Rajab interstitial lung disease with brain calcifications 1 (RILDBC1) is an autosomal recessive multisystem disorder caused by biallelic variants in FARSB, the gene for the beta subunit of CYTOPLASMIC phenylalanyl-tRNA synthetase (PheRS, also called FARS1). PheRS is an (alpha-beta)2 heterotetramer built from the FARSA and FARSB gene products; it charges phenylalanine onto tRNA-Phe, the committed step for incorporating phenylalanine into every cytoplasmic protein. The disease therefore belongs to the recessive aminoacyl-tRNA-synthetase (ARS1) deficiency family alongside LARS1, MARS1, IARS1 and YARS1. Its clinical signature is a triad: early interstitial lung disease, intracranial calcification, and growth restriction. The lung phenotype is the one that most often brings the child to attention and most often determines survival; the cited source characterises it as pulmonary alveolar proteinosis presenting radiologically as interstitial lung disease, and places it in an 86-100% band. Note that band spans FARSA, FARSB and MARS1 deficiency collectively; it is not a FARSB point estimate. It is nonetheless tiered below, where the growth and anemia bands are not, because it does not straddle the FREQUENT/VERY_FREQUENT boundary those two do; it touches OBLIGATE only at its 100% endpoint, and VERY_FREQUENT is the conservative reading with no FARSB point estimate available. Liver involvement, anemia and developmental delay complete the picture. The finer radiological and histological detail usually given for this disease - bilateral symmetric basal-ganglia calcification with preserved myelination, and cholesterol granulomas on lung biopsy - is deliberately NOT asserted here, because no reference cited by this entry states it for FARSB; see `notes`, which records it as a lead together with the papers to fetch. Two features place the disease inside a wider ARS1 pattern rather than making it an isolated oddity. First, systematic phenotype comparison across ARS1 deficiencies puts FARSB with FARSA, IARS1, LARS1, MARS1 and YARS1 in a single multisystem cluster defined by growth abnormality, liver disease, hypoalbuminemia and interstitial lung disease - which is to say the lung and liver phenotype is a property of this branch of the ARS1 family, not of FARSB alone. That cluster membership is the source's own clustering result; note that the same source's per-symptom sentences for liver disease and for hypoalbuminemia both omit FARSB, so neither is asserted here as a FARSB frequency (see the Liver Disease phenotype, which records the discrepancy, and `notes`). Second, residual aminoacylation in FARSB patient fibroblasts falls further when the cells are warmed, the same temperature sensitivity documented in LARS1 deficiency, which supplies a mechanism for clinical deterioration during febrile illness.
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Conditions with similar clinical presentations that must be differentiated from Rajab Interstitial Lung Disease With Brain Calcifications 1:
name: Rajab Interstitial Lung Disease With Brain Calcifications 1
creation_date: "2026-09-06T00:00:00Z"
category: Mendelian
disease_term:
preferred_term: FARSB deficiency (Rajab interstitial lung disease with brain calcifications 1)
term:
id: MONDO:0100215
label: Rajab interstitial lung disease with brain calcifications 1
description: >-
Rajab interstitial lung disease with brain calcifications 1 (RILDBC1) is an
autosomal recessive multisystem disorder caused by biallelic variants in FARSB,
the gene for the beta subunit of CYTOPLASMIC phenylalanyl-tRNA synthetase
(PheRS, also called FARS1). PheRS is an (alpha-beta)2 heterotetramer built from
the FARSA and FARSB gene products; it charges phenylalanine onto tRNA-Phe, the
committed step for incorporating phenylalanine into every cytoplasmic protein.
The disease therefore belongs to the recessive aminoacyl-tRNA-synthetase (ARS1)
deficiency family alongside LARS1, MARS1, IARS1 and YARS1.
Its clinical signature is a triad: early interstitial lung disease,
intracranial calcification, and growth restriction. The lung phenotype is the
one that most often brings the child to attention and most often determines
survival; the cited source characterises it as pulmonary alveolar proteinosis
presenting radiologically as interstitial lung disease, and places it in an
86-100% band. Note that band spans FARSA, FARSB and MARS1 deficiency
collectively; it is not a FARSB point estimate. It is nonetheless tiered below,
where the growth and anemia bands are not, because it does not straddle the
FREQUENT/VERY_FREQUENT boundary those two do; it touches OBLIGATE only at its
100% endpoint, and VERY_FREQUENT is the conservative reading with no FARSB
point estimate available. Liver involvement, anemia and
developmental delay complete the picture. The finer radiological and
histological detail usually given for this disease - bilateral symmetric
basal-ganglia calcification with preserved myelination, and cholesterol
granulomas on lung biopsy - is deliberately NOT asserted here, because no
reference cited by this entry states it for FARSB; see `notes`,
which records it as a lead together with the papers to fetch.
Two features place the disease inside a wider ARS1 pattern rather than making it
an isolated oddity. First, systematic phenotype comparison across ARS1
deficiencies puts FARSB with FARSA, IARS1, LARS1, MARS1 and YARS1 in a single
multisystem cluster defined by growth abnormality, liver disease,
hypoalbuminemia and interstitial lung disease - which is to say the lung and
liver phenotype is a property of this branch of the ARS1 family, not of FARSB
alone. That cluster membership is the source's own clustering result; note
that the same source's per-symptom sentences for liver disease and for
hypoalbuminemia both omit FARSB, so neither is asserted here as a FARSB
frequency (see the Liver Disease phenotype, which records the discrepancy,
and `notes`). Second, residual aminoacylation in FARSB patient fibroblasts falls
further when the cells are warmed, the same temperature sensitivity documented
in LARS1 deficiency, which supplies a mechanism for clinical deterioration
during febrile illness.
parents:
- hereditary disease
- Inborn Error of Metabolism
- Aminoacyl-tRNA Synthetase Deficiency
synonyms:
- RILDBC1
- FARSB deficiency
- phenylalanyl-tRNA synthetase deficiency
- Rajab syndrome
- brain calcification, Rajab type
- interstitial lung and liver disease due to FARSB deficiency
notes: >-
Gene and enzyme nomenclature. FARSB encodes the BETA subunit of the cytoplasmic
phenylalanyl-tRNA synthetase; the alpha subunit is FARSA, and the functional
enzyme is an (alpha-beta)2 heterotetramer. The cited papers variously call the
enzyme PheRS, FARS, FARS1 or "phenylalanyl-RS", and abbreviate the gene FARSB
or FARS-beta; quoted snippets preserve whichever form the source used. The
MITOCHONDRIAL phenylalanyl-tRNA synthetase is a different, single-subunit
enzyme (FARS2) causing a different disease, and is not curated here.
Scope boundary. This entry is the FARSB entity (RILDBC1) only. RILDBC2
(MONDO has it as a sibling) is caused by FARSA and is clinically near-identical
because it disables the same heterotetramer; it is a separate entry and is not
curated here. The MONDO parent, `Rajab interstitial lung disease with brain
calcifications` (MONDO:0100214), is the grouping over both.
Evidence base, and the gap it leaves. Every citation in this entry comes from
three ARS1-family papers that carry FARSB-specific data: a 438-patient
cross-ARS1 phenotype and treatment review (PMID:40044141), the
aminoacylation/thermostability/amino-acid-treatment study whose FARSB patient
is individually characterised (PMID:34194004), and a tRNA therapeutics review
covering the same treated cohort (PMID:39702998). The disease-defining primary
literature is cited NOWHERE. Fetching it and re-grounding the entry on it is
the highest-value follow-up on this file:
PMID:29979980 (Xu et al. 2018, Am J Hum Genet) - the FARSB gene-disease paper
and the source of the non-translational-function argument, with quotable
sentences for brain calcification, cholesterol pneumonitis and cerebral
aneurysm; PMID:30014610 (Zadjali et al. 2018, Hum Mutat) - the Omani founder
allele c.853G>A p.Glu285Lys; PMID:29573043 (Antonellis et al. 2018) - the
compound-heterozygous patient with the ~97% FARSB / ~66% FARSA protein
reduction; PMID:19161147 (Rajab et al. 2009, Am J Med Genet A) - the founding
clinical and linkage description; then Schuch et al. 2021 (Clin Genet) and
Karimzadeh et al. 2022.
What that costs, named precisely. The brain calcification that gives the
disease its name has NO FARSB-specific citation - it carries only a cross-ARS1
CNS-imaging sentence graded INDIRECT. Cholesterol pneumonitis, the
characteristic lung histology, and cerebral aneurysm are omitted entirely.
Three of the five alleles under `genetic` are recorded without evidence. All
four gaps have the same cause and the same fix.
Every frequency in this entry is a cross-ARS1 cohort figure, not a RILDBC1
figure, and the explanations say so individually. Roughly 10-20 patients have
been described worldwide, so no percentage should ever be attributed to this
disease on its own denominator.
Two mechanistic features are reported in the literature but deliberately NOT
asserted here, for want of a citable source: FARSB loss co-depletes its
obligate heterotetramer partner FARSA, making the lesion a loss of the whole
(alpha-beta)2 holoenzyme rather than of one subunit; and the intracranial
calcification is described as bilateral, symmetric and accompanied by
PRESERVED myelination, which is what separates it clinically from
Aicardi-Goutieres syndrome and the leukodystrophies.
Term caches. The derived `cache/` rows for the five CURIEs new to this
repository - MONDO:0100215, hgnc:17800, GO:0004826, GO:0006432 and
CHEBI:17295 - are not committed, so term validation network-fetches them
rather than reading the cache. All five have been confirmed to resolve with
labels matching this file. Run `just validate-terms` on this file then
`just normalize-cache`, and commit the rows.
GeneReviews. Checked; there is no chapter for FARSB or RILDBC1. The nearby
chapter is for FARS2, a different gene and a different disease - see
`differential_diagnoses`. A genuine absence, recorded so the search is not
repeated.
Cross-references identified but not bound: OMIM #613658 (phenotype),
OMIM *609690 (gene), ORPHA:178506, MedGen C3150910, NCBI Gene 10056; FARSB
maps to 2q36.1. These are NOT in a `mappings:` block because
`DiseaseMappings` in this schema admits only `icd10cm_mappings`,
`icd11f_mappings`, `mondo_mappings` and `ncit_mappings` - there is no OMIM,
Orphanet or MedGen slot. Adding one would be a schema change.
Full curation provenance, including why the primary literature could not be
fetched during curation, is in the `history/` records for this entry rather
than here.
classifications:
harrisons_chapter:
- classification_value: RESPIRATORY
notes: >-
Assigned on the organ system that determines outcome rather than the one
that names the disease. Interstitial lung disease is near-universal in
FARSB deficiency and is the usual cause of death, while the intracranial
calcification which gives the disease its name is an imaging finding whose
clinical weight is much lower. This differs from the sibling cytoplasmic-ARS
entry Neurodevelopmental_Disorder_with_Microcephaly_Seizures_and_Cortical_Atrophy
(VARS1), which is NEUROLOGIC because its presentation is essentially
confined to the CNS; here the CNS findings coexist with a dominant
pulmonary and hepatic picture.
evidence:
- reference: PMID:40044141
reference_title: "Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Respiratory symptoms, mainly consisting of pulmonary alveolar proteinosis (interstitial lung disease), are extremely common in FARSA‐, FARSB‐, and MARS1‐deficiency (86%–100%)"
explanation: The respiratory involvement, at the frequency that makes it the chapter-determining organ system.
icimd_category:
- classification_value: non_mitochondrial_trna_metabolism
notes: >-
FARSB encodes the beta subunit of the CYTOPLASMIC phenylalanyl-tRNA
synthetase, so the disorder belongs with the non-mitochondrial tRNA
metabolism disorders, alongside the other cytoplasmic ARS1 deficiencies.
The mitochondrial counterpart enzyme is FARS2 and is a different disease -
see `differential_diagnoses`.
inheritance:
- name: Autosomal Recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Biallelic FARSB variants. The individually characterised patient in the
treatment study carried two different FARSB alleles in trans, a start-loss
and a missense, which is the compound-heterozygous configuration expected of
a recessive disease outside a consanguineous kindred.
evidence:
- reference: PMID:34194004
reference_title: Treatment of ARS deficiencies with specific amino acids.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "PFARSB: compound heterozygous FARSB-variants (NM_005687.5): c.3G>T p.Met1? and c.1118G>C p.Gly373Ala (OMIM 609690)"
explanation: Documents biallelic FARSB variants in trans in an affected individual, with the transcript and both allele descriptions.
genetic:
- name: FARSB
gene_term:
preferred_term: FARSB
term:
id: hgnc:17800
label: FARSB
relationship_type: CAUSATIVE
notes: >-
FARSB encodes the beta subunit of cytoplasmic phenylalanyl-tRNA synthetase.
Biallelic damaging variants reduce, but do not abolish, aminoacylation
capacity - the characterised patient retained 28% of control FARS activity,
which is the quantitative statement of why this is a hypomorphic rather than
a null disease and why residual function can be pushed over a cliff by fever
or by phenylalanine limitation.
On the allele list below: it comes from the deep-research report accompanying
this PR and is deliberately unevidenced except for the first pair. Each of the
three remaining alleles has a real published source, named in its description
and in the entry `notes`; none of those papers could be fetched into
`references_cache/`, and an
evidence item whose snippet cannot be checked against a committed cache file
is exactly the pattern CLAUDE.md warns produces a silent CI pass. Ground these
properly when the papers are cached.
variants:
- name: c.3G>T p.Met1?
description: >-
Start-loss allele, in trans with c.1118G>C in the patient whose fibroblasts
give the 28% residual-activity and thermolability measurements cited here.
This is the one allele pair in this entry that carries a verified quote.
- name: c.1118G>C p.Gly373Ala
description: Missense allele, in trans with the start-loss above.
- name: c.853G>A p.Glu285Lys
description: >-
Homozygous founder allele reported in an extended consanguineous Omani
kindred. Recorded WITHOUT evidence: the reporting paper (PMID:30014610) is
not in this repository's reference cache, so no quote can be verified
against it. See `notes`.
- name: c.767C>T p.Thr256Met
description: >-
Missense allele reported compound heterozygous with a frameshift
(c.1486delCinsAA p.His496LysfsTer14) in the patient showing ~97% reduction
of FARSB protein and ~66% of FARSA. Recorded without evidence for the same
reason as above (PMID:29573043 is uncached).
- name: c.848+1G>A
description: >-
Splice-donor allele. Recorded without evidence for the same reason
(PMID:29979980 is uncached).
evidence:
- reference: PMID:34194004
reference_title: Treatment of ARS deficiencies with specific amino acids.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We confirmed pathogenicity of the variants with decreased aminoacylation activity in patient-derived fibroblasts to 23% and 21% IARS activity in PIARS and PIARS-2, respectively, 27% LARS activity in PLARS, 28% FARS activity in PFARSB"
explanation: Functional confirmation that the FARSB genotype produces a partial, quantified loss of phenylalanyl-tRNA synthetase activity in patient cells.
prevalence:
- population: Worldwide, published cases
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Roughly 10-20 individuals have been reported worldwide, across a small number
of kindreds and case series. Recorded WITHOUT evidence: Orphanet gives a point
prevalence of <1/1,000,000 for ORPHA:178506, but this repository's Orphanet
cache holds only 349 of the 8,823 ORPHA records and does not include this one,
and `just structured-rebuild-orphanet` needs the Orphadata bulk download, which
is not available here. No numeric rate is asserted for that
reason. Fetch ORPHA:178506 and replace this with a quoted epidemiology row.
pathophysiology:
- name: Biallelic FARSB Variants
biological_scale: MOLECULAR
description: >-
The primary lesion is biallelic damage to FARSB, encoding the beta subunit of
the cytoplasmic phenylalanyl-tRNA synthetase heterotetramer. Reported alleles
include start-loss and missense changes carried in trans.
mechanism_confidence: ESTABLISHED
genes:
- preferred_term: FARSB
term:
id: hgnc:17800
label: FARSB
downstream:
- target: Reduced Cytoplasmic Phenylalanyl-tRNA Synthetase Activity
causal_link_type: DIRECT
evidence:
- reference: PMID:34194004
reference_title: Treatment of ARS deficiencies with specific amino acids.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We confirmed pathogenicity of the variants with decreased aminoacylation activity in patient-derived fibroblasts to 23% and 21% IARS activity in PIARS and PIARS-2, respectively, 27% LARS activity in PLARS, 28% FARS activity in PFARSB"
explanation: Ties the FARSB genotype directly to measured loss of aminoacylation activity in cells from the same patient, which is the edge rather than either node alone.
evidence:
- reference: PMID:34194004
reference_title: Treatment of ARS deficiencies with specific amino acids.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "PFARSB: compound heterozygous FARSB-variants (NM_005687.5): c.3G>T p.Met1? and c.1118G>C p.Gly373Ala (OMIM 609690)"
explanation: Records the biallelic FARSB genotype that constitutes this node.
- name: Reduced Cytoplasmic Phenylalanyl-tRNA Synthetase Activity
biological_scale: MOLECULAR
description: >-
The heterotetramer retains partial activity: roughly a quarter of control
aminoacylation in patient fibroblasts. Because the enzyme catalyses the
committed step that charges phenylalanine onto tRNA-Phe, the deficit is
upstream of all cytoplasmic protein synthesis rather than of one pathway.
mechanism_confidence: ESTABLISHED
molecular_functions:
- preferred_term: phenylalanyl-tRNA synthetase activity
term:
id: GO:0004826
label: phenylalanine-tRNA ligase activity
modifier: DECREASED
biological_processes:
- preferred_term: phenylalanyl-tRNA aminoacylation
term:
id: GO:0006432
label: phenylalanyl-tRNA aminoacylation
modifier: DECREASED
downstream:
- target: Temperature-Sensitive Collapse of Residual Aminoacylation
causal_link_type: DIRECT
- target: Translation Failure Under Phenylalanine Limitation
causal_link_type: DIRECT
evidence:
- reference: PMID:34194004
reference_title: Treatment of ARS deficiencies with specific amino acids.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "patient fibroblast proliferation was normal at high concentrations, but decreased in a dose-dependent manner at lower concentrations of isoleucine for PIARS and PIARS-2, leucine for PLARS, and phenylalanine for PFARSB"
explanation: Shows the reduced-activity enzyme becomes rate-limiting specifically as its cognate amino acid falls, which is the causal step from low activity to failure of cell growth.
evidence:
- reference: PMID:39702998
reference_title: Transfer RNA and small molecule therapeutics for aminoacyl-tRNA synthetase diseases.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Patient‐derived fibroblasts with pathogenic variants in IARS, LARS, the beta‐subunit of phenylalanyl‐tRNA synthetase (FARSB), and SARS all showed reduced aminoacylation activity."
explanation: Independent restatement that FARSB variants reduce aminoacylation activity in patient cells.
- name: Temperature-Sensitive Collapse of Residual Aminoacylation
biological_scale: MOLECULAR
description: >-
The residual enzyme is thermolabile. Aminoacylation in patient fibroblasts
does not merely sit low at 37 degrees Celsius; it falls further on warming,
reaching zero at 40 degrees in the characterised FARSB patient. This is the
mechanistic account of why these children decompensate during febrile
illness, when body temperature and translational demand rise together, and it
is the same behaviour documented in LARS1 deficiency.
mechanism_confidence: ESTABLISHED
downstream:
- target: Translation Failure Under Phenylalanine Limitation
causal_link_type: DIRECT
evidence:
- reference: PMID:34194004
reference_title: Treatment of ARS deficiencies with specific amino acids.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "LARS activity of PLARS decreased to 5%, and FARS activity of PFARSB to 0%"
explanation: The thermostability measurement itself, showing residual FARS activity falling with temperature in the FARSB patient's fibroblasts.
- reference: PMID:40044141
reference_title: "Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In some patients with LARS1‐ and FARSB‐deficiency, aminoacylation deficiency in fibroblasts worsened during higher temperatures, which could be reflective of clinical deterioration during infections"
explanation: States the temperature sensitivity for FARSB specifically and links it to clinical deterioration during infection.
- name: Translation Failure Under Phenylalanine Limitation
biological_scale: CELLULAR
description: >-
With a crippled synthetase, cytoplasmic translation becomes conditional on
phenylalanine supply. Patient fibroblasts grow normally when phenylalanine is
plentiful and fail dose-dependently as it falls, whereas control cells do not
- so the cellular lesion is not a fixed translational deficit but a loss of
reserve. Tissues with the highest secretory protein throughput and the
fastest growth would therefore be expected to fail first. That last
sentence is an inference from the conditional-reserve result, not a
finding: none of the cited sources reports tissue tropism directly.
mechanism_confidence: ESTABLISHED
biological_processes:
- preferred_term: cytoplasmic translation
term:
id: GO:0002181
label: cytoplasmic translation
modifier: DECREASED
downstream:
- target: Alveolar Lipoproteinaceous Accumulation
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Impaired Somatic Growth
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Liver Disease
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
One of the parallel organ branches. No cited source traces a mechanism
from translational insufficiency to hepatocellular injury in FARSB
deficiency, and the frequency of liver disease in this genotype is itself
disputed within the source (see the Liver Disease phenotype), so the edge
is typed as having unknown intermediates and carries no evidence.
- target: Global Developmental Delay
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
A parallel organ branch with no established intermediate steps in this
disease.
- target: Microcytic Anemia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
A parallel organ branch. Anemia is well documented across this ARS1
cluster but no cited source explains how the translational lesion
produces it.
- target: Cerebral Calcification
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The weakest branch in this entry and marked as such. Nothing available to
this entry cites explains, or even directly documents, calcification
in FARSB deficiency; the edge records that the disease's defining CNS
feature hangs off the same initiating lesion, and nothing more.
evidence:
- reference: PMID:34194004
reference_title: Treatment of ARS deficiencies with specific amino acids.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "patient fibroblast proliferation was normal at high concentrations, but decreased in a dose-dependent manner at lower concentrations of isoleucine for PIARS and PIARS-2, leucine for PLARS, and phenylalanine for PFARSB"
explanation: Demonstrates the conditional, phenylalanine-dependent proliferation defect that defines this node.
- name: Alveolar Lipoproteinaceous Accumulation
biological_scale: TISSUE
description: >-
The lung lesion of FARSB deficiency is described as pulmonary alveolar
proteinosis - accumulation of lipoproteinaceous material in the alveolar
space - presenting radiologically as interstitial lung disease. It is near
universal in this branch of the ARS1 family and is the usual cause of death.
Note the entry does NOT assert a specific surfactant-handling mechanism for
the accumulation; no cached source establishes one for FARSB, and the step
from failed translational reserve to alveolar filling is recorded here as
indirect for that reason.
mechanism_confidence: PROVISIONAL
downstream:
- target: Interstitial Lung Disease
causal_link_type: DIRECT
description: >-
The alveolar filling process is what the clinical and radiological
diagnosis of interstitial lung disease reports on in this disease.
- target: Intraalveolar Phospholipid Accumulation
causal_link_type: DIRECT
description: >-
The same lesion seen histologically rather than radiologically; the
phenotype node is what a lung biopsy reports.
evidence:
- reference: PMID:40044141
reference_title: "Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Respiratory symptoms, mainly consisting of pulmonary alveolar proteinosis (interstitial lung disease), are extremely common in FARSA‐, FARSB‐, and MARS1‐deficiency (86%–100%)"
explanation: Names the lung lesion, its radiological reading, and its frequency in FARSB deficiency specifically.
- name: Impaired Somatic Growth
biological_scale: ORGANISM
description: >-
Growth restriction is one of the three features in the disease's clinical
triad and is common across the multisystem ARS1 cluster to which FARSB
belongs.
mechanism_confidence: ESTABLISHED
downstream:
- target: Growth Restriction
causal_link_type: DIRECT
- target: Failure to Thrive
causal_link_type: DIRECT
evidence:
- reference: PMID:40044141
reference_title: "Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Growth abnormalities (encompassing failure to thrive and small for gestational age among others) were common in many (AARS1‐, CARS1‐, FARSA‐, FARSB‐, IARS1‐, LARS1‐, MARS1‐, QARS1‐, VARS1‐, WARS1‐ and YARS1‐deficiency; prevalence 50%–100%)"
explanation: Gives FARSB-specific inclusion in the 50-100% growth-abnormality band of a systematic multi-gene series; the band itself spans eleven genes and is not a FARSB point estimate.
phenotypes:
- category: Respiratory
name: Interstitial Lung Disease
description: >-
Near-universal interstitial lung disease, characterised in the cited source
as pulmonary alveolar proteinosis presenting as interstitial lung disease.
It is usually what brings the child to attention and what determines
survival. The bilateral ground-glass and subpleural-cyst appearance
conventionally described for this disease is NOT asserted here; no cached
reference states it for FARSB (see entry `notes`).
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: interstitial lung disease
term:
id: HP:0006530
label: Abnormal pulmonary interstitial morphology
evidence:
- reference: PMID:40044141
reference_title: "Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Respiratory symptoms, mainly consisting of pulmonary alveolar proteinosis (interstitial lung disease), are extremely common in FARSA‐, FARSB‐, and MARS1‐deficiency (86%–100%)"
explanation: >-
Establishes interstitial lung disease in FARSB deficiency and places it in
an 86-100% band. The band is shared across FARSA, FARSB and MARS1 rather
than being a FARSB point estimate. Unlike the growth and anemia bands it
does not straddle the FREQUENT/VERY_FREQUENT boundary, so a tier can be
assigned; it does reach OBLIGATE at its 100% endpoint, and VERY_FREQUENT
is the conservative choice absent a FARSB-specific figure.
- reference: PMID:40044141
reference_title: "Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "One cluster of remarkably similar, multisystemic phenotypes comprises FARSA‐, FARSB‐, IARS1‐, LARS1‐, MARS1‐, and YARS1‐deficient patients, who present with growth abnormalities (intra‐uterine as well as later in life for IARS1‐ and LARS1‐deficiency), liver disease, hypoalbuminemia, and interstitial lung disease."
explanation: >-
Places FARSB deficiency in the multisystem ARS1 cluster whose shared
features include interstitial lung disease, which is the basis for this
entry's framing of the lung phenotype as a property of that branch of the
family rather than of FARSB alone.
- category: Respiratory
name: Intraalveolar Phospholipid Accumulation
description: >-
The histopathological substrate of the lung disease, reported as pulmonary
alveolar proteinosis.
phenotype_term:
preferred_term: pulmonary alveolar proteinosis
term:
id: HP:0006517
label: Intraalveolar phospholipid accumulation
evidence:
- reference: PMID:40044141
reference_title: "Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Respiratory symptoms, mainly consisting of pulmonary alveolar proteinosis (interstitial lung disease), are extremely common in FARSA‐, FARSB‐, and MARS1‐deficiency (86%–100%)"
explanation: Names pulmonary alveolar proteinosis as the respiratory lesion in FARSB deficiency.
- category: Neurological
name: Cerebral Calcification
description: >-
Intracranial calcification, characteristically basal ganglia, is the feature
that names the disease. IMPORTANT - see the entry `notes`: no reference
cited by this entry makes this claim about FARSB specifically.
The evidence attached below is a cross-ARS1 frequency and is graded INDIRECT
for exactly that reason. This phenotype needs re-evidencing from the FARSB
primary literature before it should be relied on.
phenotype_term:
preferred_term: intracranial calcification
term:
id: HP:0002514
label: Cerebral calcification
evidence:
- reference: PMID:40044141
reference_title: "Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "includes, for example, abnormal cerebral white matter morphology, cerebral/cerebellar atrophy/dysplasia, cerebral calcification, CNS demyelination"
explanation: >-
Establishes only that cerebral calcification is among the CNS imaging
abnormalities seen across the ARS1 deficiencies. It does not name FARSB,
so it supports this phenotype at one inferential remove and no further.
- category: Growth
name: Growth Restriction
description: >-
Poor growth and failure to thrive, typically from infancy. No `frequency` is
recorded: the only available figure is a 50-100% band spanning eleven ARS1
genes, which straddles the FREQUENT/VERY_FREQUENT boundary and is not a
FARSB point estimate.
phenotype_term:
preferred_term: growth delay
term:
id: HP:0001510
label: Growth delay
evidence:
- reference: PMID:40044141
reference_title: "Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Growth abnormalities (encompassing failure to thrive and small for gestational age among others) were common in many (AARS1‐, CARS1‐, FARSA‐, FARSB‐, IARS1‐, LARS1‐, MARS1‐, QARS1‐, VARS1‐, WARS1‐ and YARS1‐deficiency; prevalence 50%–100%)"
explanation: Gives FARSB-specific inclusion in the 50-100% growth-abnormality band.
- category: Growth
name: Failure to Thrive
description: Failure to thrive, in the treated cohort severe enough to require tube feeding.
phenotype_term:
preferred_term: failure to thrive
term:
id: HP:0001508
label: Failure to thrive
evidence:
- reference: PMID:39702998
reference_title: Transfer RNA and small molecule therapeutics for aminoacyl-tRNA synthetase diseases.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "ranged from dysmaturity, failure to thrive requiring tube feeding and oxygen supply, anemia, liver disease, global developmental delay, and interstitial lung disease."
explanation: Lists failure to thrive requiring tube feeding among the presenting features of the cohort that includes the FARSB patient.
- category: Hematological
name: Microcytic Anemia
description: >-
Anemia, mostly microcytic where characterised, is common in FARSB
deficiency. No `frequency` is recorded: the source gives a 47-82% band
shared across FARSB, LARS1 and YARS1 deficiency, which straddles the
FREQUENT/VERY_FREQUENT boundary and is not a FARSB point estimate.
phenotype_term:
preferred_term: microcytic anemia
term:
id: HP:0001935
label: Microcytic anemia
evidence:
- reference: PMID:40044141
reference_title: "Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Anemia (not always further specified, but when reported, mostly microcytic) is very common in FARSB‐, LARS1‐, and YARS1‐deficiencies (47%–82%)"
explanation: Gives both the microcytic character and the 47-82% frequency band including FARSB deficiency.
- category: Neurological
name: Global Developmental Delay
description: Developmental delay is part of the multisystem presentation.
phenotype_term:
preferred_term: global developmental delay
term:
id: HP:0001263
label: Global developmental delay
evidence:
- reference: PMID:39702998
reference_title: Transfer RNA and small molecule therapeutics for aminoacyl-tRNA synthetase diseases.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "ranged from dysmaturity, failure to thrive requiring tube feeding and oxygen supply, anemia, liver disease, global developmental delay, and interstitial lung disease."
explanation: Lists global developmental delay among the presenting features of the treated ARS1 cohort including the FARSB patient.
- category: Hepatic
name: Liver Disease
description: >-
Liver involvement, which in the characterised FARSB patient progressed to
fatal liver failure. NOTE a discrepancy inside this entry's principal
source, surfaced here rather than resolved: that paper's per-symptom
sentence lists the liver-disease-prone ARS1 genes and FARSB is NOT among
them, while the same paper's clustering analysis places FARSB in a cluster
whose shared features include liver disease. Both statements are cited
below. The FARSB patient in the treatment study did die of liver failure,
which favours the cluster reading, but the frequency in FARSB deficiency
should be treated as unsettled until the primary literature is available.
phenotype_term:
preferred_term: liver disease
term:
id: HP:0001392
label: Abnormality of the liver
evidence:
- reference: PMID:39702998
reference_title: Transfer RNA and small molecule therapeutics for aminoacyl-tRNA synthetase diseases.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "ranged from dysmaturity, failure to thrive requiring tube feeding and oxygen supply, anemia, liver disease, global developmental delay, and interstitial lung disease."
explanation: Records liver disease among the cohort's presenting features.
- reference: PMID:40044141
reference_title: "Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "One cluster of remarkably similar, multisystemic phenotypes comprises FARSA‐, FARSB‐, IARS1‐, LARS1‐, MARS1‐, and YARS1‐deficient patients, who present with growth abnormalities (intra‐uterine as well as later in life for IARS1‐ and LARS1‐deficiency), liver disease, hypoalbuminemia, and interstitial lung disease."
explanation: The clustering analysis that does place FARSB deficiency among the ARS1 deficiencies sharing liver disease.
- reference: PMID:40044141
reference_title: "Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "Liver disease is very common in patients with CARS1‐, FARSA‐, IARS1‐, LARS1‐, MARS1‐, and YARS1‐deficiency (50%–100%), and much less or not at all in other ARS1 deficiencies"
explanation: >-
The same paper's per-symptom sentence, which omits FARSB from the
liver-disease-prone genes and so places it in the "much less or not at
all" remainder. Recorded as REFUTE against liver disease being a frequent
FARSB feature; it is the other half of the discrepancy named in the
description.
differential_diagnoses:
- name: FARS2-related disease
description: >-
The distinction that matters most for anyone reading or extending this entry.
FARS2 encodes the MITOCHONDRIAL phenylalanyl-tRNA synthetase, a single-subunit
enzyme; FARSB encodes the beta subunit of the CYTOPLASMIC heterotetramer. They
are different genes, different compartments and different diseases, and FARS2
causes a combined oxidative phosphorylation deficiency / epileptic
encephalopathy phenotype rather than the lung-and-calcification picture here.
The only GeneReviews chapter in this neighbourhood is for FARS2, which is a
live trap: it is not a GeneReviews chapter for this disease.
distinguishing_features:
- Mitochondrial rather than cytoplasmic phenylalanyl-tRNA synthetase
- Epileptic encephalopathy and OXPHOS deficiency rather than interstitial lung disease
- name: Rajab interstitial lung disease with brain calcifications 2 (FARSA)
description: >-
Caused by biallelic FARSA variants, the alpha subunit of the same
heterotetramer, and clinically near-identical because it disables the same
enzyme. Distinguished by gene, not by phenotype.
distinguishing_features:
- Causal gene is FARSA rather than FARSB
- name: Aicardi-Goutieres syndrome and other interferonopathies
description: >-
The main non-ARS differential for a child with intracranial calcification and
developmental delay. Reported to be separable here by preserved myelination
and a non-progressive calcification course, but note this entry does not
assert either of those features, because no cached source states them for
FARSB. Treat this row as a pointer for the differential rather than as a
curated distinguishing finding.
distinguishing_features:
- Progressive neurodegeneration and interferon signature, reported absent in FARSB deficiency
- name: Primary familial brain calcification
description: >-
Calcification without the interstitial lung disease, liver involvement or
growth restriction that define this entity.
distinguishing_features:
- No interstitial lung disease or hepatic involvement
treatments:
- name: L-Phenylalanine Supplementation
description: >-
Supplementation with the cognate amino acid, the rationale being that the
hypomorphic synthetase is substrate-limited rather than absent, so raising
phenylalanine availability should recover aminoacylation flux. Patient
fibroblasts supply the direct rationale: they fail dose-dependently as
phenylalanine falls. The evidence in patients is early and must not be
overstated - the reported FARSB patient received 40-100 mg/kg/day and died
soon after starting, of complications of liver failure that predated
treatment. The cohort-level reports of improvement pool several ARS1
genotypes and are not FARSB-specific outcome data.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: cognate amino acid supplementation
term:
id: NCIT:C15433
label: Nutritional Support
therapeutic_agent:
- preferred_term: L-phenylalanine
term:
id: CHEBI:17295
label: L-phenylalanine
target_mechanisms:
- target: Translation Failure Under Phenylalanine Limitation
description: >-
Raising extracellular phenylalanine is intended to act on the substrate
limitation that makes translation conditional in these cells.
evidence:
- reference: PMID:34194004
reference_title: Treatment of ARS deficiencies with specific amino acids.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "patient fibroblast proliferation was normal at high concentrations, but decreased in a dose-dependent manner at lower concentrations of isoleucine for PIARS and PIARS-2, leucine for PLARS, and phenylalanine for PFARSB"
explanation: The dose-response that supplies the mechanistic rationale for targeting this node with phenylalanine.
evidence:
- reference: PMID:34194004
reference_title: Treatment of ARS deficiencies with specific amino acids.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "PFARSB and PSARS received L-phenylalanine (40–100 mg/kg/day), and L-serine (85.7–97.5 mg/kg/day), respectively"
explanation: The administered L-phenylalanine dose range in the reported FARSB patient, which is the dose this entry's description states.
- reference: PMID:39702998
reference_title: Transfer RNA and small molecule therapeutics for aminoacyl-tRNA synthetase diseases.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Patients were subsequently treated with the amino acid (l‐isoleucine, l‐leucine, l‐phenylalanine or l‐serine) cognate to the defective aaRS, and all patients improved over the course of the treatment, with noticeable improvements in growth, head circumference, development, and oxygen dependency"
explanation: >-
Reports cohort-level improvement on cognate amino acid supplementation,
L-phenylalanine being the arm relevant to FARSB. Supports the approach at
the level of the ARS1 cohort, not of FARSB outcomes specifically.
- reference: PMID:40044141
reference_title: "Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All patients tolerated the treatment well"
explanation: Supports the tolerability of cognate amino acid supplementation across the treated ARS1 cohort.
- reference: PMID:40044141
reference_title: "Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "Treatment did not alleviate the most severe phenotypes"
explanation: >-
Cuts against efficacy where it matters most for this disease, whose FARSB
presentation sits at the severe end. This is the paper's own negative
conclusion rather than an inference from a single death.
- reference: PMID:40044141
reference_title: "Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "the patient with FARSB‐deficiency, with a severe phenotype, died relatively soon after starting the treatment due to complications of pre‐treatment liver failure"
explanation: >-
The only FARSB-specific treatment outcome reported: the one treated FARSB
patient died shortly after starting. Note the paper attributes the death
to liver failure that predated treatment, so this refutes benefit in this
genotype without attributing harm to the treatment.
- name: Supportive Respiratory Care
description: >-
Oxygen supplementation and general supportive care for the interstitial lung
disease. The cohort description records oxygen dependency as a treated
endpoint.
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
target_mechanisms:
- target: Interstitial Lung Disease
description: >-
Oxygen and general supportive measures palliate the lung phenotype; they
do not act on the underlying translational lesion.
evidence:
- reference: PMID:39702998
reference_title: Transfer RNA and small molecule therapeutics for aminoacyl-tRNA synthetase diseases.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "ranged from dysmaturity, failure to thrive requiring tube feeding and oxygen supply, anemia, liver disease, global developmental delay, and interstitial lung disease."
explanation: Records oxygen supply and tube feeding as the supportive measures these patients required.
references:
- reference: PMID:40044141
title: "Setting the Stage for Treatment of Aminoacyl-tRNA Synthetase (ARS)1-Deficiencies: Phenotypic Characterization and a Review of Treatment Effects."
- reference: PMID:34194004
title: Treatment of ARS deficiencies with specific amino acids.
- reference: PMID:39702998
title: Transfer RNA and small molecule therapeutics for aminoacyl-tRNA synthetase diseases.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Create: Rajab Interstitial Lung Disease With Brain Calcifications 1 · 2026-09-06T00:47:17Z · View source
Created the FARSB entity (RILDBC1) from the stubs/ queue; the stub is deleted in the same change. Deep research: the requested provider (falcon/Edison) could NOT run - this sandbox's network egress policy returns 403 for api.futurehouse.org, so Edison authentication failed. The provider actually used was claude_code (research/Rajab_Interstitial_Lung_Disease_With_Brain_Calcifications_1-deep-research-claude_code.md), which works here because it drives server-side WebSearch rather than an external provider API: 40 web searches, 48 turns, 23 citations, 414s. No --fallback flag was used because the fallback would have hit the same egress policy for every other external provider (openscientist, asta, perplexity, openai are all blocked); claude_code was selected deliberately, not by automatic fallback, and this note is the record of that substitution. The report carries no reference_validation or term_validation frontmatter block because both of those checks also require blocked hosts (eutils, OLS). CRITICAL LIMITATION on the evidence base: NCBI E-utilities is blocked, so just fetch-reference could cache no new reference at all (verified: PMID:29979980 returns 'Tunnel connection failed: 403 Forbidden'). Every citation in the entry is therefore drawn from the pre-existing references_cache/, which holds no FARSB-specific primary paper. The three cited references are ARS1-family papers that do carry genuine FARSB-specific data - PMID:40044141 (438-patient cross-ARS1 phenotype/treatment review, full text), PMID:34194004 (the aminoacylation/thermostability/amino-acid treatment study whose FARSB patient is individually characterised, full text) and PMID:39702998 (tRNA therapeutics review covering the same treated cohort, full text). The disease-defining primary literature (PMID:29979980 Xu 2018 AJHG, PMID:30014610 Zadjali 2018, PMID:29573043 Antonellis 2018, PMID:19161147 Rajab 2009, Schuch 2021) is cited nowhere and is named in the entry notes as the fetch-first list for the next curator. The named consequence, disclosed in the entry: the brain calcification that names the disease carries only a cross-ARS1 CNS-imaging frequency graded directness INDIRECT, and cholesterol pneumonitis plus the variant spectrum are omitted entirely, because no cached source states them for FARSB. Cross-ARS1 cohort frequencies are labelled as such in the explanations rather than being presented as RILDBC1 figures. Validation actually run and passed: just validate schema step (No issues found); just count-verified-snippets 29/29 verified; check-entity-refs OK; check-causal-targets OK; check-duplicate-keys OK; check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-enum-values, check-qualifier-terms all OK. A pre-PR red-team review pass then found and fixed: a folded-scalar hyphen split on 'Aicardi-Goutieres' that had turned check-folded-hyphens red; two snippets truncated immediately before the clause their explanation relied on (the FARSB thermolability figure and the ARS1 cluster sentence), both re-quoted in full; one evidence item that made two opposite claims in a single sentence, split into a SUPPORT for tolerability and two REFUTE items including the paper's own negative conclusion; inconsistent directness grading, with the four other cross-cohort claims now marked INDIRECT like the calcification one; a calcification snippet that never mentioned calcification, replaced; and a duplicate description key introduced while wiring the graph. Also surfaced a discrepancy inside the principal source, whose per-symptom sentence omits FARSB from the liver-disease-prone genes while its own clustering analysis includes it - both sentences are now cited against the Liver Disease phenotype as SUPPORT and REFUTE and the tension is recorded rather than resolved. The pathograph is now fully connected: every phenotype has an incoming edge, with the organ branches typed INDIRECT_UNKNOWN_INTERMEDIATES and uncited, since no cited source traces those mechanisms. Validation NOT passed: the term-validation step cannot complete - OLS returns 403 through the proxy. Run offline against the committed cache, exactly two distinct CURIEs fail and both only because they are new to this repo: MONDO:0100215 (disease term) and hgnc:17800 (FARSB). Every other binding (all HP, GO, NCIT terms) validates offline. Those two are corroborated by the MONDO-derived stub record and by the deep-research report, but are NOT machine-verified and must be re-validated with network access before this entry should be trusted or merged.
MONDO:0100215 | OMIM #613658 | Orphanet ORPHA:178506 | Gene: FARSB (OMIM *609690, HGNC:17800, chr2q36.1)
Overview. Rajab interstitial lung disease with brain calcifications 1 (RILDBC1) is a rare, autosomal recessive, multisystem disorder of highly variable severity — ranging from a relatively mild neurodevelopmental phenotype to a lethal infantile multi-organ disease. It is caused by biallelic (homozygous or compound heterozygous) loss-of-function variants in FARSB, which encodes the beta subunit of cytoplasmic phenylalanyl-tRNA synthetase (FARS1/PheRS). The disease is one of two genetically distinct forms of "Rajab interstitial lung disease with brain calcifications": RILDBC1 (FARSB, OMIM #613658) and RILDBC2 (FARSA, OMIM #619013), which together with related reports form the broader "FARS1-related disorder" spectrum (Schuch et al., 2021, Clin Genet 99:789–801, DOI:10.1111/cge.13943, ResearchGate PDF).
Most affected individuals present in infancy or early childhood with intrauterine growth restriction (IUGR), poor growth/failure to thrive, and progressive, sometimes fatal, interstitial lung disease (ILD). Additional features include developmental delay, hypotonia, liver dysfunction, and — in a subset — skeletal, renal, and vascular (cerebral aneurysm) abnormalities. Neuroimaging in nearly all reported patients shows characteristic bilateral, symmetric intracranial calcifications (basal ganglia, subcortical white matter, cerebellum, cortex), often with preserved myelination and normal-to-mildly-impaired cognition despite motor delay (OMIM #613658; MedGen C3150910).
Key identifiers:
| Resource | ID |
|---|---|
| OMIM (phenotype) | #613658 — RILDBC1 |
| OMIM (gene) | 609690 — FARSB* |
| Orphanet | ORPHA:178506 — "Interstitial lung disease-brain calcification syndrome" (historically also "Brain calcification, Rajab type") |
| MONDO | MONDO:0100215 |
| MedGen | C3150910 |
| HGNC | 17800 (FARSB) |
| NCBI Gene | 10056 (FARSB) |
| Related disorder | RILDBC2, OMIM #619013 (FARSA, 602918) |
Synonyms/alternative names: RILDBC1; Rajab syndrome; brain calcification, Rajab type; FARS1-related disorder (FARSB-related); phenylalanyl-tRNA synthetase-related disease of growth restriction, brain calcification, and interstitial lung disease; recessive aminoacyl-tRNA synthetase (ARS1)-related disease.
Data provenance. Nearly all current knowledge derives from aggregated case series and family reports in the medical literature (not large EHR cohorts): the original clinical/linkage description of two consanguineous Omani kindreds (Rajab et al., 2009, Am J Med Genet A 149A:129–137, PMID:19161147, PMC2800951), the gene-identification papers (Zadjali et al. 2018; Antonellis et al. 2018; Xu/Ling et al. 2018 — see §4), subsequent case reports/series (Karimzadeh et al. 2022; others), and a systematic literature-review/phenotype paper (Schuch et al. 2021; Hoytema van Konijnenburg et al. 2025, J Inherit Metab Dis, DOI:10.1002/jimd.70017). As of 2026, media coverage of a newly diagnosed U.S. toddler (Wrenley Lantaff, diagnosed October 2025) reiterates that only "about 10" cases have been formally reported worldwide (Respiratory Therapy, 2026; 14 News, July 2026) — this figure should be treated as an approximate, informally tracked count rather than a registry-verified prevalence estimate.
Disease causal factors — genetic/mechanistic, monogenic. RILDBC1 is caused by biallelic (homozygous or compound heterozygous) pathogenic variants in FARSB, which reduce or abolish function of cytoplasmic phenylalanyl-tRNA synthetase (FARS1/PheRS), the enzyme that charges tRNA^Phe with phenylalanine during protein translation and additionally appears to have non-canonical/non-translational roles important to vascular and pulmonary tissue homeostasis (Xu et al., 2018, AJHG 103:100–114, PMID:29979980, PMC6035289). There is no known infectious, toxic, or purely environmental cause; RILDBC1 is a purely Mendelian (single-gene) disorder.
Genetic risk factors: - Causal biallelic variants in FARSB (2q36.1) — see §4 for specific alleles. - Consanguinity is a strong risk factor for homozygosity at this rare recessive locus: essentially all reported kindreds are from consanguineous unions (Omani, Iranian, and other Middle Eastern families are over-represented in the literature). - Founder variant: c.853G>A (p.Glu285Lys) segregates as a founder allele in an extended Omani kindred (8 affected individuals; Zadjali et al., 2018, Hum Mutat 39:1355–1359, PMID:30014610) — this variant is absent from gnomAD, ExAC, 1000 Genomes, and Iranome, consistent with a rare, population-restricted allele rather than a common polymorphism. - Modifier/severity factors: Genotype (null/loss-of-function vs. hypomorphic missense; homozygous vs. compound heterozygous) appears to correlate with phenotypic severity across the FARS1-related-disorder spectrum, per the pooled genotype–phenotype analysis in Schuch et al. (2021) and Hoytema van Konijnenburg et al. (2025) — patients with near-complete loss of FARSB/FARS1 activity (e.g., the compound-heterozygous T256M + frameshift patient of Antonellis et al. 2018, with 97% reduction of FARSB protein) tend toward the most severe, early-lethal end of the spectrum.
Environmental risk factors: None have been identified as causal. Given the pulmonary phenotype, it is plausible (but not established in the literature reviewed here) that intercurrent respiratory infections or environmental lung insults could exacerbate the interstitial lung disease course, analogous to other genetic pediatric ILDs — this should be treated as an inference, not a documented finding for RILDBC1 specifically.
Protective factors: None reported. No protective genetic variants, modifier alleles, or environmental/lifestyle protective factors are described in the literature identified.
Gene–environment interactions: Not established for this monogenic disorder; no GxE studies were identified.
RILDBC1 is multisystemic. Frequencies below are qualitative ("most," "some," "occasional") as reported by OMIM's clinical synopsis aggregation and the case series/reviews cited, since no large denominator cohort exists to generate precise percentages.
| Phenotype | Notes | Suggested HP term* |
|---|---|---|
| Interstitial lung disease | Core, near-universal feature; progressive, can be fatal | HP:0006530 (Interstitial pneumonitis) |
| Cholesterol pneumonitis (histologic pattern) | Intra-alveolar/interstitial cholesterol granulomas on lung biopsy — an early, characteristic histologic signature across FARS1-related disease (Schuch et al. 2021) | — (histopathologic finding; consider NCIT/SNOMED coding) |
| Recurrent respiratory infections/failure | Reported in severe cases | HP:0002205 / HP:0002205-adjacent terms |
| Pneumothorax (in a subset, per the FARSB c.848+1G>A cohort) | Xu et al. 2018 | HP:0002107 |
| Phenotype | Notes | Suggested HP term* |
|---|---|---|
| Intracranial (brain) calcifications | Bilateral, symmetric; basal ganglia, subcortical cerebrum, cerebellum, subcortical nuclei; nearly universal finding on neuroimaging | HP:0002514 (verify — "Basal ganglia calcification"-type term) or a general "Intracranial calcification" term |
| Periventricular cysts | Reported particularly in RILDBC2 (FARSA) but also in some RILDBC1 patients | — |
| Cerebral volume loss / atrophy | Reported | HP:0002087 (adjust) |
| Incomplete closure of the Sylvian fissures | Distinctive imaging feature | — |
| Preserved (normal) myelination | Distinguishes from many leukodystrophies/AGS | — |
| Developmental delay | Mild-to-moderate in Omani cohort; cognition often relatively preserved | HP:0001263 |
| Microcephaly | Reported in the original Omani kindreds | HP:0000252 |
| Hypotonia | Common | HP:0001252 |
| Motor developmental delay | Some patients | HP:0001270 |
| Cerebral/intracranial aneurysms | Reported in the Xu et al. 2018 cohort (vascular/connective-tissue component) | HP:0004944 |
| Phenotype | Notes |
|---|---|
| Liver dysfunction / cirrhosis | Reported across the spectrum; more prominent in RILDBC2 (FARSA) but also seen in FARSB patients (Xu et al. 2018) |
| Hepatosplenomegaly | Reported, e.g., diagnosed before age 2 in RILDBC2-type presentations; hepatomegaly/abdominal distension was also the presenting sign in the 2025–2026 U.S. case (progressing to liver failure) |
| Cholestasis / coagulopathy | Reported in the broader FARS1-deficiency literature (more consistently documented for FARSA) |
| Phenotype | Notes |
|---|---|
| Osteopenia | Documented in the original Omani families |
| Skeletal abnormalities (scoliosis, pectus deformity) | Reported in the Xu et al. cohort — framed as connective-tissue involvement |
| Renal abnormalities | Reported but non-specific and inconsistent across families |
| Intestinal malrotation | Reported in at least one cohort |
| Facial dysmorphism | Variable, reported in the broader FARS1 literature |
Phenotype characteristics: - Onset: Most patients present in infancy/early childhood; some features (IUGR) are prenatal. - Severity/progression: Highly variable — from a milder, largely neurodevelopmental/skeletal phenotype without early lethality (original Omani kindreds, Rajab et al. 2009) to a rapidly progressive, fatal multisystem disease in infancy (Antonellis et al. 2018 patient died at 32 months; the 2025–2026 U.S. patient developed liver failure awaiting transplant). - Neurological course: A notable feature emphasized by Rajab et al. (2009) is the absence of progressive neurological deterioration despite static brain calcifications — this distinguishes RILDBC from progressive leukoencephalopathies. - Quality-of-life impact: Not formally studied with standardized instruments (no EQ-5D/SF-36/PedsQL data identified). Qualitatively, disease burden is driven by respiratory insufficiency, growth failure, and (when present) liver failure requiring transplantation; developmental/cognitive impact is comparatively mild in most reported patients.
HP term IDs above are best-effort suggestions based on standard HPO nomenclature for these clinical concepts; exact CURIEs should be verified against the HPO browser/OAK before curation*, per this KB's ontology-term contract — some (e.g., the specific basal-ganglia-calcification and cerebral-volume-loss terms) were not independently confirmed via a live HPO lookup in this research session.
Gene: FARSB — Phenylalanyl-tRNA synthetase subunit beta (aliases: FARSLB, FRSB, PheHB, PheRS-beta). HGNC:17800; NCBI Gene ID 10056; OMIM 609690; located at chromosome 2q36.1* (GRCh38: chr2:222,566,899–222,656,092). Encodes a 589-amino-acid, ~66 kDa protein.
Function: Cytoplasmic phenylalanyl-tRNA synthetase (FARS1/PheRS) is a heterotetramer (α2β2): two catalytic alpha subunits (FARSA, OMIM 602918) and two regulatory beta subunits (FARSB). In the presence of ATP, the enzyme charges tRNA^Phe with L-phenylalanine, an essential step in cytoplasmic mRNA translation. Beyond canonical aminoacylation, evidence supports non-canonical (non-translational) functions* of FARS1 relevant to vascular and pulmonary development/homeostasis (Xu et al., 2018, PMID:29979980).
Causal variants reported to date (biallelic in all cases; autosomal recessive):
| Variant (cDNA/protein) | Zygosity | Patients | Publication |
|---|---|---|---|
| c.853G>A, p.Glu285Lys (homozygous founder allele) | Homozygous | 8 individuals, extended consanguineous Omani kindred | Zadjali et al. 2018, Hum Mutat 39:1355–1359, PMID:30014610 |
| c.767C>T, p.Thr256Met (editing-domain missense) + c.1486delCinsAA, p.His496LysfsTer14 (frameshift) | Compound heterozygous | 1 boy (died at 32 months) | Antonellis et al. 2018, Hum Mutat 39:834–840, PMID:29573043 |
| c.848+1G>A (5′ splice-junction variant, causing exon skipping/frameshift, loss-of-function) + six distinct missense variants (one shared between unrelated individuals) | Compound heterozygous / biallelic | 5 individuals, 4 families | Xu et al. 2018, AJHG 103:100–114, PMID:29979980 |
| c.1618+17G>A | — | Reported in ClinVar | ClinVar RCV002494045 |
Functional consequences: Western blot in the Antonellis et al. (2018) patient's fibroblasts showed a 97% reduction in FARSB protein and a 66% reduction in FARSA protein relative to controls, indicating that loss of the beta (regulatory) subunit destabilizes the catalytic alpha subunit and severely impairs holoenzyme (FARS1) activity — consistent with a loss-of-function mechanism. The c.848+1G>A splice variant similarly produces decreased transcript/protein levels, again consistent with loss-of-function.
Variant classification: Reported variants are classified pathogenic/likely pathogenic under ACMG/AMP criteria based on segregation with disease, absence/extreme rarity in population databases (gnomAD, ExAC, 1000 Genomes, Iranome all show zero frequency for the E285K founder allele), and functional/protein-level evidence of loss-of-function.
Allele frequency: All reported pathogenic FARSB variants are private or population-restricted (e.g., the Omani founder E285K allele) and are essentially absent from gnomAD — consistent with the disease's extreme rarity.
Somatic vs. germline: Exclusively germline (constitutional), autosomal recessive.
Modifier genes: None specifically identified for FARSB-related disease; genotype (allele severity, e.g., null vs. hypomorphic) itself functions as the principal determinant of phenotypic severity across the FARS1-related-disorder spectrum (Schuch et al. 2021; Hoytema van Konijnenburg et al. 2025).
Epigenetic information / chromosomal abnormalities: None reported specific to RILDBC1; this is a classic monogenic sequence-variant disorder, not a copy-number or epigenetic condition.
Related gene — FARSA: Biallelic FARSA variants cause the phenotypically overlapping but genetically distinct RILDBC2 (OMIM #619013), and a growing, partially overlapping literature on "FARSA deficiency" describes neonatal cholestasis progressing to multisystem disease with liver cirrhosis (Aelvoet et al. 2025, JIMD Reports), systemic inflammatory syndrome (PMC9303323), and fatal systemic disease (PMC9344665) — useful comparator literature for curating the FARSB entry's "related disorders" context.
No environmental, occupational, toxic, or lifestyle causal or contributory factors have been identified for RILDBC1 in the literature reviewed — it is a purely monogenic autosomal recessive disorder. No infectious agents are implicated (notably, the brain-calcification phenotype must be actively distinguished from congenital TORCH infections, which are a key differential diagnosis rather than a cause — see §10 differential diagnosis). No CTD/TOXNET/EPA entries or infectious-agent associations were found.
Upstream vs. downstream: The FARSB loss-of-function lesion and consequent FARS1 holoenzyme deficiency are clearly upstream/initiating; the pulmonary (cholesterol pneumonitis/ILD), hepatic (cirrhosis), neurological (calcification, developmental delay), skeletal (osteopenia), and vascular (aneurysm) manifestations are downstream, organ-specific consequences that appear to arise largely in parallel rather than in a strict linear cascade from one another — i.e., this is best modeled as one causal trigger with several parallel downstream organ-specific branches, rather than a single linear chain (the ordered list above reflects that branching explicitly at steps 4–8).
Organ level: - Primary: Lungs (interstitial lung disease, cholesterol pneumonitis), brain (calcifications), liver (dysfunction/cirrhosis). - Secondary: Skeleton (osteopenia, scoliosis, pectus deformity), kidneys (nonspecific renal abnormalities), cerebral vasculature (aneurysms), gastrointestinal tract (intestinal malrotation in some), craniofacial structures (dysmorphism in some). - Body systems: Respiratory, nervous, hepatobiliary, skeletal, renal, cardiovascular (cerebrovascular).
Suggested UBERON terms: - UBERON:0002048 (lung) - UBERON:0000955 (brain) / UBERON:0002420 (basal ganglion) - UBERON:0002107 (liver) - UBERON:0001474 (bone element) — for skeletal involvement - UBERON:0002113 (kidney) - UBERON:0002049 (vasculature) / cerebral artery structures — for aneurysms
Tissue/cell level: Alveolar epithelium and interstitium (pulmonary), hepatocytes, basal ganglia/subcortical neural tissue and its vasculature (site of calcification), osteoblast/osteoclast-mediated bone tissue (osteopenia). Specific single-cell profiling of affected tissue was not identified.
Subcellular level: No cellular-compartment-specific pathology (e.g., mitochondrial, ER) is specifically implicated beyond the cytoplasmic localization of FARS1 itself (GO Cellular Component: GO:0017101, aminoacyl-tRNA synthetase multienzyme complex, or GO:0005737 cytoplasm) — this is distinct from the mitochondrial FARS2-related disease (see §10 differential diagnosis), a common point of confusion given the similarly named gene.
Localization/lateralization: Brain calcifications are characteristically bilateral and symmetric (a distinguishing feature from many acquired/vascular calcification patterns).
Epidemiology: - Prevalence: Orphanet lists ORPHA:178506 ("Interstitial lung disease-brain calcification syndrome") prevalence as <1/1,000,000. - Approximately 10 or fewer molecularly confirmed cases have been reported in the literature/media as of 2026, spanning the original Omani kindred (8 individuals), the Antonellis et al. 2018 patient, the Xu et al. 2018 cohort (5 individuals/4 families), the Karimzadeh et al. 2022 Iranian siblings, and the 2025-diagnosed U.S. toddler — noting overlap/possible double-counting across these reports is plausible and a rigorous unique-patient census was not attempted here. - No incidence estimates, sex-ratio data, or age-distribution statistics were identified — consistent with the disease's extreme rarity and absence of large-scale registries.
Inheritance pattern: Autosomal recessive.
Penetrance: Presumed complete for the reported biallelic loss-of-function genotypes, though this has not been formally studied given the small number of cases; phenotypic expressivity is markedly variable (see §8).
Expressivity: Markedly variable — from a relatively mild neurodevelopmental/skeletal phenotype to fatal infantile multisystem disease, apparently correlating in part with the severity of the underlying variant(s) (null/loss-of-function vs. partial hypomorph) per the pooled analysis in Schuch et al. (2021) and Hoytema van Konijnenburg et al. (2025).
Genetic anticipation: Not applicable/not reported (not a repeat-expansion disorder).
Germline mosaicism: Not specifically reported for FARSB.
Founder effects: A founder allele, c.853G>A (p.Glu285Lys), segregates in an extended consanguineous Omani kindred (Zadjali et al. 2018) — the clearest documented founder effect for this gene.
Consanguinity: A major contributing factor — the majority of reported families (Omani, Iranian) are consanguineous, consistent with autosomal recessive inheritance of a very rare allele.
Carrier frequency: Not established in population databases; the causal alleles are essentially absent from gnomAD, ExAC, 1000 Genomes, and Iranome.
Population demographics: Reported cases cluster in Middle Eastern populations (Oman, Iran) with documented consanguinity, plus at least one North American (U.S.) case (2025–2026, ancestry not specified in available reporting) and cases reported from other unspecified families in the Xu et al. 2018 cohort. No robust geographic-distribution or ethnic-prevalence data exist beyond these case reports.
Clinical tests: - Chest imaging (CT): identifies interstitial lung disease pattern. - Lung biopsy/histopathology: characteristic finding is cholesterol pneumonitis — intra-alveolar and interstitial cholesterol granulomas — described as an early, distinguishing histologic feature across the FARS1-related-disorder spectrum (Schuch et al. 2021). - Brain imaging (CT/MRI): bilateral, symmetric calcifications of basal ganglia, subcortical white matter, cerebellum, and cortex; periventricular cysts (more typical of RILDBC2); preserved myelination; incomplete Sylvian fissure closure; cerebral volume loss. - Liver function tests / liver biopsy: assess for cholestasis, coagulopathy, cirrhosis. - Skeletal survey: for osteopenia, scoliosis, pectus deformity. - Functional/biochemical assay: FARS1 (PheRS) enzymatic activity or FARSA/FARSB protein levels can be assessed in patient-derived fibroblasts by Western blot, as demonstrated in Antonellis et al. (2018) — a research-grade rather than routine clinical assay.
Genetic testing: - Recommended approach: Given the extreme rarity and phenotypic overlap with other genetic ILD/brain-calcification syndromes, whole-exome sequencing (WES) is the diagnostic modality used in essentially all published cases (Zadjali et al. 2018; Antonellis et al. 2018; Xu et al. 2018), often following genome-wide linkage analysis in consanguineous families. Whole-genome sequencing (WGS) would be expected to have similar or greater utility, particularly for detecting the reported splice-region variants, but was not the primary method used historically for this gene. - Gene panels: A FARSB single-gene test or a targeted panel for genetic pediatric interstitial lung disease (chILD) / aminoacyl-tRNA synthetase-related disease panels would be expected to include FARSB and FARSA; specific commercial panel names were not catalogued in this search. - Single-gene testing: Feasible once a specific familial variant or strong phenotypic suspicion exists (e.g., in a consanguineous family from a population with a known founder allele). - Chromosomal microarray/karyotype/FISH: Not informative — this is a sequence-variant (not copy-number or structural chromosomal) disorder. - Mitochondrial DNA testing: Not relevant to FARSB (cytoplasmic enzyme) — important differential-diagnostic caveat: do not confuse with FARS2 (mitochondrial phenylalanyl-tRNA synthetase), which causes a clinically distinct, unrelated mitochondrial disease ("FARS2 deficiency," covered by its own GeneReviews chapter, NCBI Bookshelf NBK538658) with combined oxidative phosphorylation deficiency and epilepsy — a naming-based confusion risk worth flagging explicitly during curation.
Clinical criteria: No formal consensus diagnostic criteria (e.g., DSM/ICD-style) exist for this ultra-rare disorder; diagnosis rests on the combination of characteristic multisystem phenotype (ILD + brain calcification + growth failure ± liver/skeletal/renal findings) plus molecular confirmation of biallelic FARSB variants.
Differential diagnosis (as explicitly discussed by Rajab et al. 2009 and general brain-calcification-syndrome literature): - Aicardi–Goutières syndrome (AGS) — considered and explicitly distinguished by Rajab et al. (2009); AGS typically shows progressive neurological deterioration, elevated CSF interferon-alpha/CSF lymphocytosis, and leukodystrophy, which are not features of RILDBC1. - Coats plus syndrome — also explicitly considered and excluded by Rajab et al. (2009) based on divergent clinical features. - Congenital TORCH infections (CMV, toxoplasmosis, etc.) — can produce intracranial calcifications and hepatosplenomegaly; excluded by negative infectious serologies/PCR. - FARSA-related disease (RILDBC2) — clinically overlapping (ILD, liver disease, brain calcifications/periventricular cysts) but genetically distinct; distinguished by molecular testing. - FARS2 deficiency (mitochondrial PheRS) — a different, unrelated disease despite the similar gene name; distinguished by molecular testing and by its distinct clinical/biochemical (mitochondrial) profile. - Other genetic pediatric interstitial lung diseases (e.g., surfactant protein gene disorders — SFTPC, ABCA3) — distinguished by the combination of brain calcification and multisystem (hepatic/skeletal) involvement, which is atypical for isolated surfactant dysfunction disorders. - Primary familial brain calcification (PFBC) — typically adult-onset and without the pulmonary/hepatic phenotype; distinguished on clinical grounds and by molecular testing (PFBC genes: SLC20A2, PDGFB, PDGFRB, XPR1, MYORG).
Screening: No population or newborn screening program exists for this ultra-rare condition; case-finding is clinical (presentation with ILD/growth failure/brain calcification) followed by genetic confirmation. Carrier screening could theoretically be offered in populations with a known founder allele (e.g., the Omani E285K allele) for at-risk consanguineous families, though this was not explicitly documented as an established practice in the sources reviewed.
There is no disease-specific approved therapy for RILDBC1; management is supportive and organ-directed, informed by the broader FARS1-related-disorder / aminoacyl-tRNA synthetase (ARS1)-deficiency literature.
Pharmacotherapy / experimental disease-modifying approach: - Cognate amino acid supplementation (i.e., supplementation with phenylalanine, the amino acid product of the deficient enzyme's charging reaction, by analogy with strategies used in other aaRS deficiencies) has been described across the pooled FARS1-related-disorder literature: Hoytema van Konijnenburg et al. (2025, J Inherit Metab Dis, DOI:10.1002/jimd.70017) report that amino-acid supplementation was attempted in a substantial number of patients (reported in the broader FARS1-deficiency literature as having been tried in roughly two dozen patients across the FARSA/FARSB spectrum) with beneficial effects on growth, development, and liver/lung disease in the majority, but with poor response in the most severely affected patients, and with difficulty distinguishing true treatment effect from natural disease history given the absence of controlled trials. This should be treated as a general FARS1-related-disorder therapeutic strategy, not a treatment specifically validated in a controlled trial for FARSB/RILDBC1 alone. Suggested NCIT term: NCIT:C15447 (Dietary Intervention) or NCIT:C15433 (Nutritional Support), used cautiously per this KB's guidance that supplement-type interventions frequently name a specific compound rather than a behavioral/dietary pattern. - No small-molecule, enzyme-replacement, gene-therapy, or RNA-based therapy specific to FARSB/RILDBC1 was identified in the literature reviewed.
Advanced therapeutics: None reported — no gene therapy, cell therapy, or targeted molecular therapy specific to this disease has reached even early clinical description.
Surgical/interventional: - Liver transplantation — required in the most severe hepatic phenotype (the 2025–2026 U.S. index case was reported awaiting liver transplant for progressive liver failure). Suggested NCIT term: NCIT:C15289 (Organ Transplantation). - Management of cerebral aneurysms, where present, would follow standard neurovascular/neurosurgical practice (not specifically described for this disease in the literature reviewed). - Orthopedic management (e.g., for scoliosis) as clinically indicated — NCIT:C16186 (Orthopedic Surgical Procedure).
Supportive and rehabilitative care: - Nutritional support for growth failure/failure to thrive (NCIT:C15447 Dietary Intervention). - Respiratory supportive care (supplemental oxygen, management of infections, and — in end-stage disease — consideration of lung transplantation, though no specific report of lung transplantation for RILDBC1 was identified in this search) — NCIT:C15747 (Supportive Care). - Physical/occupational therapy for hypotonia and motor delay (NCIT:C15302 Physical Therapy). - Immunomodulatory therapy for interstitial lung disease is used empirically in genetic pediatric ILDs generally (corticosteroids, hydroxychloroquine), but no report specifically documenting these agents' use or efficacy in RILDBC1/FARSB-confirmed patients was identified in this search — this should be flagged as an evidence gap rather than asserted as an established RILDBC1 treatment.
Genetic counseling — recommended for families given the autosomal recessive inheritance pattern and elevated recurrence risk (25% per pregnancy for carrier couples), particularly relevant in consanguineous families and populations carrying the Omani founder allele. NCIT:C15240 (Genetic Counseling).
Treatment outcomes: No systematic response-rate or adverse-event data exist. The overarching message from the most recent pooled review (Hoytema van Konijnenburg et al. 2025) is that current therapies (chiefly amino acid supplementation and organ-directed supportive/transplant care) have not eliminated the most severe phenotypes, and international collaboration/longitudinal natural-history data are explicitly called for to refine genotype–phenotype correlation and develop better treatments.
Experimental treatments in clinical trials: No disease-specific registered clinical trial (ClinicalTrials.gov) for FARSB/RILDBC1 was identified in this search.
No naturally occurring veterinary or wildlife disease attributable to FARSB loss-of-function was identified in this search (no OMIA entries or veterinary case reports were found). FARSB orthologs exist across mammals (mouse, and others) and more distantly across vertebrates, consistent with the gene's essential, highly conserved role in cytoplasmic translation, but no spontaneous animal disease model analogous to RILDBC1 has been reported in the literature reviewed. Given that complete loss of an essential translation-machinery gene would be expected to be embryonic lethal in most vertebrate models (see §15), it is plausible that no viable naturally occurring null animal phenotype exists — this is an inference, not a documented finding.
No dedicated, published animal or cellular disease model specifically engineered to recapitulate FARSB-related RILDBC1 was identified in this search (no zebrafish, mouse conditional-knockout, or patient-iPSC-derived organoid model of FARSB loss-of-function was found in the literature reviewed).
https://www.informatics.jax.org, MGI:1346035) before being asserted as an established finding in a curated entry.WebFetch tool was unavailable (proxy connection refused) for the full duration of research, so OMIM, Orphanet, and PubMed full-text/abstract pages could not be directly fetched and parsed; all information above was synthesized from WebSearch result snippets, which sometimes provide only excerpted or aggregated text rather than verbatim primary-source quotations. Direct fetches of OMIM #613658, OMIM *609690, Orphanet ORPHA:178506, and the primary PMIDs cited (19161147, 29573043, 29979980, 30014610) are recommended as a follow-up verification step before finalizing any curated entry, to obtain exact verbatim abstract quotations for evidence snippet: fields.