SECISBP2 Deficiency

Metabolic Disorder MONDO:0800046 Pathograph 5 Show in embeddings browser Selenoprotein Biosynthesis Disorder Trace Element Metabolism Disorder

SECISBP2 deficiency is an autosomal recessive inborn error of selenoprotein synthesis caused by biallelic SECISBP2 variants. SECISBP2/SBP2 is part of the SECIS-recognition machinery that recodes UGA codons for selenocysteine insertion, so partial loss of function reduces synthesis of many human selenoproteins. The downstream pathograph includes impaired deiodinase-driven thyroid hormone metabolism, oxidative-stress vulnerability from antioxidant selenoprotein deficiency, growth failure with delayed bone maturation, and variable neurodevelopmental involvement.

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1
Inheritance
4
Pathophys.
11
Phenotypes
5
Pathograph
1
Genes
🏷

Classifications

ICIMD (Inherited Metabolic Disorders)
trace element other
👪

Inheritance

1
Autosomal Recessive HP:0000007
Autosomal recessive inheritance
Show evidence (2 references)
PMID:16228000 SUPPORT Human Clinical
"Systematic linkage analysis of genes involved in DIO2 synthesis and degradation led to the identification of an inherited Sec incorporation defect, caused by a homozygous missense mutation in SECISBP2 (also called SBP2)."
The originally described family had a homozygous SECISBP2 variant causing the Sec incorporation defect.
PMID:21084748 SUPPORT Human Clinical
"Here, we describe subjects with compound heterozygous defects in the SECISBP2 gene."
Compound heterozygosity in affected subjects supports recessive inheritance.
⚙

Pathophysiology

4
SECISBP2-dependent Sec incorporation defect
SECISBP2/SBP2 loss impairs SECIS-mediated recoding of UGA as selenocysteine, creating a proximal defect in selenocysteine incorporation during translation.
SECISBP2 hgnc:30972 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SECISBP2 (hgnc:30972). hgnc:30972 is a gene from the HUGO Gene Nomenclature Committee.
selenocysteine incorporation GO:0001514 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased selenocysteine incorporation (GO:0001514). GO:0001514 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Reduced selenoprotein synthesis Failed SECISBP2-dependent Sec incorporation reduces synthesis of multiple human selenoproteins.
Show evidence (1 reference)
PMID:16228000 SUPPORT Human Clinical
"Systematic linkage analysis of genes involved in DIO2 synthesis and degradation led to the identification of an inherited Sec incorporation defect, caused by a homozygous missense mutation in SECISBP2 (also called SBP2)."
Directly identifies the proximal disease mechanism as an inherited SECISBP2-mediated selenocysteine incorporation defect.
Reduced selenoprotein synthesis
Decreased Sec insertion reduces synthesis of multiple selenoproteins, including deiodinases and antioxidant enzymes, creating a multisystem selenoprotein deficiency state.
selenocysteine incorporation GO:0001514 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased selenocysteine incorporation (GO:0001514). GO:0001514 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired thyroid hormone metabolism Reduced synthesis of deiodinase selenoproteins disrupts thyroid hormone activation and inactivation.
Oxidative-stress vulnerability Deficiency of antioxidant selenoproteins increases cellular reactive oxygen species and stress sensitivity.
Show evidence (1 reference)
PMID:21084748 SUPPORT Human Clinical
"These individuals have reduced synthesis of most of the 25 known human selenoproteins, resulting in a complex phenotype."
Establishes the generalized selenoprotein synthesis defect.
Impaired thyroid hormone metabolism
Deiodinases are selenoproteins required for thyroid hormone metabolism. Their reduced activity produces the characteristic abnormal thyroid function tests observed in SECISBP2 deficiency.
thyroid hormone metabolic process GO:0042403 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased thyroid hormone metabolic process (GO:0042403). GO:0042403 is a biological process from the Gene Ontology. ↓ DECREASED
endocrine system UBERON:0000949 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in endocrine system (UBERON:0000949). UBERON:0000949 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:16228000 SUPPORT Human Clinical
"Deiodinases (DIOs) are selenoproteins involved in thyroid hormone metabolism."
Supports the mechanistic bridge from reduced selenoprotein synthesis to thyroid hormone metabolism abnormalities.
Oxidative-stress vulnerability
Loss of antioxidant selenoprotein capacity increases cellular reactive oxygen species and vulnerability to oxidative injury.
fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
response to oxidative stress GO:0006979 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to oxidative stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (1 reference)
PMID:21084748 SUPPORT Human Clinical
"Cutaneous deficiencies of antioxidant selenoenzymes, increased cellular ROS, and susceptibility to ultraviolet radiation-induced oxidative damage may mediate the observed photosensitivity."
Supports increased ROS and oxidative stress susceptibility in SECISBP2 deficiency.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for SECISBP2 Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

11
Ear 1
Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21084748 SUPPORT Human Clinical
"Otoacoustic emissions showed absent responses at all frequencies, whereas brainstem auditory evoked responses were normal (data"
Documents a cochlear-level sensorineural hearing defect in an affected SECISBP2-deficient proband.
Genitourinary 1
Azoospermia HP:0000027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Azoospermia (HP:0000027). HP:0000027 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21084748 SUPPORT Human Clinical
"Azoospermia, with failure of the latter stages of spermatogenesis, was associated with a lack of testis-enriched selenoproteins."
Directly supports azoospermia due to loss of testis-enriched selenoproteins in SECISBP2 deficiency.
Integument 1
Cutaneous photosensitivity HP:0000992 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cutaneous photosensitivity (HP:0000992). HP:0000992 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21084748 SUPPORT Human Clinical
"Cutaneous deficiencies of antioxidant selenoenzymes, increased cellular ROS, and susceptibility to ultraviolet radiation-induced oxidative damage may mediate the observed photosensitivity."
Supports photosensitivity mediated by cutaneous antioxidant selenoenzyme deficiency and increased ROS.
Musculoskeletal 2
Delayed skeletal maturation HP:0002750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed skeletal maturation (HP:0002750). HP:0002750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22247018 SUPPORT Human Clinical
"A Japanese boy presented with unusual thyroid function tests (normal or slightly elevated TSH, low-normal or slightly decreased free T(3) (FT(3)), and elevated free thyroxine (FT(4))), short stature without GH deficiency, and delayed bone maturation."
Directly supports delayed bone maturation in an SBP2/SECISBP2 deficiency patient.
Muscular dystrophy HP:0003560 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Axial muscular dystrophy, annotated with Muscular dystrophy (HP:0003560). HP:0003560 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21084748 SUPPORT Human Clinical
"An axial muscular dystrophy was also present, with features similar to myopathies caused by mutations in selenoprotein N (SEPN1)."
Supports axial muscular dystrophy phenocopying SELENON/SEPN1-related myopathy in SECISBP2 deficiency.
Nervous System 2
Neurodevelopmental involvement Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39315526 SUPPORT Human Clinical
"Thyroid hormone treatment improved motor development, whereas speech and intellectual impairments persisted."
Supports persistent intellectual and speech impairment as part of the neurodevelopmental phenotype.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39315526 SUPPORT Human Clinical
"Four probands presented a complex neurodevelopmental profile, including absent speech, autistic features, and seizures."
Supports seizures in SECISBP2 deficiency.
Growth 2
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39315526 SUPPORT Human Clinical
"Genetic and laboratory investigations were performed in affected members from 6 families presenting with short stature and failure to thrive."
Supports short stature in affected SECISBP2 deficiency families.
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39315526 SUPPORT Human Clinical
"Genetic and laboratory investigations were performed in affected members from 6 families presenting with short stature and failure to thrive."
Supports failure to thrive in SECISBP2 deficiency.
Other 2
Abnormal thyroid physiology Abnormality of thyroid physiology HP:0002926 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of thyroid physiology (HP:0002926). HP:0002926 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16228000 SUPPORT Human Clinical
"We identified three of seven siblings with clinical evidence of abnormal thyroid hormone metabolism."
Supports abnormal thyroid hormone metabolism as a clinical phenotype.
Abnormal T cell physiology HP:0011840 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Impaired T lymphocyte proliferation, annotated with Abnormal T cell physiology (HP:0011840). HP:0011840 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21084748 SUPPORT Human Clinical
"Reduced levels of selenoproteins in peripheral blood cells were associated with impaired T lymphocyte proliferation, abnormal mononuclear cell cytokine secretion, and telomere shortening."
Supports impaired T lymphocyte proliferation and altered cytokine secretion in SECISBP2 deficiency.
🧬

Genetic Associations

1
SECISBP2 pathogenic variants (Loss-of-function)
Gene: SECISBP2 hgnc:30972 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SECISBP2 (hgnc:30972). hgnc:30972 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:16228000 SUPPORT Human Clinical
"An unrelated child with a similar phenotype was compound heterozygous with respect to mutations in SECISBP2."
Supports SECISBP2 as the causal disease gene in an independent affected child.
PMID:22247018 SUPPORT Human Clinical
"The patient showed typical symptoms of SBP2 deficiency, and novel compound heterozygous mutations were identified in SBP2 (p.M515fsX563/p.Q79X)."
Supports additional pathogenic SECISBP2/SBP2 variant classes in affected individuals.
🗃️

External Assertions

2
OMIM SECISBP2 deficiency record
OMIM disease record OMIM:609698
OMIM phenotype record corresponding to SECISBP2 deficiency.
Orphanet SECISBP2 deficiency record
Orphanet structured disease record ORPHA:171706
Orphanet structured disease record corresponding to SECISBP2 deficiency.
{ }

Source YAML

click to show 
name: SECISBP2 Deficiency
creation_date: "2026-07-06T05:15:58Z"
category: Metabolic Disorder
parents:
- Selenoprotein Biosynthesis Disorder
- Trace Element Metabolism Disorder
description: >-
  SECISBP2 deficiency is an autosomal recessive inborn error of selenoprotein
  synthesis caused by biallelic SECISBP2 variants. SECISBP2/SBP2 is part of
  the SECIS-recognition machinery that recodes UGA codons for selenocysteine
  insertion, so partial loss of function reduces synthesis of many human
  selenoproteins. The downstream pathograph includes impaired deiodinase-driven
  thyroid hormone metabolism, oxidative-stress vulnerability from antioxidant
  selenoprotein deficiency, growth failure with delayed bone maturation, and
  variable neurodevelopmental involvement.
disease_term:
  preferred_term: SECISBP2 deficiency
  term:
    id: MONDO:0800046
    label: thyroid hormone metabolism, abnormal 1
synonyms:
- selenocysteine insertion sequence-binding protein 2 deficiency
- SBP2 deficiency
- SECISBP2-related multisystem selenoprotein deficiency
notes: >-
  WP-079 seed identifiers: OMIM:609698 and ORPHA:171706. The top-level
  disease_term is anchored to MONDO:0800046 ("thyroid hormone metabolism,
  abnormal 1"), which carries exactly those two seed cross-references
  (xref OMIM:609698; definition sourced from Orphanet:171706) and is
  gene-anchored to SECISBP2 (RO:0004003 HGNC:30972). The MONDO label is
  thyroid-skewed relative to the multisystem selenoprotein-deficiency scope
  modeled here, so preferred_term retains "SECISBP2 deficiency"; the entity is
  the same, and no more specific MONDO class exists in the local snapshot.
external_assertions:
- name: OMIM SECISBP2 deficiency record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:609698
  url: https://omim.org/entry/609698
  description: OMIM phenotype record corresponding to SECISBP2 deficiency.
- name: Orphanet SECISBP2 deficiency record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:171706
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=171706
  description: Orphanet structured disease record corresponding to SECISBP2 deficiency.
classifications:
  icimd_category:
  - classification_value: trace_element_other
    notes: >-
      ICIMD category 22, "Disorders of trace elements and metals", other
      trace-element metabolism. SECISBP2 deficiency disrupts the use of
      selenium as selenocysteine in human selenoproteins.
    evidence:
    - reference: PMID:21084748
      reference_title: "Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Selenium, a trace element that is fundamental to human health, is
        incorporated into some proteins as selenocysteine (Sec), generating a
        family of selenoproteins.
      explanation: >-
        Supports classification under trace-element metabolism through impaired
        selenium incorporation into selenoproteins.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:16228000
    reference_title: "Mutations in SECISBP2 result in abnormal thyroid hormone metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Systematic linkage analysis of genes involved in DIO2 synthesis and
      degradation led to the identification of an inherited Sec incorporation
      defect, caused by a homozygous missense mutation in SECISBP2 (also called
      SBP2).
    explanation: >-
      The originally described family had a homozygous SECISBP2 variant causing
      the Sec incorporation defect.
  - reference: PMID:21084748
    reference_title: "Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe subjects with compound heterozygous defects in the
      SECISBP2 gene.
    explanation: >-
      Compound heterozygosity in affected subjects supports recessive
      inheritance.
genetic:
- name: SECISBP2 pathogenic variants
  gene_term:
    preferred_term: SECISBP2
    term:
      id: hgnc:30972
      label: SECISBP2
  association: Loss-of-function
  presence: Positive
  notes: >-
    Reported homozygous and compound heterozygous SECISBP2 variants impair the
    SECIS-binding protein required for selenocysteine insertion. Residual
    activity is consistent with survival and variable multisystem severity.
  evidence:
  - reference: PMID:16228000
    reference_title: "Mutations in SECISBP2 result in abnormal thyroid hormone metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An unrelated child with a similar phenotype was compound heterozygous
      with respect to mutations in SECISBP2.
    explanation: >-
      Supports SECISBP2 as the causal disease gene in an independent affected
      child.
  - reference: PMID:22247018
    reference_title: "Novel compound heterozygous mutations in the SBP2 gene: characteristic clinical manifestations and the implications of GH and triiodothyronine in longitudinal bone growth and maturation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient showed typical symptoms of SBP2 deficiency, and novel compound
      heterozygous mutations were identified in SBP2 (p.M515fsX563/p.Q79X).
    explanation: >-
      Supports additional pathogenic SECISBP2/SBP2 variant classes in affected
      individuals.
pathophysiology:
- name: SECISBP2-dependent Sec incorporation defect
  description: >-
    SECISBP2/SBP2 loss impairs SECIS-mediated recoding of UGA as
    selenocysteine, creating a proximal defect in selenocysteine incorporation
    during translation.
  genes:
  - preferred_term: SECISBP2
    term:
      id: hgnc:30972
      label: SECISBP2
  biological_processes:
  - preferred_term: selenocysteine incorporation
    term:
      id: GO:0001514
      label: selenocysteine incorporation
    modifier: DECREASED
  chemical_entities:
  - preferred_term: selenocysteine
    term:
      id: CHEBI:9093
      label: selenocysteine
  evidence:
  - reference: PMID:16228000
    reference_title: "Mutations in SECISBP2 result in abnormal thyroid hormone metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Systematic linkage analysis of genes involved in DIO2 synthesis and
      degradation led to the identification of an inherited Sec incorporation
      defect, caused by a homozygous missense mutation in SECISBP2 (also called
      SBP2).
    explanation: >-
      Directly identifies the proximal disease mechanism as an inherited
      SECISBP2-mediated selenocysteine incorporation defect.
  downstream:
  - target: Reduced selenoprotein synthesis
    description: >-
      Failed SECISBP2-dependent Sec incorporation reduces synthesis of multiple
      human selenoproteins.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21084748
      reference_title: "Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These individuals have reduced synthesis of most of the 25 known human
        selenoproteins, resulting in a complex phenotype.
      explanation: >-
        Supports reduced selenoprotein synthesis downstream of SECISBP2 defects.
- name: Reduced selenoprotein synthesis
  description: >-
    Decreased Sec insertion reduces synthesis of multiple selenoproteins,
    including deiodinases and antioxidant enzymes, creating a multisystem
    selenoprotein deficiency state.
  biological_processes:
  - preferred_term: selenocysteine incorporation
    term:
      id: GO:0001514
      label: selenocysteine incorporation
    modifier: DECREASED
  chemical_entities:
  - preferred_term: selenocysteine
    term:
      id: CHEBI:9093
      label: selenocysteine
  evidence:
  - reference: PMID:21084748
    reference_title: "Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These individuals have reduced synthesis of most of the 25 known human
      selenoproteins, resulting in a complex phenotype.
    explanation: >-
      Establishes the generalized selenoprotein synthesis defect.
  downstream:
  - target: Impaired thyroid hormone metabolism
    description: >-
      Reduced synthesis of deiodinase selenoproteins disrupts thyroid hormone
      activation and inactivation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39315526
      reference_title: "Severe neurodevelopmental phenotype, diagnostic, and treatment challenges in patients with SECISBP2 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Defects in the gene encoding selenocysteine insertion sequence binding
        protein 2, SECISBP2, result in global impaired selenoprotein synthesis
        manifesting a complex syndrome with characteristic serum thyroid
        function tests due to impaired thyroid hormone metabolism.
      explanation: >-
        Links impaired selenoprotein synthesis to thyroid hormone metabolism
        abnormalities in SECISBP2 deficiency.
  - target: Oxidative-stress vulnerability
    description: >-
      Deficiency of antioxidant selenoproteins increases cellular reactive
      oxygen species and stress sensitivity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21084748
      reference_title: "Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Cutaneous deficiencies of antioxidant selenoenzymes, increased cellular
        ROS, and susceptibility to ultraviolet radiation-induced oxidative
        damage may mediate the observed photosensitivity.
      explanation: >-
        Supports antioxidant selenoenzyme deficiency and increased ROS as a
        downstream cellular dysfunction.
- name: Impaired thyroid hormone metabolism
  description: >-
    Deiodinases are selenoproteins required for thyroid hormone metabolism.
    Their reduced activity produces the characteristic abnormal thyroid
    function tests observed in SECISBP2 deficiency.
  biological_processes:
  - preferred_term: thyroid hormone metabolic process
    term:
      id: GO:0042403
      label: thyroid hormone metabolic process
    modifier: DECREASED
  locations:
  - preferred_term: endocrine system
    term:
      id: UBERON:0000949
      label: endocrine system
  evidence:
  - reference: PMID:16228000
    reference_title: "Mutations in SECISBP2 result in abnormal thyroid hormone metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deiodinases (DIOs) are selenoproteins involved in thyroid hormone
      metabolism.
    explanation: >-
      Supports the mechanistic bridge from reduced selenoprotein synthesis to
      thyroid hormone metabolism abnormalities.
- name: Oxidative-stress vulnerability
  description: >-
    Loss of antioxidant selenoprotein capacity increases cellular reactive
    oxygen species and vulnerability to oxidative injury.
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:21084748
    reference_title: "Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cutaneous deficiencies of antioxidant selenoenzymes, increased cellular
      ROS, and susceptibility to ultraviolet radiation-induced oxidative damage
      may mediate the observed photosensitivity.
    explanation: >-
      Supports increased ROS and oxidative stress susceptibility in SECISBP2
      deficiency.
phenotypes:
- name: Abnormal thyroid physiology
  description: >-
    SECISBP2 deficiency produces abnormal thyroid hormone metabolism and
    characteristic thyroid function tests.
  phenotype_term:
    preferred_term: Abnormality of thyroid physiology
    term:
      id: HP:0002926
      label: Abnormality of thyroid physiology
  evidence:
  - reference: PMID:16228000
    reference_title: "Mutations in SECISBP2 result in abnormal thyroid hormone metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified three of seven siblings with clinical evidence of abnormal
      thyroid hormone metabolism.
    explanation: >-
      Supports abnormal thyroid hormone metabolism as a clinical phenotype.
- name: Short stature
  description: >-
    Growth failure is part of the multisystem presentation.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:39315526
    reference_title: "Severe neurodevelopmental phenotype, diagnostic, and treatment challenges in patients with SECISBP2 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic and laboratory investigations were performed in affected members
      from 6 families presenting with short stature and failure to thrive.
    explanation: >-
      Supports short stature in affected SECISBP2 deficiency families.
- name: Failure to thrive
  description: >-
    Failure to thrive accompanies growth impairment in multiple reported
    SECISBP2 deficiency families.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:39315526
    reference_title: "Severe neurodevelopmental phenotype, diagnostic, and treatment challenges in patients with SECISBP2 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic and laboratory investigations were performed in affected members
      from 6 families presenting with short stature and failure to thrive.
    explanation: >-
      Supports failure to thrive in SECISBP2 deficiency.
- name: Delayed skeletal maturation
  description: >-
    Delayed bone maturation has been reported with SECISBP2/SBP2 deficiency,
    consistent with impaired thyroid hormone action at the growth plate.
  phenotype_term:
    preferred_term: Delayed skeletal maturation
    term:
      id: HP:0002750
      label: Delayed skeletal maturation
  evidence:
  - reference: PMID:22247018
    reference_title: "Novel compound heterozygous mutations in the SBP2 gene: characteristic clinical manifestations and the implications of GH and triiodothyronine in longitudinal bone growth and maturation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A Japanese boy presented with unusual thyroid function tests (normal or
      slightly elevated TSH, low-normal or slightly decreased free T(3) (FT(3)),
      and elevated free thyroxine (FT(4))), short stature without GH deficiency,
      and delayed bone maturation.
    explanation: >-
      Directly supports delayed bone maturation in an SBP2/SECISBP2 deficiency
      patient.
- name: Neurodevelopmental involvement
  description: >-
    Some affected individuals have complex neurodevelopmental involvement,
    including speech and intellectual impairment and seizures.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:39315526
    reference_title: "Severe neurodevelopmental phenotype, diagnostic, and treatment challenges in patients with SECISBP2 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thyroid hormone treatment improved motor development, whereas speech and
      intellectual impairments persisted.
    explanation: >-
      Supports persistent intellectual and speech impairment as part of the
      neurodevelopmental phenotype.
- name: Seizure
  description: >-
    Seizures are part of the reported neurodevelopmental presentation in some
    SECISBP2 deficiency probands.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:39315526
    reference_title: "Severe neurodevelopmental phenotype, diagnostic, and treatment challenges in patients with SECISBP2 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four probands presented a complex neurodevelopmental profile, including
      absent speech, autistic features, and seizures.
    explanation: >-
      Supports seizures in SECISBP2 deficiency.
- name: Azoospermia
  description: >-
    Loss of testis-enriched selenoproteins in SECISBP2 deficiency causes
    azoospermia from failure of the later stages of spermatogenesis, a
    recognized cause of male infertility in affected men.
  phenotype_term:
    preferred_term: Azoospermia
    term:
      id: HP:0000027
      label: Azoospermia
  evidence:
  - reference: PMID:21084748
    reference_title: "Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Azoospermia, with failure of the latter stages of spermatogenesis, was
      associated with a lack of testis-enriched selenoproteins.
    explanation: >-
      Directly supports azoospermia due to loss of testis-enriched
      selenoproteins in SECISBP2 deficiency.
- name: Muscular dystrophy
  description: >-
    An axial muscular dystrophy occurs in SECISBP2 deficiency, resembling the
    myopathy caused by deficiency of the selenoprotein SELENON (SEPN1),
    reflecting the shared dependence on selenoprotein synthesis.
  phenotype_term:
    preferred_term: Axial muscular dystrophy
    term:
      id: HP:0003560
      label: Muscular dystrophy
  evidence:
  - reference: PMID:21084748
    reference_title: "Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An axial muscular dystrophy was also present, with features similar to
      myopathies caused by mutations in selenoprotein N (SEPN1).
    explanation: >-
      Supports axial muscular dystrophy phenocopying SELENON/SEPN1-related
      myopathy in SECISBP2 deficiency.
- name: Cutaneous photosensitivity
  description: >-
    Cutaneous deficiency of antioxidant selenoenzymes with increased reactive
    oxygen species increases susceptibility to ultraviolet-induced oxidative
    damage, producing photosensitivity.
  phenotype_term:
    preferred_term: Cutaneous photosensitivity
    term:
      id: HP:0000992
      label: Cutaneous photosensitivity
  evidence:
  - reference: PMID:21084748
    reference_title: "Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cutaneous deficiencies of antioxidant selenoenzymes, increased cellular
      ROS, and susceptibility to ultraviolet radiation-induced oxidative damage
      may mediate the observed photosensitivity.
    explanation: >-
      Supports photosensitivity mediated by cutaneous antioxidant selenoenzyme
      deficiency and increased ROS.
- name: Sensorineural hearing impairment
  description: >-
    Bilateral sensorineural hearing loss with a cochlear-level defect has been
    documented in SECISBP2 deficiency, consistent with the impaired
    selenoprotein-dependent thyroid hormone action needed for cochlear
    development.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:21084748
    reference_title: "Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Otoacoustic emissions showed absent responses at all frequencies, whereas
      brainstem auditory evoked responses were normal (data
    explanation: >-
      Documents a cochlear-level sensorineural hearing defect in an affected
      SECISBP2-deficient proband.
- name: Abnormal T cell physiology
  category: Cellular
  description: >-
    Reduced selenoprotein levels in peripheral blood cells impair T lymphocyte
    proliferation and alter mononuclear cell cytokine secretion, indicating an
    immune component of the multisystem selenoprotein deficiency.
  phenotype_term:
    preferred_term: Impaired T lymphocyte proliferation
    term:
      id: HP:0011840
      label: Abnormal T cell physiology
  evidence:
  - reference: PMID:21084748
    reference_title: "Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Reduced levels of selenoproteins in peripheral blood cells were
      associated with impaired T lymphocyte proliferation, abnormal mononuclear
      cell cytokine secretion, and telomere shortening.
    explanation: >-
      Supports impaired T lymphocyte proliferation and altered cytokine
      secretion in SECISBP2 deficiency.