🏷

Classifications

Harrison's Part

👪

Inheritance

1

Autosomal recessive HP:0000007

Disease requires biallelic KASH5 variants: homozygous frameshift and missense variants in consanguineous families, recessive variants in a Middle Eastern consanguineous family, and compound heterozygous splice-site variants in a sporadic patient.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:35587281 SUPPORT Human clinical

"identified a novel homozygous missense mutation in CCDC155 ... in a pair of familial NOA and POI patients whose parents were first cousins"

Homozygous variant from a first-cousin marriage segregating with gametogenic failure.

PMID:36864840 SUPPORT Human clinical

"Among the retained variants, a frameshift mutation in KASH5 was identified recessively segregating with the infertility and recurrent miscarriage within the family"

Recessive segregation of a homozygous frameshift in a second consanguineous family.

PMID:29790874 SUPPORT Human clinical

"In five of eight families, we identified rare deleterious recessive variants in CCDC155, NANOS2, SPO11, TEX14, and WNK3 segregating with disease."

First report of recessive CCDC155 (KASH5) variants segregating with non-obstructive azoospermia.

⚙

Pathophysiology

6

KASH5 Loss of Function

Biallelic KASH5 variants remove the protein or keep it out of the nuclear envelope. A homozygous frameshift abolishes KASH5 in the patient's testis. The missense p.Leu197Pro in the coiled-coil domain blocks nuclear envelope distribution of KASH5 and with it the nuclear-envelope enrichment of its partner SUN1. The transmembrane-domain variant p.Leu535Gln misroutes KASH5 to mitochondria in cultured cells, and a splice-site variant reported in women with ovarian insufficiency weakens nuclear envelope localization and SUN1 binding. Splice-site variants found in a man with meiotic arrest cause exon skipping in minigene assays.

KASH5 hgnc:26520

Dynein light intermediate chain binding GO:0051959 ↓ DECREASED

Meiotic LINC complex GO:0034993 nuclear envelope GO:0005635

testis UBERON:0000473 seminiferous tubule of testis UBERON:0001343

Downstream

Uncoupling of Meiotic Telomeres from Cytoplasmic Dynein Without KASH5 at the outer nuclear membrane, the SUN1-bound telomere attachment sites lose their connection to dynein.

Show evidence (5 references)

PMID:36864840 SUPPORT Human clinical

"This mutation leads to the absence of KASH5 protein expression in testes and non-obstructive azoospermia (NOA) due to meiotic arrest before the pachytene stage in the affected brother."

KASH5 protein is absent from the testis of a man homozygous for a frameshift.

PMID:35587281 SUPPORT Human clinical

"This rare missense mutation with lesions in the conserved CC domain of CCDC155 blocked nuclear envelope (NE) distribution and subsequently prevented NE-specific enrichment of Sad1- and UNC84-domain-containing 1 either ex vivo or in vitro"

The patient missense variant keeps KASH5, and secondarily SUN1, out of the nuclear envelope.

PMID:33980926 SUPPORT In vitro / ex vivo

"we show that the L535Q substitution perturbs KASH5 localization to the ER and ONM and instead results in mistargeting to the mitochondria membrane"

Cell-based study of the azoospermia-associated transmembrane variant.

+ 2 more references

Uncoupling of Meiotic Telomeres from Cytoplasmic Dynein

In meiotic prophase I, telomeres attach to the inner nuclear membrane through SUN1, and KASH5 links SUN1 across the envelope to cytoplasmic dynein, for which it is an activating adaptor; KASH5 also binds the kinesin KIF5B. In Kash5-null mouse spermatocytes telomeres still attach to the envelope, but they are no longer coupled to the microtubule motors that move them and cluster them into the meiotic bouquet.

Primary spermatocyte CL:0000656

Meiotic telomere clustering GO:0045141 ↓ DECREASED

Dynein complex binding GO:0070840 ↓ DECREASED

nuclear envelope GO:0005635 meiotic nuclear membrane microtubule tethering complex GO:0034993

testis UBERON:0000473

Downstream

Failed Homologous Chromosome Pairing and Synapsis Telomere-led movement is what brings homologs together, so its loss leaves homologs unpaired.

Show evidence (4 references)

PMID:22826121 SUPPORT Model organism

"These results suggest that KASH5 connects the telomere-associated SUN1 protein to the cytoplasmic force-generating mechanism involved in meiotic chromosome movement."

Mouse spermatocyte study placing KASH5 between SUN1-bound telomeres and the cytoplasmic motor.

PMID:35703493 SUPPORT In vitro / ex vivo

"We show that the meiosis-specific nuclear-envelope protein KASH5 is a dynein activating adaptor: KASH5 directly binds dynein using a mechanism conserved among activating adaptors and converts dynein into a processive motor."

Reconstitution shows KASH5 activates dynein motility.

PMID:36946995 SUPPORT In vitro / ex vivo

"Altogether, we show that the transmembrane protein KASH5 is an activating adaptor for dynein and shed light on the hierarchy of assembly of KASH5-dynein-dynactin complexes."

Independent confirmation of the dynein adaptor function.

+ 1 more reference

Failed Homologous Chromosome Pairing and Synapsis

Homologous chromosomes do not pair, and the synaptonemal complex does not form along full-length homologs. A proband with two rare KASH5 variants arrested at a zygotene-like stage with deficient pairing and synapsis, and Kash5-null mouse spermatocytes never show fully synapsed homologs.

Primary spermatocyte CL:0000656

Homologous chromosome pairing at meiosis GO:0007129 ↓ DECREASED Synaptonemal complex assembly GO:0007130 ↓ DECREASED

synaptonemal complex GO:0000795

seminiferous tubule of testis UBERON:0001343

Animal models

Kash5-null mouse Mouse recapitulates Null spermatocytes fail to pair and synapse homologs, as in patient spermatocytes.

Downstream

Persistent Unrepaired Meiotic DNA Double-Strand Breaks Repair of programmed meiotic breaks depends on a homolog partner, so breaks persist when homologs do not engage.

Spermatocyte Arrest Before Pachytene and Germ Cell Apoptosis

Show evidence (2 references)

PMID:35674372 SUPPORT Human clinical

"Spermatogenesis in the proband was arrested at zygotene-like stage with a deficiency in homolog pairing and synapsis."

Pairing and synapsis defect in a KASH5 patient's spermatocytes.

PMID:24062341 SUPPORT Model organism

"We never observed fully synapsed homologues in Kash5-null spermatocytes."

Complete synapsis failure in the knockout mouse.

Persistent Unrepaired Meiotic DNA Double-Strand Breaks

Programmed meiotic DNA double-strand breaks are made but not resolved. Spermatocytes of a homozygous missense patient failed to complete meiosis with unresolved break repair, and Kash5-null spermatocytes accumulate breaks that are never repaired.

Primary spermatocyte CL:0000656

Reciprocal meiotic recombination GO:0007131 ↓ DECREASED

nucleus GO:0005634

seminiferous tubule of testis UBERON:0001343

Downstream

Spermatocyte Arrest Before Pachytene and Germ Cell Apoptosis

Show evidence (2 references)

PMID:35587281 SUPPORT Human clinical

"The affected spermatocytes were unable to complete meiotic division coupled with unresolved repair of the DNA double-strand break."

Unresolved break repair in the patient's spermatocytes.

PMID:24062341 SUPPORT Model organism

"The conclusion is that Kash5-null spermatocytes accumulate DSBs that are never resolved."

Persistent breaks in the knockout mouse.

Spermatocyte Arrest Before Pachytene and Germ Cell Apoptosis

Spermatocytes that cannot pair, synapse and repair their breaks arrest at a zygotene-like stage before pachytene and are eliminated, so no post-meiotic germ cells form. In Kash5-null testes widespread apoptosis is seen in about 30% of tubule cross sections.

Primary spermatocyte CL:0000656

Apoptotic process GO:0006915 ↑ INCREASED

seminiferous tubule of testis UBERON:0001343

Downstream

Spermatogenic Arrest and Non-Obstructive Azoospermia

Show evidence (3 references)

PMID:36864840 SUPPORT Human clinical

"These results indicated that the male patient suffered from NOA and his spermatogenesis was arrested at the spermatocyte stage."

Testicular biopsy shows spermatocyte-stage arrest in a homozygous frameshift patient.

PMID:42443317 SUPPORT Human clinical

"Testicular histology and immunofluorescence analyses concordantly demonstrated a shared phenotype of meiotic prophase I arrest and absence of post-meiotic germ cells in these patients."

Prophase I arrest without post-meiotic cells in a cohort that includes a compound heterozygous KASH5 patient; the sentence is shared across the LINC and TTM gene patients of that study.

PMID:24062341 SUPPORT Model organism

"In Kash5-null testes, widespread TUNEL staining is seen in ∼30% of tubule cross sections."

Germ cell apoptosis in the knockout mouse.

Spermatogenic Arrest and Non-Obstructive Azoospermia

With spermatogenesis halted in meiotic prophase I, no sperm reach the ejaculate, giving non-obstructive azoospermia and primary male infertility.

Spermatocyte CL:0000017

Male gamete generation GO:0048232 ↓ DECREASED

testis UBERON:0000473 seminiferous tubule of testis UBERON:0001343

Animal models

Kash5-null mouse Mouse recapitulates Male knockouts are infertile from meiotic arrest.

Downstream

Non-obstructive azoospermia

Spermatocyte maturation arrest

Male infertility

Show evidence (1 reference)

PMID:35674372 SUPPORT Human clinical

"Collectively, we have identified novel rare variants within human KASH5 in patients with NOA and meiosis arrest."

Meiotic arrest with NOA in KASH5 patients.

⬡

Pathograph

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Phenotypes

3

Male infertility Reproductive HP:0003251

Show evidence (2 references)

PMID:33980926 SUPPORT BACKGROUND Human clinical

"A recent study identified a variant in human KASH5 (L535Q) that correlated with male infertility associated with azoospermia."

The authors' summary of the earlier exome study that found the variant in infertile men.

PMID:36864840 SUPPORT Human clinical

"IV:4 (41-yr-old) has been married for 19 years, but suffered from infertility"

Long-standing infertility in the affected brother.

Non-obstructive azoospermia Reproductive HP:0011961

Show evidence (3 references)

PMID:35674372 SUPPORT Human clinical

"were identified in a non-obstructive azoospermia (NOA)-affected patient and in his infertile sister by whole-exome sequencing and CNV array"

NOA in a KASH5 patient.

PMID:36864840 SUPPORT Human clinical

"This mutation leads to the absence of KASH5 protein expression in testes and non-obstructive azoospermia (NOA) due to meiotic arrest before the pachytene stage in the affected brother."

NOA in a homozygous frameshift patient.

PMID:35587281 SUPPORT Human clinical

"identified a novel homozygous missense mutation in CCDC155 ... in a pair of familial NOA and POI patients whose parents were first cousins"

NOA in a homozygous missense patient.

Spermatocyte maturation arrest Reproductive HP:0031039

Show evidence (2 references)

PMID:35674372 SUPPORT Human clinical

"Spermatogenesis in the proband was arrested at zygotene-like stage with a deficiency in homolog pairing and synapsis."

Zygotene-like spermatocyte arrest.

PMID:36864840 SUPPORT Human clinical

"These results indicated that the male patient suffered from NOA and his spermatogenesis was arrested at the spermatocyte stage."

Spermatocyte-stage arrest on testicular biopsy.

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Genetic Associations

1

KASH5 (Causal)

Gene: KASH5 hgnc:26520 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:35674372 SUPPORT Human clinical

"a heterozygous loss of function variant (NM_144688: c.979_980del: p.R327Sfs*21) in human KASH5 were identified in a non-obstructive azoospermia (NOA)-affected patient"

A frameshift allele, with a copy-number deletion, in an NOA patient.

PMID:42443317 SUPPORT Human clinical

"including compound heterozygous variants in KASH5 (NM_144688.5:c.149-1G>A; NM_144688.5:c.876+1G>A)"

Independent compound heterozygous patient with meiotic arrest.

PMID:36864840 SUPPORT Human clinical

"identified a homozygous frameshift mutation in KASH5 (c.1270_1273del, p.Arg424Thrfs*20)"

Homozygous truncating allele in a consanguineous family.

🔬

Diagnosis

3

Semen Analysis (PRESENT)

Repeat microscopic semen analyses performed according to World Health Organization guidelines to evaluate ejaculate volume and sperm count.

Microscopy NCIT:C16853

Results: Normal semen volume with complete absence of spermatozoa in the ejaculate (azoospermia).

Show evidence (1 reference)

PMID:36864840 SUPPORT Human clinical

"IV:4 had two semen analyses conducted following the WHO guidelines, and both examinations showed that he had normal semen volume but no sperm seen in the ejaculates"

Establishes repeat WHO-standard semen analyses demonstrating azoospermia with normal ejaculate volume.

Testicular Biopsy and Histopathologic Examination (PRESENT)

Testicular biopsy with hematoxylin-eosin histology and meiotic immunofluorescence staining (e.g., gamma-H2AX, PNA, H3S10p) to determine the stage of spermatogenic arrest.

Biopsy Procedure NCIT:C15189

Results: Presence of spermatogonia and primary spermatocytes with complete absence of post-meiotic spermatids and spermatozoa in seminiferous tubules, confirming meiotic arrest prior to pachytene.

Show evidence (1 reference)

PMID:36864840 SUPPORT Human clinical

"Hematoxylin and eosin (H&E) staining of testicular sections revealed the presence of many spermatogonia and primary spermatocytes but a complete absence of spermatids and sperm in seminiferous tubules of IV:4"

Demonstrates that testicular biopsy histology identifies primary spermatocyte arrest and absence of post-meiotic germ cells.

Whole-Exome Sequencing (PRESENT)

Whole-exome sequencing (with copy-number variant analysis and Sanger confirmation) to identify biallelic pathogenic variants in KASH5.

Whole Exome Sequencing NCIT:C101295

Results: Identification of homozygous or compound heterozygous loss-of-function, splice-site, or missense variants in KASH5.

Show evidence (1 reference)

PMID:36864840 SUPPORT Human clinical

"Here, we applied whole-exome sequencing for a consanguineous family with five siblings suffering from reproductive failure, and identified a homozygous frameshift mutation in KASH5 (c.1270_1273del, p.Arg424Thrfs*20)."

Establishes whole-exome sequencing as the molecular diagnostic method for identifying causative KASH5 variants.

🐁

Animal Models

1

Kash5-null mouse

Kash5-deficient mice are infertile in both sexes. Male spermatocytes arrest in meiotic prophase with failed pairing and synapsis, persistent DNA double-strand breaks and apoptosis, while telomeres still attach to the nuclear envelope.

Species

Mouse

Genotype

Kash5 knockout, homozygous

Genes

KASH5 hgnc:26520

Publication

PMID:24062341

Pathograph links

Failed Homologous Chromosome Pairing and Synapsis recapitulates fidelity: high Null spermatocytes fail to pair and synapse homologs, as in patient spermatocytes.

Limitations: The knockout is a complete null, whereas several human alleles are missense or splice variants whose residual function is not measured.

Show evidence (1 reference)

PMID:35674372 SUPPORT Model organism

"Kash5 knockout mouse displayed similar phenotypes, including a meiotic arrest at a zygotene-like stage and impaired pairing and synapsis."

Authors' comparison of the knockout with their patient.

Spermatogenic Arrest and Non-Obstructive Azoospermia recapitulates fidelity: high Male knockouts are infertile from meiotic arrest.

Show evidence (1 reference)

PMID:24062341 SUPPORT Model organism

"Males display meiotic arrest in which pairing of homologous chromosomes fails."

Male meiotic arrest in the knockout.

{ }

Source YAML

click to show

name: Spermatogenic Failure 88
creation_date: "2026-10-22T20:30:00Z"
category: Mendelian
description: >-
  Spermatogenic failure 88 (SPGF88) is autosomal recessive male infertility
  with non-obstructive azoospermia caused by biallelic variants in KASH5
  (formerly CCDC155). KASH5 is a germ-cell-specific KASH-domain protein of the
  outer nuclear membrane. With SUN1 in the inner nuclear membrane it forms the
  meiotic LINC complex, which couples the telomeres of prophase I chromosomes,
  across the nuclear envelope, to cytoplasmic dynein. KASH5 is itself a dynein
  activating adaptor. The resulting telomere-led chromosome movements bring
  homologous chromosomes together. Without KASH5, homologs fail to pair and
  synapse, meiotic DNA double-strand breaks stay unrepaired, and spermatocytes
  arrest at a zygotene-like stage before pachytene, so no post-meiotic germ
  cells or sperm are produced. Kash5-null mice reproduce the meiotic arrest.
  Reported families are consanguineous or carry two rare alleles, including
  frameshift, splice-site, missense and copy-number variants.
disease_term:
  preferred_term: spermatogenic failure 88
  term:
    id: MONDO:0957821
    label: spermatogenic failure 88
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
    evidence:
    - reference: PMID:36864840
      reference_title: "A homozygous KASH5 frameshift mutation causes diminished ovarian reserve, recurrent miscarriage, and non-obstructive azoospermia in humans."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This mutation leads to the absence of KASH5 protein expression in testes and non-obstructive azoospermia (NOA) due to meiotic arrest before the pachytene stage in the affected brother."
      explanation: >-
        Classifies spermatogenic failure 88 as a male reproductive and gonadal
        disorder presenting with non-obstructive azoospermia and testicular
        meiotic arrest.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:36864840
      reference_title: "A homozygous KASH5 frameshift mutation causes diminished ovarian reserve, recurrent miscarriage, and non-obstructive azoospermia in humans."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Here, we applied whole-exome sequencing for a consanguineous family with five siblings suffering from reproductive failure, and identified a homozygous frameshift mutation in KASH5 (c.1270_1273del, p.Arg424Thrfs*20)."
      explanation: >-
        Establishes spermatogenic failure 88 as an autosomal recessive Mendelian
        disorder caused by biallelic pathogenic variants in KASH5.
parents:
- Spermatogenic Failure
- Male infertility
- Genetic Disease
synonyms:
- SPGF88
- spermatogenic failure 88
- KASH5-related non-obstructive azoospermia
- CCDC155-related male infertility
notes: >-
  MONDO cross-references this disease as OMIM 620547. Scope: this entry
  covers the male phenotype only. Biallelic KASH5 variants also cause female
  premature ovarian insufficiency or diminished ovarian reserve, recorded by
  MONDO as a separate disease, premature ovarian failure 22 (MONDO:0957822),
  which has its own curation stub; the female phenotypes are therefore not
  curated here, although several cited families include affected sisters.
  A homozygous KASH5 missense variant reported in a woman with recurrent
  hydatidiform moles (PMID:42503564) likewise belongs to the female
  phenotype and is not used. No GeneReviews chapter exists for this disease.
  No ClinGen gene-disease validity curation for KASH5 was found in the
  committed ClinGen export. No treatment is curated: none of the cited
  reports describes sperm retrieval or assisted reproduction in an affected
  man, and meiotic arrest before pachytene leaves no post-meiotic germ cells
  to retrieve in the biopsies described. Abstract-only caches: PMID:35674372,
  PMID:35587281, PMID:35708642, PMID:42443317 and PMID:29790874.
inheritance:
- name: Autosomal recessive
  description: >-
    Disease requires biallelic KASH5 variants: homozygous frameshift and
    missense variants in consanguineous families, recessive variants in a
    Middle Eastern consanguineous family, and compound heterozygous
    splice-site variants in a sporadic patient.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:35587281
    reference_title: "Homozygous missense mutation in CCDC155 disrupts the transmembrane distribution of CCDC155 and SUN1, resulting in non-obstructive azoospermia and premature ovarian insufficiency in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified a novel homozygous missense mutation in CCDC155 ... in a pair of familial NOA and POI patients whose parents were first cousins"
    explanation: Homozygous variant from a first-cousin marriage segregating with gametogenic failure.
  - reference: PMID:36864840
    reference_title: "A homozygous KASH5 frameshift mutation causes diminished ovarian reserve, recurrent miscarriage, and non-obstructive azoospermia in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the retained variants, a frameshift mutation in KASH5 was identified recessively segregating with the infertility and recurrent miscarriage within the family"
    explanation: Recessive segregation of a homozygous frameshift in a second consanguineous family.
  - reference: PMID:29790874
    reference_title: "Point-of-care whole-exome sequencing of idiopathic male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In five of eight families, we identified rare deleterious recessive variants in CCDC155, NANOS2, SPO11, TEX14, and WNK3 segregating with disease."
    explanation: First report of recessive CCDC155 (KASH5) variants segregating with non-obstructive azoospermia.
pathophysiology:
- name: KASH5 Loss of Function
  description: >-
    Biallelic KASH5 variants remove the protein or keep it out of the nuclear
    envelope. A homozygous frameshift abolishes KASH5 in the patient's testis.
    The missense p.Leu197Pro in the coiled-coil domain blocks nuclear
    envelope distribution of KASH5 and with it the nuclear-envelope enrichment
    of its partner SUN1. The transmembrane-domain variant p.Leu535Gln
    misroutes KASH5 to mitochondria in cultured cells, and a splice-site
    variant reported in women with ovarian insufficiency weakens nuclear
    envelope localization and SUN1 binding. Splice-site variants found in a
    man with meiotic arrest cause exon skipping in minigene assays.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: KASH5
    term:
      id: hgnc:26520
      label: KASH5
  molecular_functions:
  - preferred_term: Dynein light intermediate chain binding
    term:
      id: GO:0051959
      label: dynein light intermediate chain binding
    modifier: DECREASED
  cellular_components:
  - preferred_term: Meiotic LINC complex
    term:
      id: GO:0034993
      label: meiotic nuclear membrane microtubule tethering complex
  - preferred_term: nuclear envelope
    term:
      id: GO:0005635
      label: nuclear envelope
  locations:
  - preferred_term: testis
    term:
      id: UBERON:0000473
      label: testis
  - preferred_term: seminiferous tubule of testis
    term:
      id: UBERON:0001343
      label: seminiferous tubule of testis
  downstream:
  - target: Uncoupling of Meiotic Telomeres from Cytoplasmic Dynein
    causal_link_type: DIRECT
    description: >-
      Without KASH5 at the outer nuclear membrane, the SUN1-bound telomere
      attachment sites lose their connection to dynein.
    evidence:
    - reference: PMID:35587281
      reference_title: "Homozygous missense mutation in CCDC155 disrupts the transmembrane distribution of CCDC155 and SUN1, resulting in non-obstructive azoospermia and premature ovarian insufficiency in humans."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "eventually leading to disruptive NE anchoring of chromosome-induced meiotic arrest in both sexes"
      explanation: Patient-variant study linking loss of KASH5 nuclear envelope distribution to failed chromosome anchoring at the envelope.
  evidence:
  - reference: PMID:36864840
    reference_title: "A homozygous KASH5 frameshift mutation causes diminished ovarian reserve, recurrent miscarriage, and non-obstructive azoospermia in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This mutation leads to the absence of KASH5 protein expression in testes and non-obstructive azoospermia (NOA) due to meiotic arrest before the pachytene stage in the affected brother."
    explanation: KASH5 protein is absent from the testis of a man homozygous for a frameshift.
  - reference: PMID:35587281
    reference_title: "Homozygous missense mutation in CCDC155 disrupts the transmembrane distribution of CCDC155 and SUN1, resulting in non-obstructive azoospermia and premature ovarian insufficiency in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This rare missense mutation with lesions in the conserved CC domain of CCDC155 blocked nuclear envelope (NE) distribution and subsequently prevented NE-specific enrichment of Sad1- and UNC84-domain-containing 1 either ex vivo or in vitro"
    explanation: The patient missense variant keeps KASH5, and secondarily SUN1, out of the nuclear envelope.
  - reference: PMID:33980926
    reference_title: "A human infertility-associated KASH5 variant promotes mitochondrial localization."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we show that the L535Q substitution perturbs KASH5 localization to the ER and ONM and instead results in mistargeting to the mitochondria membrane"
    explanation: Cell-based study of the azoospermia-associated transmembrane variant.
  - reference: PMID:35708642
    reference_title: "Homozygous Variant in KASH5 Causes Premature Ovarian Insufficiency by Disordered Meiotic Homologous Pairing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro studies found the variant disturbed the nuclear membrane localization of KASH5 and its binding with SUN1."
    explanation: >-
      A splice-site variant found in women with ovarian insufficiency
      impairs the same nuclear membrane localization and SUN1 binding; cited
      for the molecular lesion, not for the female phenotype.
  - reference: PMID:42443317
    reference_title: "Novel variants in LINC and TTM complexes of meiotic chromosome dynamics are associated with meiotic arrest and non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Minigene assays demonstrated that the splice-site variants in KASH5 (c.149-1G>A; c.876+1G>A), TERB2 (c.522A>G), and MAJIN (c.219+1G>T) induced aberrant exon-skipping events."
    explanation: Minigene assays show both splice-site alleles of a compound heterozygous NOA patient disrupt KASH5 splicing.
- name: Uncoupling of Meiotic Telomeres from Cytoplasmic Dynein
  description: >-
    In meiotic prophase I, telomeres attach to the inner nuclear membrane
    through SUN1, and KASH5 links SUN1 across the envelope to cytoplasmic
    dynein, for which it is an activating adaptor; KASH5 also binds the
    kinesin KIF5B. In Kash5-null mouse spermatocytes telomeres still attach
    to the envelope, but they are no longer coupled to the microtubule
    motors that move them and cluster them into the meiotic bouquet.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Primary spermatocyte
    term:
      id: CL:0000656
      label: primary spermatocyte
  biological_processes:
  - preferred_term: Meiotic telomere clustering
    term:
      id: GO:0045141
      label: meiotic telomere clustering
    modifier: DECREASED
  molecular_functions:
  - preferred_term: Dynein complex binding
    term:
      id: GO:0070840
      label: dynein complex binding
    modifier: DECREASED
  cellular_components:
  - preferred_term: nuclear envelope
    term:
      id: GO:0005635
      label: nuclear envelope
  - preferred_term: meiotic nuclear membrane microtubule tethering complex
    term:
      id: GO:0034993
      label: meiotic nuclear membrane microtubule tethering complex
  locations:
  - preferred_term: testis
    term:
      id: UBERON:0000473
      label: testis
  downstream:
  - target: Failed Homologous Chromosome Pairing and Synapsis
    causal_link_type: DIRECT
    description: Telomere-led movement is what brings homologs together, so its loss leaves homologs unpaired.
    evidence:
    - reference: PMID:24062341
      reference_title: "A mammalian KASH domain protein coupling meiotic chromosomes to the cytoskeleton."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These findings demonstrate that telomere attachment to the NE is insufficient to promote pairing and that telomere attachment sites must be coupled to cytoplasmic dynein and the microtubule system to ensure meiotic progression."
      explanation: The Kash5 knockout separates telomere attachment from telomere movement and shows movement is needed for pairing.
  evidence:
  - reference: PMID:22826121
    reference_title: "A conserved KASH domain protein associates with telomeres, SUN1, and dynactin during mammalian meiosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These results suggest that KASH5 connects the telomere-associated SUN1 protein to the cytoplasmic force-generating mechanism involved in meiotic chromosome movement."
    explanation: Mouse spermatocyte study placing KASH5 between SUN1-bound telomeres and the cytoplasmic motor.
  - reference: PMID:35703493
    reference_title: "The KASH5 protein involved in meiotic chromosomal movements is a novel dynein activating adaptor."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that the meiosis-specific nuclear-envelope protein KASH5 is a dynein activating adaptor: KASH5 directly binds dynein using a mechanism conserved among activating adaptors and converts dynein into a processive motor."
    explanation: Reconstitution shows KASH5 activates dynein motility.
  - reference: PMID:36946995
    reference_title: "The meiotic LINC complex component KASH5 is an activating adaptor for cytoplasmic dynein."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Altogether, we show that the transmembrane protein KASH5 is an activating adaptor for dynein and shed light on the hierarchy of assembly of KASH5-dynein-dynactin complexes."
    explanation: Independent confirmation of the dynein adaptor function.
  - reference: PMID:40501626
    reference_title: "Kinesin drive meiotic chromosome dynamics via interaction with the KASH5-LINC complex."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Altogether, our findings identify kinesins, particularly KIF5B, as a previously unrecognized component of the force-generating machinery that drives chromosome movement during meiotic prophase I, acting through KASH5 as a specific nuclear membrane adaptor."
    explanation: Mouse spermatocyte and recombinant-protein study adding kinesin to the motors coupled through KASH5.
- name: Failed Homologous Chromosome Pairing and Synapsis
  description: >-
    Homologous chromosomes do not pair, and the synaptonemal complex does
    not form along full-length homologs. A proband with two rare KASH5
    variants arrested at a zygotene-like stage with deficient pairing and
    synapsis, and Kash5-null mouse spermatocytes never show fully synapsed
    homologs.
  biological_scale: CELLULAR
  conforms_to: "meiotic_prophase_failure#Meiotic Prophase I Entry and Homolog Pairing"
  cell_types:
  - preferred_term: Primary spermatocyte
    term:
      id: CL:0000656
      label: primary spermatocyte
  biological_processes:
  - preferred_term: Homologous chromosome pairing at meiosis
    term:
      id: GO:0007129
      label: homologous chromosome pairing at meiosis
    modifier: DECREASED
  - preferred_term: Synaptonemal complex assembly
    term:
      id: GO:0007130
      label: synaptonemal complex assembly
    modifier: DECREASED
  cellular_components:
  - preferred_term: synaptonemal complex
    term:
      id: GO:0000795
      label: synaptonemal complex
  locations:
  - preferred_term: seminiferous tubule of testis
    term:
      id: UBERON:0001343
      label: seminiferous tubule of testis
  downstream:
  - target: Persistent Unrepaired Meiotic DNA Double-Strand Breaks
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Repair of programmed meiotic breaks depends on a homolog partner, so
      breaks persist when homologs do not engage.
  - target: Spermatocyte Arrest Before Pachytene and Germ Cell Apoptosis
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:35674372
    reference_title: "Novel bi-allelic variants in KASH5 are associated with meiotic arrest and non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spermatogenesis in the proband was arrested at zygotene-like stage with a deficiency in homolog pairing and synapsis."
    explanation: Pairing and synapsis defect in a KASH5 patient's spermatocytes.
  - reference: PMID:24062341
    reference_title: "A mammalian KASH domain protein coupling meiotic chromosomes to the cytoskeleton."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We never observed fully synapsed homologues in Kash5-null spermatocytes."
    explanation: Complete synapsis failure in the knockout mouse.
- name: Persistent Unrepaired Meiotic DNA Double-Strand Breaks
  description: >-
    Programmed meiotic DNA double-strand breaks are made but not resolved.
    Spermatocytes of a homozygous missense patient failed to complete meiosis
    with unresolved break repair, and Kash5-null spermatocytes accumulate
    breaks that are never repaired.
  biological_scale: CELLULAR
  conforms_to: "meiotic_prophase_failure#Homologous Recombination Repair of Meiotic DNA Breaks"
  cell_types:
  - preferred_term: Primary spermatocyte
    term:
      id: CL:0000656
      label: primary spermatocyte
  biological_processes:
  - preferred_term: Reciprocal meiotic recombination
    term:
      id: GO:0007131
      label: reciprocal meiotic recombination
    modifier: DECREASED
  cellular_components:
  - preferred_term: nucleus
    term:
      id: GO:0005634
      label: nucleus
  locations:
  - preferred_term: seminiferous tubule of testis
    term:
      id: UBERON:0001343
      label: seminiferous tubule of testis
  downstream:
  - target: Spermatocyte Arrest Before Pachytene and Germ Cell Apoptosis
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:35587281
    reference_title: "Homozygous missense mutation in CCDC155 disrupts the transmembrane distribution of CCDC155 and SUN1, resulting in non-obstructive azoospermia and premature ovarian insufficiency in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected spermatocytes were unable to complete meiotic division coupled with unresolved repair of the DNA double-strand break."
    explanation: Unresolved break repair in the patient's spermatocytes.
  - reference: PMID:24062341
    reference_title: "A mammalian KASH domain protein coupling meiotic chromosomes to the cytoskeleton."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The conclusion is that Kash5-null spermatocytes accumulate DSBs that are never resolved."
    explanation: Persistent breaks in the knockout mouse.
- name: Spermatocyte Arrest Before Pachytene and Germ Cell Apoptosis
  description: >-
    Spermatocytes that cannot pair, synapse and repair their breaks arrest
    at a zygotene-like stage before pachytene and are eliminated, so no
    post-meiotic germ cells form. In Kash5-null testes widespread apoptosis
    is seen in about 30% of tubule cross sections.
  biological_scale: CELLULAR
  conforms_to: "meiotic_prophase_failure#Pachytene Checkpoint Arrest and Germ Cell Apoptosis"
  cell_types:
  - preferred_term: Primary spermatocyte
    term:
      id: CL:0000656
      label: primary spermatocyte
  biological_processes:
  - preferred_term: Apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  locations:
  - preferred_term: seminiferous tubule of testis
    term:
      id: UBERON:0001343
      label: seminiferous tubule of testis
  downstream:
  - target: Spermatogenic Arrest and Non-Obstructive Azoospermia
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:36864840
    reference_title: "A homozygous KASH5 frameshift mutation causes diminished ovarian reserve, recurrent miscarriage, and non-obstructive azoospermia in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results indicated that the male patient suffered from NOA and his spermatogenesis was arrested at the spermatocyte stage."
    explanation: Testicular biopsy shows spermatocyte-stage arrest in a homozygous frameshift patient.
  - reference: PMID:42443317
    reference_title: "Novel variants in LINC and TTM complexes of meiotic chromosome dynamics are associated with meiotic arrest and non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Testicular histology and immunofluorescence analyses concordantly demonstrated a shared phenotype of meiotic prophase I arrest and absence of post-meiotic germ cells in these patients."
    explanation: >-
      Prophase I arrest without post-meiotic cells in a cohort that includes
      a compound heterozygous KASH5 patient; the sentence is shared across
      the LINC and TTM gene patients of that study.
  - reference: PMID:24062341
    reference_title: "A mammalian KASH domain protein coupling meiotic chromosomes to the cytoskeleton."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In Kash5-null testes, widespread TUNEL staining is seen in ∼30% of tubule cross sections."
    explanation: Germ cell apoptosis in the knockout mouse.
- name: Spermatogenic Arrest and Non-Obstructive Azoospermia
  description: >-
    With spermatogenesis halted in meiotic prophase I, no sperm reach the
    ejaculate, giving non-obstructive azoospermia and primary male
    infertility.
  biological_scale: TISSUE
  conforms_to: "meiotic_prophase_failure#Spermatogenic Arrest and Non-Obstructive Azoospermia"
  cell_types:
  - preferred_term: Spermatocyte
    term:
      id: CL:0000017
      label: spermatocyte
  biological_processes:
  - preferred_term: Male gamete generation
    term:
      id: GO:0048232
      label: male gamete generation
    modifier: DECREASED
  locations:
  - preferred_term: testis
    term:
      id: UBERON:0000473
      label: testis
  - preferred_term: seminiferous tubule of testis
    term:
      id: UBERON:0001343
      label: seminiferous tubule of testis
  downstream:
  - target: Non-obstructive azoospermia
    causal_link_type: DIRECT
  - target: Spermatocyte maturation arrest
    causal_link_type: DIRECT
  - target: Male infertility
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:35674372
    reference_title: "Novel bi-allelic variants in KASH5 are associated with meiotic arrest and non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Collectively, we have identified novel rare variants within human KASH5 in patients with NOA and meiosis arrest."
    explanation: Meiotic arrest with NOA in KASH5 patients.
phenotypes:
- category: Reproductive
  name: Male infertility
  description: Primary infertility is the presenting complaint in affected men.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:33980926
    reference_title: "A human infertility-associated KASH5 variant promotes mitochondrial localization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "A recent study identified a variant in human KASH5 (L535Q) that correlated with male infertility associated with azoospermia."
    explanation: The authors' summary of the earlier exome study that found the variant in infertile men.
  - reference: PMID:36864840
    reference_title: "A homozygous KASH5 frameshift mutation causes diminished ovarian reserve, recurrent miscarriage, and non-obstructive azoospermia in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IV:4 (41-yr-old) has been married for 19 years, but suffered from infertility"
    explanation: Long-standing infertility in the affected brother.
- category: Reproductive
  name: Non-obstructive azoospermia
  diagnostic: true
  description: No sperm in the ejaculate because spermatogenesis fails, not because of obstruction.
  phenotype_term:
    preferred_term: Non-obstructive azoospermia
    term:
      id: HP:0011961
      label: Non-obstructive azoospermia
  evidence:
  - reference: PMID:35674372
    reference_title: "Novel bi-allelic variants in KASH5 are associated with meiotic arrest and non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "were identified in a non-obstructive azoospermia (NOA)-affected patient and in his infertile sister by whole-exome sequencing and CNV array"
    explanation: NOA in a KASH5 patient.
  - reference: PMID:36864840
    reference_title: "A homozygous KASH5 frameshift mutation causes diminished ovarian reserve, recurrent miscarriage, and non-obstructive azoospermia in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This mutation leads to the absence of KASH5 protein expression in testes and non-obstructive azoospermia (NOA) due to meiotic arrest before the pachytene stage in the affected brother."
    explanation: NOA in a homozygous frameshift patient.
  - reference: PMID:35587281
    reference_title: "Homozygous missense mutation in CCDC155 disrupts the transmembrane distribution of CCDC155 and SUN1, resulting in non-obstructive azoospermia and premature ovarian insufficiency in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified a novel homozygous missense mutation in CCDC155 ... in a pair of familial NOA and POI patients whose parents were first cousins"
    explanation: NOA in a homozygous missense patient.
- category: Reproductive
  name: Spermatocyte maturation arrest
  diagnostic: true
  description: >-
    Testicular histology shows germ cells reaching the spermatocyte stage
    and arresting in meiotic prophase I, at a zygotene-like stage before
    pachytene.
  phenotype_term:
    preferred_term: Spermatocyte maturation arrest
    term:
      id: HP:0031039
      label: Spermatocyte maturation arrest
  evidence:
  - reference: PMID:35674372
    reference_title: "Novel bi-allelic variants in KASH5 are associated with meiotic arrest and non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spermatogenesis in the proband was arrested at zygotene-like stage with a deficiency in homolog pairing and synapsis."
    explanation: Zygotene-like spermatocyte arrest.
  - reference: PMID:36864840
    reference_title: "A homozygous KASH5 frameshift mutation causes diminished ovarian reserve, recurrent miscarriage, and non-obstructive azoospermia in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results indicated that the male patient suffered from NOA and his spermatogenesis was arrested at the spermatocyte stage."
    explanation: Spermatocyte-stage arrest on testicular biopsy.
diagnosis:
- name: Semen Analysis
  presence: PRESENT
  diagnosis_term:
    preferred_term: Microscopy
    term:
      id: NCIT:C16853
      label: Microscopy
  description: >-
    Repeat microscopic semen analyses performed according to World Health
    Organization guidelines to evaluate ejaculate volume and sperm count.
  results: >-
    Normal semen volume with complete absence of spermatozoa in the ejaculate
    (azoospermia).
  evidence:
  - reference: PMID:36864840
    reference_title: "A homozygous KASH5 frameshift mutation causes diminished ovarian reserve, recurrent miscarriage, and non-obstructive azoospermia in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IV:4 had two semen analyses conducted following the WHO guidelines, and both examinations showed that he had normal semen volume but no sperm seen in the ejaculates"
    explanation: >-
      Establishes repeat WHO-standard semen analyses demonstrating azoospermia
      with normal ejaculate volume.
- name: Testicular Biopsy and Histopathologic Examination
  presence: PRESENT
  diagnosis_term:
    preferred_term: Biopsy Procedure
    term:
      id: NCIT:C15189
      label: Biopsy Procedure
  description: >-
    Testicular biopsy with hematoxylin-eosin histology and meiotic
    immunofluorescence staining (e.g., gamma-H2AX, PNA, H3S10p) to determine the
    stage of spermatogenic arrest.
  results: >-
    Presence of spermatogonia and primary spermatocytes with complete absence of
    post-meiotic spermatids and spermatozoa in seminiferous tubules, confirming
    meiotic arrest prior to pachytene.
  evidence:
  - reference: PMID:36864840
    reference_title: "A homozygous KASH5 frameshift mutation causes diminished ovarian reserve, recurrent miscarriage, and non-obstructive azoospermia in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hematoxylin and eosin (H&E) staining of testicular sections revealed the presence of many spermatogonia and primary spermatocytes but a complete absence of spermatids and sperm in seminiferous tubules of IV:4"
    explanation: >-
      Demonstrates that testicular biopsy histology identifies primary
      spermatocyte arrest and absence of post-meiotic germ cells.
- name: Whole-Exome Sequencing
  presence: PRESENT
  diagnosis_term:
    preferred_term: Whole Exome Sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  description: >-
    Whole-exome sequencing (with copy-number variant analysis and Sanger
    confirmation) to identify biallelic pathogenic variants in KASH5.
  results: >-
    Identification of homozygous or compound heterozygous loss-of-function,
    splice-site, or missense variants in KASH5.
  evidence:
  - reference: PMID:36864840
    reference_title: "A homozygous KASH5 frameshift mutation causes diminished ovarian reserve, recurrent miscarriage, and non-obstructive azoospermia in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we applied whole-exome sequencing for a consanguineous family with five siblings suffering from reproductive failure, and identified a homozygous frameshift mutation in KASH5 (c.1270_1273del, p.Arg424Thrfs*20)."
    explanation: >-
      Establishes whole-exome sequencing as the molecular diagnostic method for
      identifying causative KASH5 variants.
genetic:
- name: KASH5
  association: Causal
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: KASH5
    term:
      id: hgnc:26520
      label: KASH5
  notes: >-
    Previous symbol CCDC155. Reported male-patient alleles include homozygous
    c.1270_1273del (p.Arg424Thrfs*20) (PMID:36864840), homozygous c.590T>C
    (p.Leu197Pro) (PMID:35587281), the transmembrane-domain missense
    p.Leu535Gln from a Middle Eastern exome study (PMID:29790874, as
    described by PMID:33980926), compound heterozygous splice-site variants
    c.149-1G>A and c.876+1G>A (NM_144688.5) (PMID:42443317), and a
    heterozygous 19q13.33 deletion together with c.979_980del
    (p.Arg327Serfs*21) (PMID:35674372), whose abstract does not state the
    phase of the two alleles.
  evidence:
  - reference: PMID:35674372
    reference_title: "Novel bi-allelic variants in KASH5 are associated with meiotic arrest and non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a heterozygous loss of function variant (NM_144688: c.979_980del: p.R327Sfs*21) in human KASH5 were identified in a non-obstructive azoospermia (NOA)-affected patient"
    explanation: A frameshift allele, with a copy-number deletion, in an NOA patient.
  - reference: PMID:42443317
    reference_title: "Novel variants in LINC and TTM complexes of meiotic chromosome dynamics are associated with meiotic arrest and non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including compound heterozygous variants in KASH5 (NM_144688.5:c.149-1G>A; NM_144688.5:c.876+1G>A)"
    explanation: Independent compound heterozygous patient with meiotic arrest.
  - reference: PMID:36864840
    reference_title: "A homozygous KASH5 frameshift mutation causes diminished ovarian reserve, recurrent miscarriage, and non-obstructive azoospermia in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified a homozygous frameshift mutation in KASH5 (c.1270_1273del, p.Arg424Thrfs*20)"
    explanation: Homozygous truncating allele in a consanguineous family.
animal_models:
- name: Kash5-null mouse
  species: Mouse
  genotype: Kash5 knockout, homozygous
  publication: PMID:24062341
  description: >-
    Kash5-deficient mice are infertile in both sexes. Male spermatocytes
    arrest in meiotic prophase with failed pairing and synapsis, persistent
    DNA double-strand breaks and apoptosis, while telomeres still attach to
    the nuclear envelope.
  genes:
  - preferred_term: KASH5
    term:
      id: hgnc:26520
      label: KASH5
  modeled_mechanisms:
  - target: Failed Homologous Chromosome Pairing and Synapsis
    relationship: RECAPITULATES
    fidelity: HIGH
    description: Null spermatocytes fail to pair and synapse homologs, as in patient spermatocytes.
    limitations: >-
      The knockout is a complete null, whereas several human alleles are
      missense or splice variants whose residual function is not measured.
    evidence:
    - reference: PMID:35674372
      reference_title: "Novel bi-allelic variants in KASH5 are associated with meiotic arrest and non-obstructive azoospermia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Kash5 knockout mouse displayed similar phenotypes, including a meiotic arrest at a zygotene-like stage and impaired pairing and synapsis."
      explanation: Authors' comparison of the knockout with their patient.
  - target: Spermatogenic Arrest and Non-Obstructive Azoospermia
    relationship: RECAPITULATES
    fidelity: HIGH
    description: Male knockouts are infertile from meiotic arrest.
    evidence:
    - reference: PMID:24062341
      reference_title: "A mammalian KASH domain protein coupling meiotic chromosomes to the cytoskeleton."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Males display meiotic arrest in which pairing of homologous chromosomes fails."
      explanation: Male meiotic arrest in the knockout.

📚

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 88 · 2026-10-22T21:28:16Z · View source

New entry for spermatogenic failure 88 (MONDO:0957821, OMIM 620547), autosomal recessive non-obstructive azoospermia from biallelic KASH5 (CCDC155) variants. Scope is the male disease only; the female KASH5 phenotype is a separate MONDO disease (premature ovarian failure 22, MONDO:0957822) with its own stub, and is mentioned only in notes. Pathograph: KASH5 loss of function -> uncoupling of meiotic telomeres from cytoplasmic dynein -> failed homolog pairing and synapsis -> persistent unrepaired meiotic DSBs -> spermatocyte arrest before pachytene with apoptosis -> spermatogenic arrest and NOA, with the last four nodes conforming to meiotic_prophase_failure. Evidence comes from five human reports (PMID:29790874, 35674372, 35587281, 36864840, 42443317), the Kash5 knockout mouse (PMID:24062341), mouse spermatocyte and reconstitution studies of KASH5 as a dynein activating adaptor (PMID:22826121, 35703493, 36946995, 40501626), and an in vitro variant study (PMID:33980926). PMID:35708642 (female POI) is cited only for its in vitro localization result. No treatment curated: no cited report describes sperm retrieval or assisted reproduction in an affected man. Deep research: one openscientist report (research/Spermatogenic_Failure_88-deep-research-openscientist.md). It ran with causal_genes "not recorded" because the stub names KASH5 only in source_tags (issue #15216), but stayed on KASH5 (63 mentions; preflight-dr matched gene and OMIM 620547; SUN1 is the LINC partner, not a second disease). 9/9 references resolved; its citations overlap the set above and add nothing used here. Validation: just validate, validate-terms, count-verified-snippets (34/34), check-entity-refs, check-causal-targets, check-duplicate-keys, check-snippet-length, check-gene-activity-grounding, check-title-snippets, check-snippet-grading, check-reference-titles, check-coarse-phenotypes, check-environmental-evidence and check-genereviews (no chapter) all pass; validate-disorders run before the PR.

OpenScientist ▸

Spermatogenic Failure 88 (SPGF88): A Comprehensive Disease Characterization Report

openscientist-autonomous 8 citations 2026-10-22T21:11:42.813796

Spermatogenic Failure 88 (SPGF88): A Comprehensive Disease Characterization Report

Causal gene: KASH5 (also known as CCDC155; aliases POF22, HYDM6), chromosome 19q13.33, NCBI Gene 147872, Ensembl ENSG00000161609, UniProt Q8N6L0.

Identifier verification. The research template supplied MONDO:0957821. This term maps to OMIM 620547, MedGen C5882706, and the NCBI gene link for this concept points unambiguously to KASH5 / CCDC155 (Gene ID 147872) at 19q13.33. This report therefore describes the KASH5-related disease, not any similarly numbered SPGF entry caused by a different gene.

Summary

Spermatogenic failure 88 (SPGF88; MONDO:0957821; OMIM 620547) is an ultra-rare, autosomal recessive form of male infertility caused by biallelic loss-of-function variants in KASH5, also known as CCDC155 (NCBI Gene 147872; aliases KASH5, POF22, HYDM6), located on chromosome 19q13.33. KASH5 encodes the meiosis-specific outer-nuclear-membrane dynein adaptor of the SUN1–KASH5 LINC complex (Linker of Nucleoskeleton and Cytoskeleton). This complex physically couples meiotic telomeres, through the nuclear envelope, to cytoplasmic dynein and the microtubule cytoskeleton, generating the telomere-led chromosome movements that drive homologous-chromosome pairing and synapsis during meiotic prophase I.

When KASH5 function is lost, telomere-led chromosome movements and "bouquet" formation fail, homologous chromosomes do not pair or synapse, and meiotic DNA double-strand breaks (DSBs) are left unresolved. The consequence is an arrest of spermatogenesis at the zygotene-like (pre-pachytene) stage, which manifests clinically as non-obstructive azoospermia (NOA) — the complete absence of spermatozoa in the ejaculate due to a spermatogenic (rather than obstructive) defect. The identical molecular lesion causes premature ovarian insufficiency (POI/POF22) in females, making this a shared male–female meiotic-arrest disorder. Kash5-knockout mice faithfully recapitulate the human zygotene arrest and are infertile in both sexes, providing strong cross-species mechanistic confirmation.

Three independent human reports (Fakhro et al. 2018; Wu et al. 2022; Yang et al. 2022) establish KASH5/CCDC155 as a bona fide human NOA gene, with pathogenic alleles spanning frameshift, whole/partial-gene-deletion CNV, splice-site, and coiled-coil missense classes — all converging on loss of LINC-complex function. There is no curative therapy; management centers on genetic counseling and assisted reproduction (with donor sperm the likely route given expected poor surgical sperm-retrieval yield). This report compiles disease information, etiology, phenotypes, genetics, mechanism, affected anatomy, temporal course, epidemiology, diagnostics, prognosis, treatment, prevention, and comparative/model-organism biology across all 15 requested sections.

Key Findings

Finding 1 — SPGF88 is caused by biallelic KASH5/CCDC155 loss-of-function variants at 19q13.33

OMIM 620547 and MedGen C5882706 map SPGF88 to the gene KASH5 (NCBI Gene 147872; aliases CCDC155, POF22, HYDM6) at 19q13.33. In the index genotype, Yang et al. 2022 identified a heterozygous copy-number deletion del(19)(q13.33) (chr19:g.49894043-49903011del) in trans with a heterozygous frameshift LoF variant NM_144688:c.979_980del, p.(Arg327Serfs*21) in a man with non-obstructive azoospermia and in his infertile sister. This compound-heterozygous (biallelic) configuration abolishes functional KASH5 and produced spermatogenic arrest at a zygotene-like stage.

"a novel heterozygous copy number variation (CNV) (seq [GRCh37] del(19) (19q13.33) chr19: g.49894043-49903011del) and a heterozygous loss of function variant (NM_144688: c.979_980del: p.R327Sfs21) in human KASH5 were identified in a non-obstructive azoospermia (NOA)-affected patient and in his infertile sister"* — PMID: 35674372

This is the anchoring genetic finding: it establishes the gene, the locus, the biallelic recessive mechanism, and the loss-of-function variant classes (frameshift + CNV deletion).

Finding 2 — KASH5 loss arrests meiosis at the zygotene stage via failed homolog pairing/synapsis (conserved human–mouse mechanism)

In the human KASH5-deficient proband, spermatogenesis arrested at a zygotene-like stage with deficient homolog pairing and synapsis. This directly mirrors the original Kash5-null mouse (Horn et al. 2013), in which males show meiotic arrest with failed pairing of homologous chromosomes and resulting infertility in both sexes. The concordance across species confirms the human phenotype is a direct consequence of lost LINC-complex–mediated telomere–cytoskeleton coupling.

"Males display meiotic arrest in which pairing of homologous chromosomes fails. These findings demonstrate that telomere attachment to the NE is insufficient to promote pairing and that telomere attachment sites must be coupled to cytoplasmic dynein and the microtubule system to ensure meiotic progression." — PMID: 24062341

"Spermatogenesis in the proband was arrested at zygotene-like stage with a deficiency in homolog pairing and synapsis" — PMID: 35674372

Finding 3 — KASH5 is loss-of-function–tolerant in gnomAD, consistent with a recessive mechanism

gnomAD v4 constraint metrics for KASH5 (ENSG00000161609) show the gene is not depleted of heterozygous LoF variants: pLI ≈ 0 (2.96×10⁻²¹), observed/expected LoF = 0.85 (90% CI 0.71–1.04; LOEUF ≈ 1.04), with 72 observed vs 84 expected LoF variants. This tolerance of heterozygous LoF is exactly what is expected for an autosomal recessive disease gene — heterozygous carriers are unaffected and disease requires biallelic hits. It also argues against a dominant-negative or haploinsufficiency model.

Finding 4 — A homozygous coiled-coil missense (p.Leu197Pro) causes NOA and POI by mislocalizing the LINC complex

Wu et al. 2022 performed whole-exome sequencing on 15 consanguineous NOA/POI patients and identified a homozygous missense variant in the conserved coiled-coil (CC) domain of CCDC155/KASH5, c.590T>C, p.(Leu197Pro), in a brother–sister pair whose parents were first cousins. Functionally, the variant blocked nuclear-envelope (NE) distribution of KASH5 and prevented NE-specific enrichment of SUN1, and affected spermatocytes failed to complete meiotic division with unresolved DNA double-strand-break repair. This adds a missense variant class and an explicit DSB-repair-failure step to the mechanism. Per UniProt Q8N6L0, KASH5 is a 562-aa protein with a coiled-coil domain (residues 164–349) and a C-terminal transmembrane KASH anchor (522–542); it localizes to telomeres from leptotene to diplotene.

"identified a novel homozygous missense mutation in CCDC155 [c.590T>C (p.Leu197Pro)] in a pair of familial NOA and POI patients whose parents were first cousins" — PMID: 35587281

"blocked nuclear envelope (NE) distribution and subsequently prevented NE-specific enrichment of Sad1- and UNC84-domain-containing 1 either ex vivo or in vitro" — PMID: 35587281

Finding 5 — First human KASH5–NOA link (Fakhro et al. 2018) and the authoritative HPO annotation set

Fakhro et al. 2018 (Genetics in Medicine) performed WES across 8 consanguineous Middle Eastern (Qatari) NOA families and identified rare deleterious recessive variants in CCDC155 (KASH5) — along with NANOS2, SPO11, TEX14, and WNK3 — segregating with disease, the earliest human evidence for KASH5-related NOA and a foundational source for OMIM 620547. The official Human Phenotype Ontology annotations for OMIM:620547 (ontology.jax.org) are: HP:0003251 Male infertility (3/3 patients), HP:0011961 Non-obstructive azoospermia (3/3), HP:0031039 Spermatocyte maturation arrest (2/2), HP:0011462 Young adult onset (2/2), and HP:0000007 Autosomal recessive inheritance.

"we identified rare deleterious recessive variants in CCDC155, NANOS2, SPO11, TEX14, and WNK3 segregating with disease. These genes, which are novel to human NOA, have remarkable testis-specific expression" — PMID: 29790874

"Nonobstructive azoospermia (NOA) affects 1% of the male population" — PMID: 29790874

Section-by-Section Report

1. Disease Information

SPGF88 is a monogenic (Mendelian), autosomal recessive form of non-obstructive azoospermia — a spermatogenic failure in which no spermatozoa reach the ejaculate because germ-cell development is arrested within the testis, with patent excurrent ducts. It is one of a numbered series of "spermatogenic failure" OMIM entries, each defined by its causal gene; SPGF88's gene is KASH5/CCDC155.

Key identifiers: - OMIM: 620547 - MONDO: MONDO:0957821 - MedGen: C5882706 - Gene: KASH5 / CCDC155 (NCBI Gene 147872; Ensembl ENSG00000161609; UniProt Q8N6L0) - Locus: 19q13.33 - ICD-10: N46.x (male infertility; no SPGF88-specific code); ICD-11: GB04 (male infertility). No disease-specific ICD code exists. - Orphanet / MeSH: No SPGF88-specific entry; subsumed under azoospermia / male infertility (MeSH D053713 Azoospermia).

Synonyms / alternative names: Spermatogenic failure 88; SPGF88; non-obstructive azoospermia due to KASH5/CCDC155 deficiency. The female-manifesting counterpart at the same locus is designated POF22 (premature ovarian failure 22).

Source of information: Aggregated, disease-level resources (OMIM, MedGen, HPO) built from a small number of individual-patient case reports in consanguineous/familial cohorts — not from large EHR datasets. The total reported human caseload is a handful of patients across three publications.

2. Etiology

Primary cause — genetic. SPGF88 is caused exclusively by biallelic (homozygous or compound-heterozygous) loss-of-function variants in KASH5/CCDC155. No environmental, infectious, or acquired cause is implicated; this is a pure Mendelian meiotic defect.

Genetic risk factors. The causal variants reported span several classes, all converging on loss of KASH5 function: - Frameshift LoF: c.979_980del, p.(Arg327Serfs*21) (Yang 2022) - Whole/partial-gene deletion CNV: del(19)(q13.33) chr19:g.49894043-49903011del (Yang 2022) - Coiled-coil missense: c.590T>C, p.(Leu197Pro) (Wu 2022) - Splice-site (in the POI-manifesting form): c.747G>A (Zhang et al. 2022, POI pedigree) - Rare deleterious recessive variant(s) in CCDC155 (Fakhro 2018)

Consanguinity is the dominant risk modifier: homozygous cases arose in first-cousin unions (Wu 2022; Fakhro 2018), reflecting the general pattern for ultra-rare recessive disease.

Environmental / lifestyle / infectious risk factors: None known or expected for this monogenic disorder. General NOA risk factors (heat, toxins, chemotherapy, Y-microdeletions, Klinefelter syndrome) are differential diagnoses, not contributors to SPGF88 itself.

Protective factors: None identified. By inference, a single functional KASH5 allele is fully protective (carriers are fertile and unaffected), consistent with the gnomAD LoF tolerance (Finding 3).

Gene–environment interactions: None documented; the phenotype is fully penetrant genetically without a known environmental trigger.

3. Phenotypes

The phenotype is reproductive and, in males, essentially monosymptomatic at the organismal level.

Phenotype	HPO term	Type	Frequency (reported)	Onset	Severity/Course
Male infertility	HP:0003251	Clinical sign	3/3	Young adult	Severe, stable, lifelong
Non-obstructive azoospermia	HP:0011961	Laboratory abnormality	3/3	Young adult	Severe, stable
Spermatocyte maturation arrest	HP:0031039	Histopathology	2/2	—	Severe (zygotene arrest)
Young adult onset	HP:0011462	Onset modifier	2/2	~20s–30s	—
(Female counterpart) Premature ovarian insufficiency	HP:0008209	Clinical sign	POI pedigrees	Young adult	Progressive loss of ovarian reserve

Characteristics. Onset is effectively congenital at the cellular level (the meiotic machinery is defective from the first wave of spermatogenesis) but is clinically recognized in young adulthood when infertility prompts evaluation. Severity is severe (complete azoospermia; no spontaneous conception possible), the course is stable/non-progressive in males (no systemic decline), and penetrance for infertility appears complete in biallelic individuals.

Quality-of-life impact. The burden is confined to reproduction: inability to father children biologically, with the attendant psychological and relationship impact well documented for NOA generally. There is no systemic morbidity, pain, or reduction in life expectancy. No disease-specific QoL instrument data (EQ-5D/SF-36) exist for SPGF88; impact is inferred from the broader NOA/infertility literature.

4. Genetic/Molecular Information

Causal gene: KASH5 / CCDC155 (NCBI Gene 147872; Ensembl ENSG00000161609; UniProt Q8N6L0), 19q13.33. Transcript reference NM_144688. The protein is 562 aa with a central coiled-coil domain (aa 164–349) and a C-terminal KASH transmembrane anchor (aa 522–542).

Pathogenic variants (all germline):

Variant (cDNA / protein)	Type	Zygosity	Classification	Reference
c.979_980del / p.(Arg327Serfs*21)	Frameshift (LoF)	Compound het (with CNV)	Pathogenic	Yang 2022 [PMID 35674372]
del(19)(q13.33) chr19:g.49894043-49903011del	CNV deletion (LoF)	Compound het	Pathogenic	Yang 2022 [PMID 35674372]
c.590T>C / p.(Leu197Pro)	Missense (coiled-coil)	Homozygous	Likely pathogenic / Pathogenic	Wu 2022 [PMID 35587281]
c.747G>A	Splice-site	Homozygous	Pathogenic (POI form)	Zhang 2022 [PMID 35708642]
CCDC155 rare recessive variant(s)	Deleterious recessive	Recessive	—	Fakhro 2018 [PMID 29790874]

Allele frequency: All reported variants are rare/private; KASH5 is not depleted of LoF in gnomAD (Finding 3), consistent with rare recessive carriers in the general population.

Functional consequence: Loss of function across all variant classes — truncation/deletion removes the protein; the p.Leu197Pro missense abolishes NE localization and SUN1 recruitment. No gain-of-function or dominant-negative mechanism is supported (the gene's LoF tolerance argues against dominant effects).

Modifier genes: None established. Functional partners whose loss produces overlapping meiotic-arrest phenotypes include SUN1, SPDYA (Speedy A)/CDK2, and the telomere-attachment machinery (TERB1/TERB2/MAJIN), but these are separate SPGF/POI loci, not SPGF88 modifiers.

Epigenetic information: None specific to SPGF88 reported.

Chromosomal abnormalities: The CNV deletion at 19q13.33 removing KASH5 (Yang 2022) is the relevant large-scale lesion; otherwise the karyotype is normal (SPGF88 is distinct from Klinefelter/Y-microdeletion azoospermia).

5. Environmental Information

Not applicable. SPGF88 is a monogenic meiotic disorder with no established environmental, lifestyle (smoking/diet/alcohol/exercise), or infectious contribution. Such factors belong to the differential diagnosis of acquired/idiopathic NOA, not to this entity.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

Biallelic LoF variant in KASH5/CCDC155 (frameshift, CNV deletion, splice, or coiled-coil missense) leads to absence or mislocalization of functional KASH5 protein.
Loss of KASH5 at the outer nuclear membrane results in failure to assemble the meiosis-specific SUN1–KASH5 LINC complex at telomere attachment sites (demonstrated: p.Leu197Pro blocks NE distribution and SUN1 enrichment).
Absent LINC complex leads to failure to recruit cytoplasmic dynein and couple telomeres to the microtubule cytoskeleton (KASH5 is the dynein adaptor).
Loss of dynein/microtubule coupling results in loss of telomere-led rapid chromosome movements and failure of meiotic "bouquet" formation (inferred in human from mouse; demonstrated in mouse).
Absent chromosome movements lead to failed homologous-chromosome pairing and synapsis (demonstrated in human proband and in Kash5-null mice).
Failed synapsis results in unresolved meiotic DNA double-strand-break (DSB) repair (demonstrated for p.Leu197Pro spermatocytes).
Unresolved DSBs and asynapsis trigger the meiotic checkpoint and arrest at the zygotene-like (pre-pachytene) stage (demonstrated).
Meiotic arrest leads to germ-cell elimination / spermatocyte maturation arrest, so no haploid spermatids or spermatozoa form.
Absence of spermatozoa manifests as non-obstructive azoospermia and male infertility (clinical endpoint).
Branch (female): The identical LINC-complex failure in oocytes leads to accelerated oocyte depletion and premature ovarian insufficiency (POF22).

Upstream vs downstream: Steps 1–3 (variant → LINC assembly failure → dynein uncoupling) are upstream molecular causes; steps 5–7 (asynapsis, DSB persistence, checkpoint arrest) are the midstream meiotic failures; steps 8–9 (germ-cell loss, azoospermia) are the downstream clinical outcomes.

Molecular pathways / processes: Meiotic telomere clustering and bouquet formation; LINC-complex nucleocytoskeletal coupling; dynein/microtubule-based chromosome motility; meiotic homologous recombination / DSB repair; synaptonemal-complex assembly. KASH5 also participates in the SUN1–SPDYA–CDK2 telomere architecture (PMID: 34039995).

Protein dysfunction: Loss of the KASH anchor (truncation/deletion) or loss of coiled-coil–mediated NE targeting (p.Leu197Pro) prevents KASH5 from bridging the perinuclear space and binding SUN1 — a loss-of-function structural defect. No experimental structure of human KASH5 has been deposited in the PDB (verified); the AlphaFold model of Q8N6L0 is the available structural proxy.

Suggested GO / CL terms: - GO:0007129 homologous chromosome pairing at meiosis - GO:0007130 synaptonemal complex assembly - GO:0070197 meiotic attachment of telomere to nuclear envelope - GO:0034993 meiotic nuclear membrane microtubule tethering complex - GO:0051321 meiotic cell cycle - GO:0000724 DSB repair via homologous recombination - Cellular component: GO:0005640 nuclear outer membrane; GO:0034993 LINC complex - CL:0000017 / CL:0000656 spermatocyte; CL:0000020 spermatogonium; CL:0000023 oocyte

7. Anatomical Structures Affected

Organ level (primary): Testis (UBERON:0000473); specifically the seminiferous tubules (UBERON:0001343). Female counterpart: ovary (UBERON:0000992).
Body system: Male reproductive system (UBERON:0000079); the endocrine axis is typically intact (a hypergonadotropic pattern is possible secondary to germ-cell loss).
Tissue/cell level: Germinal epithelium; the targeted population is the primary spermatocyte (CL:0000656 / CL:0000017) arrested at zygotene. Somatic Sertoli and Leydig cells are not the primary defect. In females, oocytes (CL:0000023).
Subcellular level: Nuclear envelope / outer nuclear membrane (GO:0005640); telomere attachment sites; the LINC complex spanning the perinuclear space; nucleus–cytoskeleton interface.
Localization / lateralization: Bilateral (both testes affected), symmetric. Testicular volume may be preserved or reduced; ducts are patent (non-obstructive).

8. Temporal Development

Onset: Cellular defect is congenital (present from the first meiotic wave at puberty); clinical onset is young-adult (HP:0011462), when infertility is discovered. Onset pattern is insidious/chronic — there is no acute event.
Progression: Stable and non-progressive in males — azoospermia is a fixed developmental block, not a degenerative process; lifelong/chronic. In females, the ovarian phenotype (POF22) is progressive (accelerated depletion of the oocyte pool).
Patterns: No remission; no relapsing course. The critical period is meiotic prophase I — the window in which the LINC complex is required — which is irreversibly missed.

9. Inheritance and Population

Inheritance: Autosomal recessive (HP:0000007); biallelic variants required. Heterozygous carriers are unaffected (consistent with gnomAD LoF tolerance, Finding 3).
Penetrance: Appears complete for infertility in biallelic males within reported families (small n).
Expressivity: Consistent severe phenotype (azoospermia) in males; sex-specific expressivity (NOA in males, POI in females) at the same locus.
Consanguinity: Major contributor — homozygous cases arose in first-cousin families (Wu 2022; Fakhro 2018, Qatari cohort).
Founder effects / carrier frequency: None established; variants are private/rare. KASH5 is not LoF-depleted in gnomAD, so rare carriers exist broadly.
Epidemiology: No SPGF88-specific prevalence/incidence exists — it is an ultra-rare monogenic cause within the broad NOA category. Context: "Nonobstructive azoospermia (NOA) affects 1% of the male population" (PMID: 29790874). In the Fakhro consanguineous-cohort analysis, a genetic etiology was found in 13.3% of idiopathic NOA families vs 0 controls (p=0.001), of which CCDC155 was one contributing gene.
Demographics: Reported in Middle Eastern (Qatari) and East Asian (Chinese) consanguineous/familial settings; this reflects ascertainment in consanguineous populations rather than true geographic restriction. Sex ratio is not meaningful (the male disorder affects males; the allelic female disorder is POF22).

10. Diagnostics

Semen analysis: Confirms azoospermia (no sperm on centrifuged pellet) across ≥2 samples — the defining laboratory test.
Hormonal profile: FSH/LH/testosterone to classify as non-obstructive (often elevated FSH with germ-cell loss); distinguishes from obstructive azoospermia.
Physical/imaging: Scrotal ultrasound to exclude obstruction; testicular volume assessment.
Testicular histopathology/biopsy: Spermatocyte maturation (meiotic) arrest at zygotene/pre-pachytene (HP:0031039) — the pathognomonic histology.
Genetic testing — the definitive diagnostic: First exclude Y-chromosome microdeletions and karyotype (Klinefelter). Then whole-exome sequencing (WES) or a male-infertility/NOA gene panel including CCDC155/KASH5 identifies biallelic variants. Chromosomal microarray / CNV analysis is needed to detect the 19q13.33 deletion allele (as in Yang 2022, where one allele was a CNV). Single-gene testing of KASH5 is appropriate where a familial variant is known.
Omics: KASH5/CCDC155 shows testis-specific expression (PMID: 29790874), supporting candidacy; research scRNA-seq frameworks are emerging for NOA gene prioritization but are not clinical.
Differential diagnosis: Obstructive azoospermia (normal FSH, patent-duct defect), Klinefelter (47,XXY), Y-microdeletions (AZFa/b/c), and other monogenic meiotic-arrest genes (SYCP3, TEX11, MEIOB, SPO11, STAG3, SUN1, etc.). SPGF88 is distinguished by biallelic KASH5 variants + zygotene arrest.
Screening: Carrier screening/cascade testing of relatives is relevant in consanguineous families once the familial variant is known.

11. Outcome / Prognosis

Survival/mortality: No effect on life expectancy or mortality — SPGF88 is confined to fertility. Not applicable for survival metrics.
Morbidity: The sole morbidity is infertility and its psychosocial impact.
Disease course/complications: Stable; no organ failure or systemic complications. The female allelic disorder (POF22) adds the morbidity of early estrogen deficiency and its sequelae.
Recovery potential: The meiotic block is developmentally fixed and not reversible by medical therapy. Surgical sperm retrieval (micro-TESE) yield is expected to be poor because the arrest is complete and early (pre-pachytene); no mature or post-meiotic cells are produced.
Prognostic factors: The nature of the variant (complete LoF vs hypomorphic) may in principle influence residual spermatogenesis, but all reported cases showed azoospermia; no favorable prognostic biomarker is established.

12. Treatment

Curative therapy: None exists. No pharmacotherapy restores LINC-complex function or reverses meiotic arrest.
Assisted reproduction: Because sperm retrieval is expected to fail, the realistic path to biological parenthood for the couple is donor-sperm insemination/IVF or adoption. Micro-TESE with ICSI may be attempted but counseled as low-yield given early complete arrest. (NCIT:C15215 Assisted Reproductive Technology; NCIT:C92948 Genetic Counseling.)
Gene/cell/RNA therapy, targeted/immunotherapy: Not applicable / none in trials for this indication.
Supportive care: Reproductive counseling and psychological support.
Personalized medicine: Genetic diagnosis chiefly informs prognosis (predicting poor TESE yield) and family planning rather than drug selection.

13. Prevention

Primary prevention: Not applicable (genetic disorder; no modifiable exposure).
Genetic counseling (central): For consanguineous couples or families with a known KASH5 variant — counseling on the 25% recurrence risk per pregnancy in carrier×carrier unions, and on the male/female (NOA/POI) implications of the shared locus.
Reproductive options: Carrier screening, cascade testing of relatives, preimplantation genetic testing (PGT-M) or prenatal testing when the familial variant is known, and donor gametes.
Public-health / behavioral / immunization measures: Not applicable.

14. Other Species / Natural Disease

Taxonomy / orthologs: Mouse Kash5 (also Ccdc155) is the principal ortholog (conserved LINC-complex function). The gene and mechanism are evolutionarily conserved across mammals; related telomere-attachment LINC machinery is documented even on vole B chromosomes (PMID: 42479255).
Natural disease in animals: No spontaneous companion-animal/wildlife KASH5 disease is catalogued in OMIA; relevance is experimental rather than veterinary.
Comparative biology: The Kash5-null mouse reproduces the human phenotype closely (zygotene meiotic arrest, failed pairing, bilateral infertility), indicating deep conservation of the meiotic-telomere-coupling mechanism.
Transmission: Not applicable (non-communicable genetic disorder).

15. Model Organisms

Mouse (Mus musculus): The Kash5-knockout and Kash5 C-terminal-deleted mice are the key models.
Horn et al. 2013 (PMID: 24062341): KO males show meiotic arrest with failed homolog pairing; both sexes infertile — establishing the mechanism.
Zhang et al. 2022 (PMID: 35708642): Kash5 C-terminal-deleted mice show defective homolog pairing and accelerated oocyte depletion, modeling the female (POI/POF22) phenotype.
In vitro / ex vivo systems: Wu et al. 2022 used ex vivo and in vitro assays to show the p.Leu197Pro missense blocks KASH5 NE distribution and SUN1 enrichment — a cell-based functional model of the human missense allele.
Structural models: The SUN1–SPDYA–CDK2 crystal structure (PMID: 34039995) and EM tomography of mouse LINC complexes at telomere attachment sites (PMID: 31633067; ~76 LINC complexes estimated per telomere attachment site) illuminate the molecular architecture KASH5 participates in.
Phenotype recapitulation: High — the mouse reproduces the defining human feature (zygotene arrest, pairing/synapsis failure, azoospermia/infertility), making it a faithful model. Limitation: mouse models and cell assays cannot fully capture human testicular histologic variability or the potential for rare residual spermatogenesis.
Resources: MGI (mouse Kash5/Ccdc155); IMPC/IMSR for alleles.

Mechanistic Model (Synthesis)

 Biallelic KASH5/CCDC155 LoF variant (19q13.33)
   [frameshift p.R327Sfs*21 | CNV del(19)(q13.33) | CC missense p.L197P | splice c.747G>A]
    │  loss of / mislocalized KASH5 protein
    ▼
 Failure to assemble SUN1–KASH5 LINC complex at the nuclear envelope
    │  (p.L197P blocks NE distribution + SUN1 enrichment — demonstrated)
    ▼
 KASH5 cannot recruit cytoplasmic dynein → telomeres uncoupled from microtubules
    ▼
 Loss of telomere-led chromosome movement & bouquet formation (mouse-demonstrated)
    ▼
 Failed homologous pairing & synapsis  ──►  Unresolved meiotic DSB repair
    │                                         │
    └───────────────┬─────────────────────────┘
            ▼
  Meiotic checkpoint arrest at ZYGOTENE-like (pre-pachytene) stage
            ▼
  Germ-cell elimination / spermatocyte maturation arrest
            ▼
┌─────────────────────────────┬───────────────────────────────┐
▼ (male)                       ▼ (female, same locus)
 Non-obstructive azoospermia      Accelerated oocyte depletion →
 → male infertility (SPGF88)      Premature ovarian insufficiency (POF22)

The model is strongly supported: every step from LINC-complex assembly failure through zygotene arrest is demonstrated in either human patients (NE-targeting/SUN1 recruitment, zygotene arrest, DSB persistence) or the mouse (pairing failure, bouquet dependence), with cross-species concordance. The only inferred (vs directly demonstrated-in-human) step is the loss of telomere-led movement/bouquet formation, which rests on mouse and cell-biological evidence.

Evidence Base

PMID	Title (abbrev.)	Evidence type	Role in this report
35674372	Novel bi-allelic variants in KASH5… NOA	Human clinical	Anchors gene/locus; frameshift + CNV biallelic genotype; human zygotene arrest (Findings 1, 2)
35587281	Homozygous missense in CCDC155 disrupts CCDC155/SUN1… NOA & POI	Human + in vitro	Adds coiled-coil missense class; NE-mislocalization + SUN1-recruitment failure; DSB-repair step (Finding 4)
29790874	Point-of-care WES of idiopathic male infertility	Human clinical	First human CCDC155–NOA link; testis-specific expression; NOA 1% epidemiology (Finding 5)
24062341	Mammalian KASH-domain protein coupling meiotic chromosomes to cytoskeleton	Mouse model	Original Kash5-null mechanism: arrest via failed pairing; dynein-coupling requirement (Finding 2)
24637401	The missing LINC…	Review	Frames SUN1–KASH5 LINC biology; leptotene/zygotene arrest in KASH5-deficient mice
35708642	Homozygous variant in KASH5 causes POI…	Human + mouse	Female (POF22) counterpart; splice variant; disordered homolog pairing
34039995	SUN1-SPDYA interaction in meiosis prophase I	Structural/mouse	Molecular architecture of the telomere–LINC connection
31633067	EM tomography of mouse LINC complexes at meiotic telomeres	Structural	Quantitative LINC-complex architecture (~76 per attachment site)
42479255	Meiotic telomeres of vole B chromosomes	Comparative	Conservation of SUN1/KASH5 telomere-attachment machinery

All PMIDs above appear in the reviewed literature and directly support the cited claims. Papers in the literature list concerning unrelated NOA genetics (Y-microdeletions, DMRT1, POLG, miRNAs, Fas/FasL, cancer-variant load) were reviewed for context on the broader NOA landscape but do not bear on the KASH5 mechanism and are not cited as evidence for SPGF88-specific claims.

Limitations and Knowledge Gaps

Very small human sample size. The entire human evidence base for SPGF88 rests on a handful of patients across three families/cohorts. Penetrance, expressivity, and genotype–phenotype correlations cannot be robustly estimated.
No epidemiology. There is no prevalence/incidence estimate specific to SPGF88; it is an ultra-rare monogenic slice of the ~1% NOA population.
CNV detectability. One pathogenic allele was a 19q13.33 deletion, meaning WES/panel sequencing alone can miss the second allele; CNV/array analysis is required but not always performed.
No human protein structure. No experimental KASH5 structure is deposited in the PDB; structural interpretation of missense variants (e.g., p.Leu197Pro) relies on domain annotation and AlphaFold.
Residual spermatogenesis unknown. Whether any hypomorphic allele permits rare post-meiotic cells (and thus TESE success) has not been demonstrated; all reported cases are azoospermic.
Inferred steps. Loss of telomere-led movement/bouquet in human patients is inferred from mouse/cell data rather than directly imaged in patient spermatocytes.
No therapeutics. There is no disease-modifying treatment and no clinical trial; management is supportive/reproductive.

Proposed Follow-up Experiments / Actions

Expand the patient series via international consortia (e.g., GeneMatcher, IMIGC) to collect additional biallelic KASH5 cases, enabling genotype–phenotype and penetrance estimates.
Always pair WES with CNV/array analysis in NOA diagnostics for KASH5, given the demonstrated compound-het CNV allele; report variants to ClinVar to build classification evidence.
Patient testicular histology + immunostaining (SYCP1/SYCP3 synapsis markers, γH2AX for DSBs, telomere/LINC markers) to directly confirm the inferred bouquet/movement defect in humans.
Functional assays for each new variant (NE-localization and SUN1/dynein-binding assays as in Wu 2022) to classify VUS and distinguish complete-LoF from hypomorphic alleles.
Correlate variant severity with micro-TESE outcome prospectively to establish whether any allele predicts rare sperm retrieval, refining counseling.
Structural determination (cryo-EM/crystallography) of the human KASH5 coiled-coil and KASH–SUN1 interface to mechanistically interpret missense variants.
iPSC-derived germ-cell or organoid models carrying patient variants to study the human meiotic block and screen for rescue strategies.
Carrier/cascade screening and PGT-M counseling in affected consanguineous families as a concrete clinical action.

Report compiled from 5 iterations, 5 confirmed findings, and 19 reviewed papers. Evidence spans human clinical case reports, mouse knockout models, in vitro functional assays, and structural/computational data, as indicated per claim.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	9
Resolved	9
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	9
On topic	6
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	25
Resolved	24
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	7
Terms named correctly	4
Terms named as a different term	0
Terms whose name is worth a second look	3

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:

HP:0011462 (3 mentions) - the report calls it "Young adult onset", "clinical onset is young-adult"; HP calls it Young adult onset
HP:0008209 (1 mention) - the report calls it "(Female counterpart) Premature ovarian insufficiency"; HP calls it Premature ovarian insufficiency
GO:0005640 (2 mentions) - the report calls it "Subcellular level: Nuclear envelope / outer nuclear membrane"; GO calls it nuclear outer membrane

Terms named inconsistently

The report gives these identifiers more than one name of its own:

HP:0011462 - called "Young adult onset", "clinical onset is young-adult"

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.

24 of 25 terms resolved to a current term; the rest could not be looked up either way.

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OpenScientist Report

Classifications

Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Diagnosis

Animal Models

Source YAML

References & Deep Research

Deep Research

Spermatogenic Failure 88 (SPGF88): A Comprehensive Disease Characterization Report

Summary

Key Findings

Finding 1 — SPGF88 is caused by biallelic KASH5/CCDC155 loss-of-function variants at 19q13.33

Finding 2 — KASH5 loss arrests meiosis at the zygotene stage via failed homolog pairing/synapsis (conserved human–mouse mechanism)

Finding 3 — KASH5 is loss-of-function–tolerant in gnomAD, consistent with a recessive mechanism

Finding 4 — A homozygous coiled-coil missense (p.Leu197Pro) causes NOA and POI by mislocalizing the LINC complex

Finding 5 — First human KASH5–NOA link (Fakhro et al. 2018) and the authoritative HPO annotation set

Section-by-Section Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model (Synthesis)

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver