiology

Cause. Biallelic loss-of-function variants in CFAP57.
Genetic risk factors. I found no susceptibility loci or modifier genes.
Environmental risk factors and protective factors. None identified for this entity.
Gene–environment interactions. None identified. Environmental and lifestyle sections are therefore "not available" for this disease.

3. Phenotypes

All human data below come from Ma et al. 2023 (PMID:36752199) unless noted.

Cohort. Seven infertile men from 3 consanguineous Pakistani families. - Four were asthenozoospermic (P2, P5, P6, P7) and one (P3) was azoospermic. - AZF microdeletions and abnormal karyotypes were excluded. - Semen values and MMAF percentages appear only in Table 1, which is an image I could not read.

Phenotype	HPO (verify)	Evidence
Male infertility	HP:0003251	all affected men
Asthenozoospermia / reduced progressive motility	HP:0012206	4 of 7; OMIM description
Abnormal sperm flagellum morphology (MMAF: absent, short, coiled, bent, irregular-caliber flagella)	HP:0012864	P2, P7
Azoospermia	HP:0000027	P3 (1 of 7)
Absent sperm-tail inner dynein arms on TEM	no HPO term likely	P7

Onset, severity, progression. Not described beyond adult infertility. Infertility is a fixed defect, so there is no known progression.
Frequency. The exact proportions in Table 1 were not retrieved.
Ciliary or systemic symptoms. These were mostly absent. The authors report "no overt ciliary symptoms". The exception is P6, who reported a typhoid-like illness, headaches and occasional breathing difficulty. He declined further testing, so this is not an established PCD feature.
Emirati family (2026). A Molecular Biology Reports abstract, seen only as a search summary, reports a proband with 63% immotile sperm, 4% normal morphology and no PCD signs.
Quality of life. No data found.

4. Genetic/Molecular Information

Gene. CFAP57 (cilia and flagella associated protein 57), 1p34.2, OMIM 614259. The HGNC ID was not retrieved. Look it up and bind it as lowercase hgnc: per KB convention.
Variants (all homozygous stop-gain, all supporting an LoF mechanism):

Variant	Population	Source
c.2872C>T, p.R958*	Pakistani, family 1	PMID:36752199
c.2737C>T, p.R913*	Pakistani, families 2 and 3	PMID:36752199
c.3223C>T, p.Arg1075Ter	Emirati consanguineous family	2026 abstract; both parents heterozygous

Classification (ACMG/ClinVar). Not retrieved.
Allele frequency (gnomAD). Not retrieved.
Origin. Germline.
Functional consequence. Both Pakistani variants abolish the long-transcript CFAP57 protein in sperm. The short transcript is unaffected.
Modifier genes, epigenetics, chromosomal abnormalities. None reported.

5. Environmental Information

No environmental, lifestyle or infectious-agent contributors are described.

6. Mechanism / Pathophysiology

Causal chain (steps 1–4 are demonstrated in humans and mouse; step 5 is partly inferred): 1. A homozygous nonsense variant in CFAP57 introduces a premature stop codon in the long transcript. (Demonstrated.) 2. This leads to loss of long-isoform CFAP57 protein in spermatozoa. (Demonstrated in patient sperm and in the mouse.) 3. Loss of CFAP57 results in failed inner dynein arm (IDA) assembly in the sperm axoneme. Single-headed IDAs (markers DNAH6, DNALI1) are most affected. The double-headed IDA marker DNAH10 is less affected. Outer dynein arms are present. (Demonstrated by immunofluorescence and by TEM in P7.) 4. Testis levels of IDA proteins (DNAH1, DNAH6, DNALI1) are normal, so the defect is in assembly or incorporation and not in synthesis. (Demonstrated in the mouse.) 5. Disorganized axonemes then produce the MMAF morphology and immotile or poorly motile sperm, which leads to asthenozoospermia or azoospermia and male infertility. (Demonstrated, but the link from IDA loss to the specific flagellar shape defects is inferred.)

Branch: why there is no motile-cilia disease. The authors propose that the unaffected short transcript preserves ciliary function. This is a hypothesis and is not demonstrated.

Supporting quote from the Discussion of PMID:36752199: "loss of the long transcript of Cfap57 disrupted IDA assembly in sperm flagella". Verify this against the full text before using it as a snippet.

Cell types and terms to check. - Cell types: spermatid (CL:0000018) and spermatozoon (CL:0000019). - GO terms: axonemal dynein complex assembly, inner dynein arm assembly, sperm flagellum assembly (all need lookup). - GO cellular component: sperm flagellum, axoneme.

Not found. I found no data on omics, single-cell, metabolic, immune or epigenetic changes. The Chlamydomonas ortholog FAP57 has a similar role in IDA assembly, per the discovery paper.

7. Anatomical Structures Affected

Primary organ: testis, where spermiogenesis takes place (UBERON:0000473, verify).
Sperm flagellum axoneme: 9+2 structure retained, IDAs absent.
Laterality: not applicable (bilateral male reproductive phenotype).
Secondary involvement: none established. Respiratory or other ciliated tissue is not clearly affected.

8. Temporal Development

Onset: adult, presenting as infertility. It is lifelong and congenital in origin.
Progression, remission, critical periods: no data.

9. Inheritance and Population

Inheritance: autosomal recessive (OMIM). The Pakistani and Emirati families were consanguineous. The heterozygous parents in the Emirati family were unaffected carriers.
Founder effect: R913* was found in two families, which may suggest a recurrent or founder variant. This is my inference and the paper's text does not state it.
Not found: prevalence, incidence, carrier frequency, penetrance, sex ratio and geographic distribution beyond the Pakistani and Emirati families. Disease expression is male-limited by definition.

10. Diagnostics

Semen analysis shows asthenozoospermia, or azoospermia in rare cases. Morphology shows MMAF.
Genetic testing: WES identified the variants, confirmed by Sanger sequencing. A CFAP57 gene should be included in MMAF or male-infertility panels. I did not retrieve GTR or GeneReviews panel data.
Excluded in workup: karyotype and AZF microdeletions.
Research tools: TEM (IDA absence) and immunofluorescence (DNAH6, DNALI1).
Differential: other MMAF genes (not enumerated here from sources), and primary ciliary dyskinesia, which is notably absent.
No screening program applies.

11. Outcome/Prognosis

No survival or mortality effect is reported. The manifestation is infertility. I found no ICSI outcome data for CFAP57 patients. The discovery paper does not report ICSI results.

12. Treatment

No disease-specific treatment was found. - ICSI is the generally used route for MMAF infertility, but I found no CFAP57-specific outcome data. A relevant NCIT term to verify would be assisted reproductive technology. - No gene therapy, drugs or clinical trials were identified, and I did not search ClinicalTrials.gov directly. - Genetic counselling (NCIT:C15240, from the project's CLAUDE.md list) is appropriate for the consanguineous families and for carrier-parent counselling.

13. Prevention

No primary or secondary prevention applies. Genetic counselling and carrier testing in consanguineous families is the relevant tertiary and reproductive measure. This is general practice and not a CFAP57-specific source finding.

14. Other Species / Natural Disease

No natural veterinary disease was found, and I did not search OMIA. The mouse and Chlamydomonas orthologs are covered below.

15. Model Organisms

Mouse knock-in (Cfap57^M/M). From PMID:36752199. - Allele: c.2865-2871del, p.Lys956Phefs4, modelling the family 1 variant. - Normal growth, development and testis size. - Males infertile, with epididymal sperm counts about 5% of heterozygous controls. - All sperm morphologically abnormal (MMAF-like) and immotile by CASA. - No CFAP57 signal in the sperm tail, and disorganized axonemes in all analyzed cross-sections. - Fidelity. This recapitulates the human sperm phenotype and the lack of overt ciliary disease. The model has one allele, and the human long/short transcript logic is shared, so the mouse cannot independently test the short-transcript hypothesis. - Chlamydomonas FAP57* has a similar IDA-assembly role per the paper. - Not found: MGI or IMPC records, zebrafish or other models, and the mouse gene's NCBI ID.

Key Gaps for Curation

Confirm the MONDO ID (the header's MONDO:0975747 is unverified) and the HGNC ID for CFAP57.
Read OMIM #620917 for its clinical synopsis and the cited PMIDs.
Retrieve Table 1 of PMID:36752199 for semen parameters.
Check ClinVar and ClinGen for variant classifications and gene–disease validity. The ClinGen tier must be copied from a source and not assigned.
Evidence strength is thin. The human data are 3 families plus one 2026 abstract, and the mouse model is a single allele.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	3
Resolved	3
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	3
On topic	2
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	13
Resolved	12
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	7
Terms named correctly	2
Terms named as a different term	4
Terms whose name is worth a second look	1

Terms the report names something else

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:

DOID:0070594 (5 mentions) - the report calls it "Disease Ontology"; DOID calls it spermatogenic failure 95
MONDO:0971000 (5 mentions) - the report calls it "SPGF93"; MONDO calls it spermatogenic failure 93
HP:0012206 (1 mention) - the report calls it "Asthenozoospermia / reduced progressive motility"; HP calls it Abnormal sperm motility
HP:0012864 (1 mention) - the report calls it "Abnormal sperm flagellum morphology (MMAF: absent, short, coiled, bent, irregular-caliber flagella)"; HP calls it Abnormal sperm morphology

Terms whose name is worth a second look

The 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:

CL:0000018 (1 mention) - the report calls it "Cell types: spermatid"; CL calls it spermatid

Prefixes with no resolver

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: OMIM.

Spermatogenic Failure 95

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1. Disease Information

2. Etiology

3. Phenotypes

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6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

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13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

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Reference Validation

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Terms the report names something else

Terms whose name is worth a second look

Prefixes with no resolver